Clinical trial NCT05111249
Conditions: Early Manifest Huntington Disease
Keywords: Early Manifest Huntington Disease Branaplam LMI070 Dose Range Finding Safety HD mHTT Pharmacokinetics oral Adult
Sponsor: Novartis Pharmaceuticals
Start date: 2021-12-08; Completion date: 2023-10-27
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is the first study of branaplam in adults with Huntington's Disease (HD) to determine the correct dose required to lower mutant huntingtin protein (mHTT) levels in the cerebrospinal fluid (CSF) to a degree expected to be efficacious over longer periods of time.

Detailed description:
This study was a randomized, double-blind, placebo-controlled study with a variable duration (between approximately 17 weeks to approximately 53 weeks) for the core period and a one-year open label extension (OLE) in early-stage manifest Huntington's disease (HD) participants.

After screening period and baseline assessments, the following two Treatment Periods were planned:

• The core period consisted of a 17-week double-blind, placebo-controlled, Dose Range Finding (DRF) portion of the study, followed by a blinded extension (BE) of variable duration (up to approximately 53 weeks). The DRF Period was to evaluate the safety, tolerability, pharmacokinetivs (PK) and pharmacodynamics (PD) of branaplam, as well as determine the optimal dose(s) to explore in further clinical evaluations.

The core period was planned to consist of 3 treatment arms:

* Cohort 1: Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly
* Cohort 2: Treatment Arm B: branaplam 112 mg oral solution or matching placebo, once weekly
* Cohort 3:

Treatment Arm C: branaplam 154 mg oral solution or matching placebo, once weekly or Treatment Arm X: branaplam 84 mg oral solution or matching placebo, once weekly or Treatment Arm Y: branaplam 28 mg oral solution or matching placebo, once weekly

• The OLE was a one-year open-label extension to assess both long-term safety and tolerability, as well as the efficacy of the recommended optimal dose(s) for branaplam.

Due to safety concerns an urgent safety measure (USM) follow-up notification dated 06-Dec-2022 was issued to permanently discontinue the study treatment in all participants. At that point, only cohort 1 was enrolled. Therefore, only cohort 1 data is available for analysis (Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly). Participants who received active treatment (branaplam) were to remain in the study for follow-up for approximately one year following initial treatment discontinuation. The OLE part was not opened.

Arms: arm 1: Branaplam 56 mg oral solution once weekly arm 2: Branaplam 112 mg oral solution once weekly arm 3: (C) Branaplam 154 mg oral solution once weekly, OR (X) Branaplam 84 mg oral solution once weekly OR (Y) Branaplam 28 mg oral solution once weekly arm 4: Matching placebo oral solution once weekly
Interventions: intervention 1: Branaplam intervention 2: Placebo
Intervention descriptions: intervention 1: messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly. intervention 2: Matching placebo oral solution once weekly

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
LMI070/branaplam 
Clinical Trial Protocol CLMI070C12203 / NCT05111249
A Randomized, Double-Blind, Placebo-Controlled Dose 
Range Finding Study with Open-Label Extension to 
Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of LMI070/branaplam when 
Administered as Weekly Oral Doses in Participants with 
Early Manifest Huntington’s Disease  
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-000105-92 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
IIb 
Release date: 
30-Jan-2023 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 12 
Amendment 02 (30-Jan-2023) ........................................................................................... 15 
Summary of previous amendments ................................................................................... 18 
Amendment 01 (13-May-2022) ......................................................................................... 19 
Protocol summary .............................................................................................................. 23 
1 
Introduction ....................................................................................................................... 32 
1.1 
Background ............................................................................................................ 32 
1.2 
Purpose .................................................................................................................. 33 
2 
Objectives and endpoints ................................................................................................... 34 
2.1 
Primary estimands ................................................................................................. 36 
2.2 
Secondary estimands ............................................................................................. 37 
3 
Study design ...................................................................................................................... 37 
4 
Rationale ............................................................................................................................ 40 
4.1 
Rationale for study design ..................................................................................... 40 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 41 
4.3 
Rationale for choice of control drugs (comparator/PBO) or combination 
drugs ...................................................................................................................... 43 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 43 
4.5 
Risks and benefits .................................................................................................. 44 
4.6 
Rationale for Public health Emergency mitigation procedures ............................. 51 
5 
Study Population ............................................................................................................... 51 
5.1 
Inclusion criteria .................................................................................................... 52 
5.2 
Exclusion criteria ................................................................................................... 52 
6 
Treatment ........................................................................................................................... 56 
6.1 
Study treatment ...................................................................................................... 56 
6.1.1 
Investigational and control drugs .......................................................... 56 
6.1.2 
Treatment arms/group ........................................................................... 57 
6.1.3 
Treatment duration ................................................................................ 57 
6.2 
Other treatment(s) .................................................................................................. 58 
6.2.1 
Concomitant therapy ............................................................................. 58 
6.2.2 
Prohibited medication ........................................................................... 59 
6.3 
Participant numbering, treatment assignment, randomization .............................. 63 


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6.3.1 
Participant numbering ........................................................................... 63 
6.3.2 
Treatment assignment, randomization .................................................. 63 
6.4 
Treatment blinding ................................................................................................ 64 
6.5 
Dose escalation and dose modification.................................................................. 64 
6.5.1 
Definitions of dose limiting toxicities (DLTs) ...................................... 64 
6.5.2 
Dose modifications ................................................................................ 64 
6.6 
Additional treatment guidance ............................................................................... 69 
6.6.1 
Treatment compliance ........................................................................... 69 
6.6.2 
Recommended treatment of adverse events .......................................... 69 
6.6.3 
Emergency breaking of assigned treatment code .................................. 69 
6.7 
Preparation and dispensation ................................................................................. 70 
6.7.1 
Handling of study treatment and additional treatment .......................... 71 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 71 
7 
Informed consent procedures ............................................................................................ 73 
8 
Visit schedule and assessments ......................................................................................... 75 
8.1 
Screening ............................................................................................................... 93 
8.1.1 
Information to be collected on screening failures ................................. 94 
8.2 
Participant demographics/other baseline characteristics ....................................... 94 
8.3 
Efficacy/Pharmacodynamics ................................................................................. 94 
8.3.1 
Unified Huntington's Disease Rating Scales (UHDRS) ....................... 95 
 
 95 
 
 96 
8.3.4 
Imaging ................................................................................................. 96 
8.3.5 
Biomarkers/Pharmacodynamics ............................................................ 97 
8.3.6 
Appropriateness of efficacy assessments .............................................. 97 
8.4 
Safety/Tolerability ................................................................................................. 98 
8.4.1 
Laboratory evaluations .......................................................................... 98 
8.4.2 
Cardiac assessments ............................................................................ 100 
8.4.3 
Pregnancy and assessments of fertility ............................................... 102 
8.4.4 
Neurological assessments .................................................................... 103 
8.4.5 
Other safety evaluations ...................................................................... 104 
8.4.6 
Appropriateness of safety measurements ............................................ 105 
8.5 
Additional assessments ........................................................................................ 105 
 
 105 
8.5.2 
Pharmacokinetics ................................................................................ 107 
8.5.3 
Biomarkers .......................................................................................... 108 


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9 
Study discontinuation and completion ............................................................................ 110 
9.1 
Discontinuation and completion .......................................................................... 110 
9.1.1 
Study treatment discontinuation and study discontinuation................ 110 
9.1.2 
Withdrawal of informed consent and exercise of participants’ data 
privacy rights ....................................................................................... 111 
9.1.3 
Lost to follow-up ................................................................................. 112 
9.1.4 
Early study termination by the Novartis ............................................. 112 
9.2 
Study completion and post-study treatment ........................................................ 113 
10 Safety monitoring and reporting ...................................................................................... 113 
10.1 
Definition of adverse events and reporting requirements .................................... 113 
10.1.1 
Adverse events .................................................................................... 114 
10.1.2 
Serious adverse events ........................................................................ 115 
10.1.3 
SAE reporting...................................................................................... 116 
10.1.4 
Pregnancy reporting ............................................................................ 117 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 118 
10.2 
Additional Safety Monitoring .............................................................................. 118 
10.2.1 
Liver safety monitoring ....................................................................... 118 
10.2.2 
Renal safety monitoring ...................................................................... 121 
10.2.3 
Prospective suicidality assessment ...................................................... 122 
10.2.4 
Data Monitoring Committee ............................................................... 123 
10.2.5 
Steering Committee ............................................................................. 124 
11 Data Collection and Database management .................................................................... 124 
11.1 
Data collection ..................................................................................................... 124 
11.2 
Database management and quality control .......................................................... 124 
11.3 
Site monitoring .................................................................................................... 125 
12 Data analysis and statistical methods .............................................................................. 126 
12.1 
Analysis sets ........................................................................................................ 126 
12.2 
Participant demographics and other baseline characteristics ............................... 127 
12.3 
Treatments ........................................................................................................... 127 
12.4 
Analysis of the primary endpoint(s)/estimand(s) ................................................ 127 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ................................... 128 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 128 
12.4.3 
Handling of remaining intercurrent events of primary estimand ........ 129 
12.4.4 
Handling of missing values not related to intercurrent event ............. 129 
12.4.5 
Supportive analyses ............................................................................. 130 


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12.4.6 
Sensitivity analyses for primary endpoint/estimand ........................... 130 
12.4.7 
Supplementary analysis ....................................................................... 130 
12.5 
Analysis of secondary endpoints/estimands ........................................................ 130 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 130 
12.5.2 
Safety endpoints .................................................................................. 131 
12.5.3 
Pharmacokinetics ................................................................................ 132 
12.5.4 
Biomarkers .......................................................................................... 132 
12.5.5 
PK/PD relationships ............................................................................ 133 
 
 133 
12.6 
Analysis of exploratory endpoints ....................................................................... 133 
 
 133 
12.6.2 
Other exploratory endpoints ................................................................ 134 
 
 134 
12.7 
Interim analyses ................................................................................................... 136 
12.8 
Sample size calculation........................................................................................ 136 
12.8.1 
Primary endpoint(s) ............................................................................. 136 
12.8.2 
Secondary endpoint(s) ......................................................................... 137 
13 Ethical considerations and administrative procedures .................................................... 137 
13.1 
Regulatory and ethical compliance ...................................................................... 137 
13.2 
Publication of study protocol and results............................................................. 137 
13.3 
Quality Control and Quality Assurance ............................................................... 138 
14 Protocol adherence .......................................................................................................... 138 
14.1 
Protocol amendments........................................................................................... 138 
15 References ....................................................................................................................... 139 
16 Appendices ...................................................................................................................... 142 
16.1 
Appendix 1: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................ 142 
16.2 
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up .... 145 
16.3 
Appendix 3: PK sample log - Time schedule for blood and CSF sampling for 
PK assessments .................................................................................................... 146 
16.4 
Appendix 4: Biomarker sample log - Time schedule for blood/CSF sampling 
for Biomarker assessments .................................................................................. 148 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 34 
Table 4-1 
Rationale for Study Design ................................................................... 41 
Table 4-2 
Summary of important risks .................................................................. 45 


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Table 6-1 
Investigational and control drug ............................................................ 56 
Table 6-2 
Prohibited Medications ......................................................................... 60 
Table 6-3 
Investigator Guidance for Dose interruption/discontinuation, 
follow-up and re-initiation of study treatment for select Adverse 
Events .................................................................................................... 65 
Table 6-4 
Treatment Dose and Regimen Schedule ............................................... 72 
Table 8-1 
Allowable Visit Windows ..................................................................... 75 
Table 8-2 
Assessment Schedule, Part 1 - Core (DRF and BE) ............................. 77 
Table 8-3 
Assessment Schedule, Part 2 - BE beyond 53 weeks ............................ 85 
Table 8-4 
Assessment Schedule, Part 3 - Open Label Extension .......................... 87 
Table 8-5 
Assessment Schedule Urgent Safety Measure ...................................... 91 
Table 8-6 
Assessments & Specifications............................................................... 98 
Table 8-7 
Laboratory evaluations .......................................................................... 99 
Table 8-8 
Central ECG Collection Plan .............................................................. 100 
Table 8-9 
Nerve conduction study safety parameters ......................................... 103 
 
 120 
 
 122 
Table 12-1 
Likelihood of Identifying AEs/SAEs with Hypothetical Incidence 
Rate ..................................................................................................... 137 
Table 16-1 
Liver event and laboratory trigger definitions .................................... 142 
Table 16-2 
Follow up requirements for liver events and laboratory triggers ........ 142 
Table 16-3 
Specific Renal Alert Criteria and Actions ........................................... 145 
Table 16-4 
Renal Event Follow Up ....................................................................... 146 
Table 16-5 
Plasma PK samples for Core DRF and Blinded Extension................. 146 
Table 16-6 
Time schedule for CSF sampling for PK assessments (all patients) ... 148 
Table 16-7 
Blood and CSF Biomarkers ................................................................ 148 
 
 151 
List of figures 
Figure 3-1 
Study Design Overview ........................................................................ 37 
 


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List of abbreviations 
ADME 
absorption, distribution, metabolism and excretion 
AE 
Adverse Event 
 
  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time  
ASO 
AntiSense Oligonucleotide 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUCinf 
Represents the total drug exposure across time 
AUClast 
Area under the plasma concentration-time curve from time zero to time of last measurable 
concentration 
AUCtau 
To the end of the dosing period  
AV 
atrioventricular 
BE 
Blinded extension 
BL 
Baseline 
BUN 
Blood Urea Nitrogen 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CABG 
coronary artery bypass graft 
CAG 
cytosine-adenine-guanine 
CAP 
CAG age product 
CDT 
carbohydrate deficient transferrin 
CFR 
Code of Federal Regulation 
CGA 
Cohort Gating Assessment 
 
 
CHDI 
Child Health and Development Institute 
CK 
Creatine Kinase 
CL/F  
Apparent total clearance of the drug from plasma in oral administration 
ClinRO 
Clinician Reported Outcomes 
CMAP 
compound motor action potential 
Cmax 
Maximum concentration 
CMO&PS  
Chief Medical Office and Patient Safety 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus 19 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CT 
Computerized tomography 


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Ctrough 
The drug concentration observed at the last planned timepoint prior to dosing. 
CTP 
Clinical Trial protocol 
CTT 
Clinical Trial Team 
 
 
CV 
coefficient of variation 
CYP3A4 
Human Cytochrome P450 3A4 
DBP 
Diastolic Blood Pressure 
DCL 
diagnostic confidence level 
DDI 
Drug-Drug Interaction 
DILI 
Drug Induced Liver Injury 
DIN 
Drug-induced nephrotoxicity 
DLT 
Dose limiting toxicities 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DRF 
Dose range finding 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders Fifth Text revision 
DTI 
diffusion tensor imaging 
DTRs 
Deep tendon reflexes 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
electronic Case Report Forms 
ED50 
median effective dose 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
Emax 
maximum effect 
EOS 
End of study 
EOT 
End of treatment 
EQ VAS 
EQ Visual Analog Scale 
 
  
ERCP 
Endoscopic retrograde cholangiopancreatography 
EU 
European Union 
EXT 
Extension 
 
 
FDA 
Food and Drug Administration 
fMRI 
Functional MRI 
FSH 
Follicle Stimulating Hormone 
FU 
Follow up 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GI 
gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GLS 
Global longitudinal strain 


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g/L 
grams per liter 
h 
Hour 
 
 
HBsAg 
Hepatitis B virus surface antigen 
HSVab 
Hepatitis C antibody test 
HD 
Huntington’s disease 
HDL 
High density lipoproteins 
HbA1c 
glycated hemoglobin 
hERG 
human Ether-à-go-go-Related Gene 
HIV 
human immunodeficiency virus 
HSG 
Huntington's Study Group 
HTT 
Huntingtin 
IA 
Interim analysis 
IB 
Investigator's Brochure 
IBS 
irritable bowel syndrome 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICV 
Intracerebroventricular 
iDBL 
Interim Database Lock 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IS 
Independence Scale 
IUD 
intrauterine device 
IUS 
Intrauterine system 
L 
Liter 
LDH 
lactate dehydrogenase 
LDL 
Low density lipoproteins 
LFT 
Liver function test 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LP 
Lumbar puncture 
LPLV 
Last Participant Last Visit 
LVEF 
Left ventricular ejection fraction 
MAR 
missing at random 
MATE2-k 
Multiple Comparisons Procedure - Modelling 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCP-1 
Monocyte chemoattractant protein-1 
MCS 
mental component summary 
MCV 
Mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical dictionary for regulatory activities 


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mg 
milligram(s) 
mHTT 
mutant huntingtin protein 
MI 
multiple imputation 
mL 
milliliter(s) 
MMRM 
mixed model repeated measures 
MoA 
mechanism of action 
 
 
MPV 
mean platelet volume 
MRI 
magnetic resonance imaging 
mRNA 
Messenger RNA 
MCP-Mod 
Multiple Comparison Procedures-Modelling 
NCS 
Nerve Conduction Study 
NCV 
nerve conduction velocity 
NfL 
neurofilament light chain 
ng 
nanogram(s) 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
NTproBNP 
N-terminal (NT)-pro hormone pro B-type natriuretic peptide 
OCT 
optical coherence tomography 
OLE 
open label extension 
OLS 
ordinary least squares  
OLSAF 
Open label Safety Analysis Set 
 
 
PBO 
placebo 
PCR 
protein-creatinine ratio 
PCS 
physical component summary 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PLTs 
platelet(s) 
PRO 
Patient Reported Outcomes 
PT 
prothrombin time 
PT/INR 
prothrombin time/international normalized ratio 
QC 
Quality control 
QMS 
quality management system 
QTcB 
QT interval corrected by Bazett's formula 
QTcF 
QT interval corrected by Fridericia’s formula 
RAS 
Randomized analysis set 
RBC 
red blood cell 
ROI 
Regions of interest 
RNA 
ribonucleic acid 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAF 
Safety set 
SAP 
Statistical Analysis Plan 
SARS-
CoV-2 
Severe acute respiratory syndrome–related coronavirus 2 
SBP 
Systolic Blood Pressure 


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SC 
Steering Committee 
SD 
standard deviation 
 
 
 
 
SMA 
Spinal Muscular atrophy 
SMN 
survival motor neuron 
SMQ 
Standardised MedDRA Queries 
SNAP 
sensory nerve action potential 
SOP 
standard operating procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
 
 
T1/2 
Elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBL 
total bilirubin 
TdP 
Torsades de pointes 
TEAE 
Treatment emergent adverse events 
TFC 
total functional capacity 
THC 
Tetrahydrocannabinol 
Tmax 
time takes to reach Cmax 
TMS 
Total Motor Scale 
TSH 
thyroid stimulating hormone 
UHDRS 
Unified Huntington's Disease Rating Scale 
ULN 
upper limit of normal 
US CFR 
United States Code of Federal Regulations 
USM 
Urgent Safety Measure 
UTI 
Urinary tract infection 
VES 
Visit Evaluation Schedule 
vMRI 
Volumetric MRI 
Vz/F 
Apparent volume of distribution during terminal phase after non-intravenous administration 
WHO 
World Health Organization 
WK 
Week 
WOCB 
Women of childbearing potential 
 
 
ZFP 
Zinc Finger Proteins 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study participant  
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical trial 
activities. Examples of team members include the Study Lead, Medical Monitor, Trial 
Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by replacing 
personal identifiers with a code. 
Cohort 
A specific group of participants fulfilling certain criteria 
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. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study treatment for any 
reason (prior to the planned completion of study drug administration, if any). Participant 
agrees to the other protocol required assessments including follow-up. 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 milligrams (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 source data/documents used at 
the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant  
Enrollment 
Point/time of participant entry into the study at which informed consent must be obtained 
(i.e. prior to starting any of the procedures described in the protocol) 
Estimand  
As defined in the International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) E9(R1) addendum, estimand is a 
precise description of the treatment effect reflecting the clinical question posed by the trial 
objective. It summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of each study drug package in studies that dispense study 
drug using an Interactive Response Technology (IRT) system. 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that dispense study 
treatment using an IRT system 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study or the 
participant allocated to an invalid stratification factor 
Off-site 
Describes trial activities that are performed at remote location by an off-site healthcare 
professional, such as procedures performed at the participant's home. 


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Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as include those used in the study e.g. Nurse, 
Phlebotomist, Physician, who performs certain protocol procedures for the participant in 
an off-site location such as a participant's home. 
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 participant with the condition of interest 
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-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about the status of 
a participant's health condition without amendment or interpretation of the patient's report 
by a clinician or anyone else 
Period 
A single component of a study which contains different objectives or populations within 
that single study.  
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or control/comparator 
drug using an element of chance to determine the assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant, corresponding to a specific 
treatment arm assignment 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, he/she can 
be invited once for a new Screening visit after medical judgment and as specified by the 
protocol 
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 is screened but is not treated or randomized 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-coded 
data, such as paper or eSource 
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 drug administered to the study participants as part of the required study procedures; 
includes investigational drug (s), control(s) or non-investigational medicinal product(s) 
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. 
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may consist 
of 1 or more cohorts. 
Treatment number 
A unique identifier assigned in non-randomized studies to each dosed participant, 
corresponding to a specific treatment arm 
Variable 
A measured value or assessed response that is determined in specific assessments and 
used in data analysis to evaluate the drug being tested in the study 
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. 


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Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and/or 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. This request should be distinguished from a request to discontinue 
the study. Other study participant's privacy rights are described in the corresponding 
informed consent form.  


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Amendment 02 (30-Jan-2023)  
Amendment rationale  
This amendment documents the changes regarding follow-up of participants after the 
Urgent Safety Measure (USM) Investigator Notifications (IN) distributed on 05-Aug-2022 
and 06-Dec-2022, addressing temporary and then permanent study treatment 
discontinuation, respectively.  
The USM Investigator Notification (IN) (05-Aug-2022) was issued by Novartis to 
immediately and temporarily suspend study treatment for all participants in the study. This was 
based on the recommendation from the independent Data Monitoring Committee (DMC) and 
endorsement from the VIBRANT-HD Steering Committee (SC). This decision followed a 
planned data review by the DMC on 28-Jul-2022 which assessed unblinded data from the study. 
The DMC did not recommend terminating the study at that time and requested to review follow-
up data after study treatment interruption.  
The DMC noted several findings suggestive of branaplam-induced neurotoxicity (peripheral 
neuropathy) in some participants, including:  
• Changes in the neurological exam, predominantly new hypoactive and/or absent deep 
tendon reflexes (DTRs) observed in approximately 1/3 of participants after 13 weeks on 
treatment  
• Increased serum neurofilament light chain (sNfL) levels observed in more than half of the 
participants after 9 weeks on treatment  
• Decreased amplitude in the sural nerve (SNAP) compared to baseline in the 3 participants 
with both an increase in sNfL and decreased or absent DTRs  
• Paresthesia in the lower extremities was reported by two participants. One resolved on 
treatment within 5 days and one led to early treatment discontinuation and subsequently 
resolved.  
In this communication: 
Participants that were actively taking study treatment at the time were instructed to stop the 
study treatment immediately and to return to the site for an on-site visit no later than 7 business 
days after being informed of the USM. The USM letter provided details on the assessments to 
be conducted during that visit. Subsequent to this on-site visit participants were to continue to 
adhere to their monthly visit evaluation schedule for on-site visits as per protocol (e.g., Week 
9, 13, 17, 21, 25 etc.) until further notice. During these visits, all scheduled assessments were 
to be performed as per protocol with the following exceptions:  
• Study drug should no longer be taken by participants  
• PK 
including mHTT/HTT (plasma
) 
 
should only be collected up to 6 weeks after the last dose of study drug. The 0-Hour 
timepoint (pre-dose in the protocol pre-USM) is the only required timepoint for collection. 
• No additional lumbar puncture will be scheduled thereafter unless deemed necessary by 
the investigator.  
• Follow-up Nerve Conduction Study (NCS) evaluation may be required on a case-by-case 
basis, in consultation with the DMC. 


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Participants that had already permanently discontinued study treatment and had scheduled an 
End of Treatment (EOT) and/or follow up assessments at the time of this USM were to continue 
the previously agreed upon schedule of assessments as per discussions between investigator and 
Sponsor.  
Subsequently a Follow-up IN (24-Oct-2022) was sent to sites to provide an update on activities 
related to the ongoing study following the initial communication on 05-Aug-2022. No new 
changes were implemented as the purpose was to remind of the above schedule of assessments 
exceptions.  
The USM Follow-up IN (06-Dec-2022) was issued by Novartis to inform investigators that 
Novartis has decided to discontinue development of branaplam as a potential treatment for 
people with Huntington’s disease. The decision followed a review of unblinded data from 
VIBRANT-HD indicating that the benefit:risk of branaplam in Huntington’s disease is not 
positive. This decision was endorsed by the independent Data Monitoring Committee (DMC) 
as well as the VIBRANT-HD SC.  
Key findings from this review included: 
• Increased NfL levels in serum and/or cerebrospinal fluid (CSF) observed in the majority 
of the participants in active arm. 
• Changes in the neurological exam on two consecutive visits, predominantly new 
hypoactive and/or absent DTRs, observed in more than half of participants in the active 
arm and the majority of participants with 12 weeks or more of treatment.  
• Almost half of the participants in the active arm reported symptoms of peripheral 
neuropathy, either through the neuropathy questionnaire or as an adverse event report. 
• Decreased amplitude (50%) in the sural nerve (SNAP) compared to baseline was observed 
in 7 participants in active arm. 
• Preliminary magnetic resonance imaging (MRI) findings suggestive of an increased 
volume of the lateral ventricles were seen in majority of patients in active arm.  
• Steady state mutant HTT lowering in CSF estimated to be approximately 30% with 
weekly doses of 56 mg branaplam.  
Given the high incidence of signs/symptoms of neurotoxicity at the current dose of branaplam, 
it is considered highly unlikely that lower doses or different dose regimens can be identified 
that would be safe and provide clinically meaningful benefit.  
With the USM (06-Dec-2022) letter, study drug is now permanently discontinued in the 
VIBRANT-HD study and no further cohorts will be initiated. Both the DMC and the SC 
recommended that all participants who received active treatment (branaplam) remain in the 
study for follow-up for approximately one year following initial treatment discontinuation, 
specifically to continue to assess signs and symptoms of peripheral neuropathy as well as to 
collect additional MRI data.  
Additionally, the allocation to treatment (branaplam or placebo) for each of the participants at 
the sites was provided to investigators in separate communications. 
The following actions were to be taken by sites as part of the update to the USM in the 
VIBRANT-HD study: 


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• Upon receipt of the communication, the sites were to contact participants as soon as 
possible informing them of the following and documenting the conversation in the source 
medical records: 
• Development of branaplam in HD has been terminated due to the high incidence of 
signals of neurotoxicity at the current dose of branaplam and the low likelihood that 
lower doses or different dose regimens can be identified that would be safe and 
provide clinically meaningful benefit. All topics in the Talking Points in the USM 
must be included in the discussion with the participants; these points explain the 
safety findings observed in VIBRANT-HD, the rationale for not resuming treatment, 
and the importance for participants in the active arm to continue study visits.  
• Dosing in the VIBRANT-HD study is permanently discontinued, and no further 
cohorts will be started. 
• The treatment arm to which they were randomized. Allocation to treatment may be 
shared with participants either during an upcoming visit or over the phone.  
• Participants randomized to placebo do not require additional safety assessments and 
can be discontinued from the study at their upcoming Week 33 visit or immediately if 
this visit has already been completed. The EOT and End of Study (EOS) dispositions 
can be declared.  
• Participants randomized to branaplam are requested to continue assessments for 
approximately one year from last dose (as defined below). 
• Novartis has prepared a separate letter for the trial participants that will be sent to 
them, in local language, if required as per local law and regulation. 
With respect to the follow up schedule of assessments per USM, refer to Table 8-5. 
Upon completion of the final Week 69 visit, the EOT and the End of Study dispositions (EOS) 
can be declared for each participant. 
Participants that had already permanently discontinued study treatment and had scheduled an 
EOT and/or follow up assessments at the time of the USM dated 05-Aug-2022 should continue 
the previously agreed upon schedule of assessments as per discussions between Investigator 
and Sponsor. 
These actions were to be implemented immediately, prior to Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) or Health Authority (HA) approval. Last Patient 
Last Treatment (LPLT) in the VIBRANT-HD trial occurred 08-Aug-2022.  
Changes to the protocol: 
This protocol amendment documents the final set of cumulative modifications after the USM 
(06-Dec-2022) letter. 
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 underline for insertions. 
A revised Visit Evaluation Schedule (VES) for weeks 33, 53, 69 and EOS is included in  
Section 8 Visit schedule and assessments.  


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Additionally, several clarifications have been included in other protocol sections that are 
impacted by the early program termination (e.g., Data Analysis: all changes to analyses will be 
documented in the statistical analysis plan).  
In addition, clarifications and corrections were made to the protocol summary and the protocol 
body to improve consistency and understanding.  
IRBs/IECs 
This amended protocol will be sent to the (IRBs)/ (IECs) and HAs as a substantial amendment 
following the USM.  
The changes described above as part of the USM dated 05-Aug-2022 and Follow-up 
Notification to Investigators of 06-Dec-2022 were required to enhance monitoring of participant 
safety (i.e., necessary to eliminate immediate hazards to the trial subjects International Council 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) Good Clinical Practice (GCP) 3.3.8).  
The changes described as part of the Follow-up Notification to Investigators dated 06-Dec-2022 
were based on the new unblinded data analyses to lessen participants’ burden by reducing the 
number of assessments and visits, and therefore risk to the participant, and will be implemented 
prior to IRB/IEC approval upon receipt by Investigator of the corresponding USM Notifications. 
This information was to be shared verbally with ongoing participants with the appropriate note 
made in the participant’s source medical records.  
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
This amendment is required for patient safety (i.e., necessary to eliminate immediate hazards 
to the trial subjects ICH GCP 3.3.8). Therefore, it will be implemented prior to IRB/IEC 
approval, but will be sent for approval as well. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval an addendum to the Informed Consent that takes into account the changes described 
in this protocol amendment. 
Summary of previous amendments  
To date, one global amendment has been released with the respective rationale described below: 
Amended Protocol v01 (13-May-2022). 




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7. Section 5.2 Exclusion criteria: For exclusion criteria #13, the following language was 
removed: “Any elevation above upper limit of normal (ULN) of more than one parameter 
of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (GGT), alkaline phosphatase or serum bilirubin will exclude a participant from 
participation in the study”. Given the fact that a current exclusion exists for any single 
parameters in serum of ALT, AST, GGT, and alkaline phosphatase must not exceed 2.0 x 
ULN. 
8. Section 5.2 Exclusion criteria: For exclusion criteria #13, the following language was 
removed: “any elevation above ULN of creatinine or blood urea nitrogen (BUN) and/or urea 
values”. 
9. Section 5.2 Exclusion criteria: Exclusion criteria #13 language was updated to “Evidence 
of urinary obstruction potentially leading to an impaired renal function at screening”. 
10. Section 5.2 Exclusion criteria: Exclusion criteria #14 language was updated to include: 
“Diagnosis of chronic thrombocytopenia or a bleeding disorder”.  
11. Section 5.2 Exclusion criteria: Exclusion criteria #14 language was updated to 
“Uncontrolled hypertension (average 3 systolic blood pressure [SBP] readings) at 
screening >140 mmHg or average diastolic blood pressure [DBP] > 90 mmHg excluding 
values related to white coat syndrome (anxiety)”. 
12. Section 6.2.1.2 New section added: Concomitant SARS-CoV-2 / COVID-19 vaccines. 
13. Table 6-2 Prohibited medications: Updates to clarify that initiation of medication(s) with a 
"Known Risk of Torsade de Pointes (TdP)” or medication(s) with “Potential risk of TdP” 
only applies after a patient has received study drug if required due to life-threatening 
conditions or other exceptional circumstances. Updates to include the requirements for ECG 
monitoring thereafter. In addition, clarifications made to section on medication(s) with a 
"Conditional Risk of TdP”. 
14. Section 6.2.1 Concomitant Therapy: section was updated to include the following language 
“participants should be on a stable dose and regimen of permitted chronic concomitant 
medications for at least 6 weeks prior to receiving the first dose of study drug”. Associated 
updates have been made throughout the protocol for consistency. 
15. Table 6-3 Investigator Guidance for Dose interruption/discontinuation, follow-up and re-
initiation of study treatment for select Adverse Events: Updates to this table include the 
addition of amylase and lipase as select adverse events and associated recommendations for 
study treatment dose interruption/discontinuation. 
16. Section 8 Visit Schedule and Assessments: language, such as “missed or rescheduled visits 
should not lead to automatic discontinuation” was added to this section to comply with 
language in clinical trial protocol (CTP) v5.0 template. Also added template language “if 
the Investigator delegates tasks to an off-site healthcare professional, the Investigator must 
ensure the individual(s) is/are qualified and appropriately trained to perform assigned duties. 
The Investigator must oversee their conduct and remain responsible for the evaluation of 
the data collected”. 
17. Table 8-1 Allowable Visit Windows: visit window for dose range finding (DRF) period 
updated to ±1 day. 
18. Section 8.3.4 Imaging: language updated to include: “Brain magnetic resonance imaging 
(MRI) scans will be performed at screening and at each time point without gadolinium 


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contrast” and “in the event an MRI cannot be performed after randomization, a local 
computerized tomography (CT) may be collected under exceptional circumstances for 
safety evaluations only, using the site’s local imaging protocol and standard procedures”. 
19. Table 8-7 Laboratory Assessments: table updated to include the following: “In case of 
severe amylase/lipase elevations (> 2x ULN), a reflex fractionation amylase test is 
recommended (local testing acceptable)”. 
20. Table 8-8 Central ECG collection plan: new formatted table added to improve readability 
of the protocol required timepoints and fasting status of triplicate ECGs. No new timepoints 
were added. 
21. Section 8.4.2 Cardiac Assessments: updated to include language for the method for 
calculating for LVEF <50% (biplane Simpson method); and the central reading vendor will 
only send alert notifications to sites when the LVEF and GLS thresholds defined above are 
met. 
22. Section 8.4.3 Pregnancy and assessments of fertility: language updated to include 
clarifications for permanent sterilization and post-menopausal status at screening/baseline. 
23. Section 8.4.4 Neurological assessments: The language in this section regarding 
Neurofilament light chain (NfL) has been deleted to clarify that NfL concentrations in 
serum are not considered an established marker of peripheral nerve dysfunction in the study. 
Safety evaluation of peripheral nerve function will be exam-based and includes neurological 
examinations and nerve conduction studies. Associated updates have been made throughout 
the protocol for consistency. 
24. Section 9.1.2 Withdrawal of informed consent and exercise of patient’s data privacy rights: 
updates specify WOC definitions. 
25. Table 10-1 Guidance for capturing the study treatment errors including misuse/abuse: table 
deleted as it is no longer needed since language was incorporated into section paragraph. 
26. Section 10.1 Definition of adverse events and reporting requirements: language included 
from the new CTP v5.0 template. 
27. Section 10.1.3 SAE reporting: updated the language per protocol template v5.0 specifying 
that every SAE, regardless of causality, occurring after the participant has provided 
informed consent and until 30 days following the last administration of study treatment must 
be reported to Novartis safety immediately, without undue delay, and under no 
circumstances later than within 24 hours of learning of its occurrence, including follow-up 
information. 
28. Section 10.1.5 Updates to language on reporting of study treatment errors including 
misuse/abuse. 
29. Section 10.2.1 Liver safety monitoring: specifies follow up on potential drug-induced liver 
injury (DILI) cases. 
30. Table 10-1 new table added to include Novartis guidance on specific clinical and diagnostic 
follow up assessments for potential DILI events. 
31. Section 12.1 Data analysis and statistical methods: added new analysis group OLSAF (Open 
label Safety Analysis Set). 




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Protocol summary 
Protocol number 
CLMI070C12203 
Full Title 
A randomized, double-blind, placebo-controlled dose range finding study with open-
label extension to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of Branaplam/LMI070 when administered as weekly oral doses in 
participants with early manifest Huntington’s disease (HD) 
Brief title 
A dose range finding safety study of Branaplam/LMI070 administered as weekly oral 
doses in participants with early manifest Huntington’s disease 
Sponsor and Clinical 
Phase 
Novartis/2b 
Investigation type 
Drug 
Study type 
Interventional 
Study Indication 
/Medical Condition: 
Huntington’s disease  
Purpose and 
rationale 
This is the first study of branaplam in adult HD patients. The study aims to explore a 
range of doses in order to select a safe and tolerable dose that lowers mutant huntingtin 
protein (mHTT) levels in the cerebrospinal fluid (CSF) to a degree expected to be 
efficacious over longer periods of time. As a slowing in progression of clinical 
symptoms or biomarkers of neurodegeneration require large sample size and 
treatment duration, reduction in the amount of mHTT, in line with branaplam's expected 
mechanism of action (MoA), is thought to be a relevant biomarker to measure target 
engagement and demonstrate proof of concept and guide dose selection for later 
phase confirmatory studies. 
Study participants will be randomly assigned to treatment arms in the Core Period, and 
once all randomized participants have completed the Week 17 visit, an IA will be 
performed to determine the appropriate dose(s) for the open label extension (OLE). 
The decision for the OLE dose will be based on mHTT lowering in CSF at the end of 
the dose-range finding (DRF) period, as well as safety, tolerability and other biomarker 
data collected throughout the Core Period. All patients will then enter OLE, be assigned 
to the new dose, and continue to be assessed for safety and efficacy for approximately 
an additional year. 
Clinical and biomarker measures of HD will also be evaluated in this study. This 
includes volumetric magnetic resonance imaging (MRI) of brain, CSF and blood 
biomarkers, HD rating scales and clinical assessments. 
Primary Objective(s) 
As per the Urgent Safety Measure (USM) follow-up notification dated 06-Dec-
2022, the original objectives are no longer applicable due to permanent 
discontinuation of study treatment. All efficacy and safety data collected during 
the core (double-blinded and unblinded) will be summarized descriptively based 
on cumulative data. 
Pre-USM: 
• 
To assess the dose-response relationship of branaplam administered over  
16 weeks on mHTT protein change from baseline (BL) in CSF. 
• 
To evaluate the safety and tolerability of branaplam when administered for 16 
weeks or longer in participants with HD. 
Secondary 
Objectives 
As per the USM follow-up notification dated 06-Dec-2022, the original objectives 
are no longer applicable due to permanent discontinuation of study treatment. 
All efficacy and safety data collected during the core (double-blinded and 
unblinded) will be summarized descriptively based on cumulative data. 
• 
Pre-USM:To assess the pharmacodynamics of branaplam in participants with HD 
on clinical, imaging, and biomarker endpoints relevant to HD. 
• 
To assess pharmacokinetics of branaplam and its metabolite UFB112 in plasma 
and CSF 


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Study design 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment 
has been permanently discontinued and only Cohort 1 was enrolled. Participants 
who received active treatment (branaplam) will remain in the study for follow-up 
for approximately one year following initial treatment discontinuation. OLE is no 
longer applicable. 
Pre-USM: 
This study is a randomized, double-blind, placebo-controlled study with a variable 
treatment duration (between approximately 17 weeks to approximately 53 weeks) for 
the core period and a one-year OLE in approximately 75 early-stage manifest HD 
patients. 
After Screening period and BL assessments, this study will be conducted in two 
Treatment Periods: 
• 
The Core Period consists of a 17-week double-blind, placebo-controlled, Dose 
Range Finding (DRF) portion of the study, followed by a Blinded Extension (BE) of 
variable duration (up to approximately 53 weeks; duration is dependent on timing 
of randomization and recruitment rate). The DRF Period will evaluate the safety, 
tolerability, pharmacokinetic(s) (PK) and pharmacodynamic(s) (PD) of branaplam, 
as well as determine the optimal dose(s) to explore in further clinical evaluations 
using all available data collected at the time the last randomized patient in the 
study completes the Week 17 visit assessments which captures a full 16 weeks of 
treatment with study drug. 
• 
The OLE is a one-year open-label extension to assess both long term safety and 
tolerability, as well as the efficacy of the recommended optimal dose(s) for 
branaplam. If branaplam development in HD remains ongoing at the end of the 
OLE, the study will either be (a) amended to extend the OLE beyond a year, or (b) 
a separate extension study will be initiated to offer continued access to branaplam. 
Study participants from the OLE may be eligible to roll over into this separate 
extension study. 
The study design uses a staggered cohort approach, allowing safety and tolerability of 
lower doses to be assessed before randomizing subjects to higher doses. 
The Core Period consists of 3 treatment arms; each treatment arm will enroll 
approximately 25 patients, dependent on the total number of cohorts initiated. 
Treatment arms are defined as: 
• 
Cohort 1: Treatment Arm A: Branaplam 56 mg oral solution or matching placebo 
(PBO), once weekly 
• 
Cohort 2: Treatment Arm B: Branaplam 112 mg oral solution or matching PBO, 
once weekly 
• 
Cohort 3: 
• 
Treatment Arm C: Branaplam 154 mg oral solution or matching PBO, 
once weekly or 
• 
Treatment Arm X: Branaplam 84 mg oral solution or matching PBO, 
once weekly or 
• 
Treatment Arm Y: Branaplam 28 mg oral solution or matching PBO, 
once weekly 
At the time of the Cohort Gating Assessments (CGAs), all available data will be 
reviewed from a safety and dose finding perspective by an independent Sponsor team 
to support the decision to open the next cohort. The independent Data Monitoring 
Committee (DMC) will review the data separately. The decision to open a new cohort 
will be made by the Sponsor in consultation with the DMC. 
Cohort 1 includes Treatment Arm A (56 mg or matching placebo). Based on the 
results from the review of the data during CGA 1, a decision will be made regarding 
the initiation of Cohort 2 (Treatment Arm B, 112 mg or matching placebo). Based on 
the results from the review of the data during CGA 2, a decision will be made to 
select the Treatment Arm in Cohort 3. If Cohort 3 is initiated, and based on the data 
review during CGA 2, the decision will be made to initiate the next higher dose 


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(Treatment Arm C, 154 mg or matching placebo) or an intermediary dose (Treatment 
Arm X, 84 mg or matching placebo) or a lower dose (Treatment Arm Y, 28 mg or 
matching placebo). 
Participants will be randomized in an equal randomization rate among the open 
treatment arms, and then in a 4:1 ratio for active vs. placebo within each arm. 
After a participant completes the DRF period (Week 17) he/she will seamlessly 
transition to the BE, by continuing on his/her blinded DRF treatment. All patients will 
remain in the BE until the results of the IA are available and the recommended optimal 
extension dose(s) is/are selected for OLE. Duration in the BE is therefore variable, 
longer for those that were randomized earlier in the study. 
After the last randomized participant in the study completes all the DRF (Week 17) 
assessments, an un-blinded IA will be conducted. All data available at this time, 
including, but not limited to safety/tolerability as well as mHTT and total HTT lowering 
in CSF, plasma 
 will be assessed 
to determine optimal dose(s) for OLE. After the IA and confirmation of selected dose(s), 
all patients from the blinded Core Period will roll over to OLE; patients will be re-
assigned from their blinded Core Period dosing onto the newly selected open label 
OLE dose(s). 
OLE is a one-year open label treatment and safety monitoring part of the study. 
Population 
Approximately 75 male or female patients with confirmed Stage 1 or 2 HD and a 
UHDRS total functional capacity (TFC) score of >8 will be enrolled in this study to allow 
for approximately 25 participants per treatment arm. Fewer participants will be enrolled 
if all treatment arms are not opened. 
Manifest patients with a TFC >8 are selected because they are late enough in the 
disease process so that mHTT can be measured in their CSF and clinical symptoms 
can be readily assessed, and early enough in the disease process so that they can 
comply with the protocol defined schedule of assessments during Core blinded 
treatment period (DRF and BE) and be monitored for disease progression and safety 
throughout the OLE. Eligible patients starting at the age of 25 will be enrolled to avoid 
the very high CAG repeats associated with early disease onset as these patients could 
be considered to have a more rapidly progressing phenotype. An age cap of 75 years 
is employed to avoid age-related comorbidities that typically occur above this age. 
Key Inclusion criteria 
As per the USM follow-up notification dated 06-Dec-2022, no further participants 
will be enrolled in this study.  
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Must be capable of providing informed consent (in the opinion of the Investigator). 
3. Clinically diagnosed Stage 1 or 2 Huntington's disease with a diagnostic confidence 
level (DCL) = 4 and a Unified Huntington's Disease Rating Scale (UHDRS) Total 
Functional Capacity (TFC) >8 at screening.  
4. Genetically confirmed Huntington's disease, with presence of ≥40 cytosine-adenine-
guanine (CAG) repeats in the huntingtin gene. 
For participants without prior documentation, a sample must be sent to the central 
study laboratory and confirmation of the CAG repeat length for these participants must 
be obtained prior to randomization. 
For participants with previously existing documentation of their CAG repeat length, it 
is acceptable to use this prior data to qualify for randomization. These participants must 
also submit a sample for CAG repeat testing to be conducted by the central study 
laboratory. 
5. Male and female participants between 25 to 75 years of age, inclusive, on the day 
of Informed Consent signature. 
Key Exclusion 
criteria 
As per the USM follow-up notification 06-Dec-2022, no further participants will 
be enrolled in this study.  
Participants meeting any of the following criteria are not eligible for inclusion in this 
study: 


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1. Use of other investigational drugs within 5 half-lives of the first dose of study drug, 
or within 30 days, whichever is longer. 
2. Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless 
participant received only placebo). 
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of 
similar chemical classes. 
4a. Participants taking medications prohibited by the protocol. In addition, participants 
should be on a stable dose and regimen of permitted chronic concomitant 
medications for at least 6 weeks prior to receiving the first dose of study drug which 
in the medical judgement of the Investigator is not anticipated to change during the 
study. If new medications are initiated during Screening, laboratory evaluations 
must meet eligibility criteria before first dose of study drug. 
5. Any medical history, lumbar surgery or condition that would interfere with the ability 
to complete the protocol specified assessments, (e.g., history of brain or spinal 
injury that would interfere with the lumbar puncture (LP) or CSF circulation, 
implanted cerebrospinal shunt, conditions precluding MRI scans, herniated disc, 
etc.). 
6. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in situ cervical cancer), treated or untreated, regardless of whether 
there is evidence of local recurrence or metastases. 
7. Participant has other severe, acute or chronic medical conditions including unstable 
psychiatric conditions, or laboratory abnormalities that in the opinion of the 
Investigator may increase the risk associated with study participation, or that may 
interfere with the interpretation of the study results. 
8. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the Columbia 
Suicide Severity Rating Scale (C-SSRS), if this ideation occurred in the past 6 
months from the Screening visit, or “yes” on any item of the Suicidal Behavior 
section, except for the “Non-Suicidal Self-Injurious Behavior” (item also included in 
the Suicidal Behavior section), if this behavior occurred in the past 2 years. 
9. Pregnant or nursing (lactating) women. Women of child-bearing potential (WOCB) 
should not become pregnant during the study or 7 months after stopping study 
medication. 
10a.Sexually active males unwilling to use a condom during intercourse while taking 
study treatment and for 120 days (4 months) after the last dose of the study 
treatment. A condom is required for all sexually active male participants even if they 
are surgically sterile with a vasectomy to prevent them from fathering a child AND 
to prevent delivery of study treatment via seminal fluid to their female partner. In 
addition, male participants must not donate sperm for the time period specified 
above. 
A condom is required to be used also by vasectomized men as well during intercourse 
with a male partner of the study participant. 
The branaplam exposure in body fluids is not known. Since branaplam is genotoxic, 
sexual partners are advised to avoid direct contact with semen of participants, to 
prevent exposure to the study drug. 
11a. Women of child-bearing potential, defined as all heterosexually active women 
physiologically capable of becoming pregnant, unless they are using one highly 
effective method of contraception during dosing and for 7 months after stopping the 
study medication. Highly effective methods of birth control are those methods that 
have a less than 1% chance of an unwanted pregnancy for 1 year.  
In addition to one highly effective method of contraception, a condom is required 
for all male partners of female participants to prevent fathering a child AND to 
prevent exposure of study treatment via vaginal fluid to the partner, until at least 
7 months following the last dose of study treatment. 
WOCB potential must not donate their eggs for 7 months after the last dose of study 
treatment. 


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Oral contraception cannot be considered due to potential decreased efficacy as 
potential drug-drug interactions (DDI) with branaplam. 
Highly effective contraception methods include:  
• 
Total abstinence (when this is consistent with the preferred and usual lifestyle of 
the participant). [Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are NOT acceptable methods of 
contraception for heterosexually active participants.] 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks 
before taking investigational drug. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone 
level assessment. 
• 
Male sterilization of partners (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the sole partner. 
• 
Use of an intrauterine device (IUD) or intrauterine system (IUS) which is MRI 
compatible. 
In case local regulations are more stringent than the contraception methods listed 
above, local regulations apply and will be described in the ICF. Women are considered 
post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g., age appropriate, history of vasomotor 
symptoms). Women are considered not of child-bearing potential if they are post-
menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to 
Screening. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential. 
The branaplam exposure in body fluids is not known. Since branaplam is genotoxic, 
sexual partners are advised to avoid direct contact with vaginal fluid of participants, to 
prevent exposure to the study drug. 
12a. History of: 
• Gene therapy or cell transplantation or any other experimental brain surgery 
• Hepatitis B or hepatitis C or serologic evidence for active viral hepatitis (HBsAg and 
HCVab test) 
• Immunodeficiency diseases, including a positive human immunodeficiency virus 
(HIV) test result 
• Current evidence of drug or alcohol abuse in the 12 months prior to screening, as 
defined by the Diagnostic and Statistical Manual of Mental Disorders Fifth Text 
revision (DSM-V) criteria for substance abuse. For former abusers, abstinence 
should be confirmed by laboratory tests (drug testing and/or carbohydrate deficient 
transferrin (CDT) level in blood). 
• Use of Tetra-Hydro-Cannabinoid (THC)/ cannabinoid containing substances is 
allowed as per local regulations and/or local medical practice if in the opinion of the 
Investigator, use does not represent an exclusionary condition, does not constitute 
abuse and does not affect cognition, and provided that participants are currently 
treated with a stable regimen for at least 12 weeks prior to first dose of study drug. 
Note: If initiated during the study, use must be withheld for 72 hours prior to any 
cognitive and/or motor assessments. 
13a. Any surgical or medical condition which might put the participant at risk in case of 
participation in the study. The Investigator should make this determination in 
consideration of the participant’s medical history and/or clinical or laboratory 
evidence of any of the following at the Screening visit:  
• 
Unstable chronic gastrointestinal condition such as history of Crohn’s disease, 
Ulcerative colitis, poorly controlled Irritable Bowel Syndrome (IBS) or similar 
chronic gastrointestinal (GI) conditions  
• 
Neurologic or neuromuscular conditions other than HD 


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• 
History of or physical examination consistent with peripheral neuropathy or nerve 
conduction findings compatible with electrodiagnostic evidence of neuropathy 
• 
Participants who have a known diagnosis of diabetes mellitus or who do not have 
a known diagnosis of diabetes with a glycated hemoglobin (HbA1c) >6.5% 
• 
Lipase, total bilirubin or amylase must not exceed the 1.5x ULN 
• 
Liver disease or liver injury as indicated by abnormal liver function tests 
• 
Any of the following single parameters in serum of alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and 
alkaline phosphatase must not exceed 2.0 x ULN. 
• 
History of renal injury / renal disease or presence of severe impaired renal function 
as indicated by an estimated glomerular filtration rate (eGFR) using the 
modification of diet in renal disease (MDRD) equation <30 (mL/min/1.73 m²) 
(allowing for age-related GFR decline in the mild to moderate range) or the 
presence >3+ proteinuria/ hematuria on a single (one time) repeated urinalysis 
• 
Evidence of urinary obstruction potentially leading to an impaired renal function at 
screening  
• 
Diagnosis of testicular atrophy  
• 
Diagnosis of primary ovarian failure 
• 
Clinically significant retinal abnormalities on ophthalmologic examination by a local 
Ophthalmologist 
• 
Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed at least 3 days prior to first study drug administration (Day 1) 
• 
Any objects and/or implants in the body which may be contraindicated for MRI, 
such as pacemakers and some IUD 
• 
Diagnosis of chronic thrombocytopenia or a bleeding disorder  
14a. Cardiovascular exclusion criteria: 
• 
History or current diagnosis of electrocardiogram (ECG) abnormalities indicating 
significant risk or safety concern for study participants such as: History of 
myocardial infarction, angina pectoris, heart failure, or coronary artery bypass graft 
(CABG). Screening echocardiogram (ECHO) abnormalities per investigator’s 
medical judgement including but not limited to left ventricular ejection fraction 
(LVEF) <50%. 
• 
Screening or baseline not within normal range Troponin or N-terminal (NT)-pro 
hormone pro B-type natriuretic peptide (NTproBNP) values 
• 
History or concomitant clinically significant cardiac arrhythmias (e.g., sustained 
ventricular tachycardia, atrial fibrillation, etc.), complete left bundle branch block, 
high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and 
third-degree AV block). 
• 
History of familial long QT syndrome or known family history of Torsade de Pointes, 
risks for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of clinically significant/symptomatic bradycardia and a 
family history of idiopathic sudden death. 
• 
Resting QT interval corrected by Fridericia’s formula ( QTcF) ≥450 msec (male) or 
≥460 msec (female) at pretreatment [screening or baseline] (as mean of triplicate 
ECGs), or inability to determine the QTcF interval. 
• 
Use of agents known to prolong the QT interval or with a known or possible risk of 
Torsade de Pointes unless it can be permanently discontinued or replaced with a 
permitted medication for the duration of study. (See Table 6-2) 
• 
Uncontrolled hypertension (average 3 systolic blood pressure [SBP] readings) at 
screening >140 mmHg or average diastolic blood pressure [DBP] > 90 mmHg 
excluding values related to white coat syndrome (anxiety-related), per 
Investigator’s judgement.  


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15a. Any clinically significant hematological abnormality as assessed by the Site 
Investigator at screening and/or laboratory evidence of any of the following: 
• 
International Normalized Ratio (INR), PT, or APTT that are not within normal 
ranges 
• 
Hemoglobin <110 grams per liter (g/L) (females) or <120 g/L (males) 
• 
Platelets ≤100 x 109/ Liter (L) 
• 
Platelet count >500 x 109/L 
• 
Neutrophil count <1.5 x 109/L 
• 
Leukocytes <3.0 x 109/L 
Study treatment 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment 
has been permanently discontinued; the last dose administered was 08-Aug-22; 
and no further enrollment is allowed.  
The investigational treatment for this study is branaplam and matching placebo. 
Novartis will supply branaplam and matching placebo in 6 mL vials containing 5 mL of 
study treatment. The vials will be packed in boxes containing 4 vials each. All eligible 
participants will be randomized via Interactive Response Technology (IRT) to one of 
the available treatment arms. 
At the Week 1 visit, participants will be randomized to one of the following treatment 
arms in a ratio of 4:1, active vs. PBO: 
• 
Treatment Arm A: 56 mg oral solution or matching PBO, weekly 
• 
Treatment Arm B: 112 mg oral solution or matching PBO, weekly 
• 
Treatment Arm C: 154 mg oral solution or matching PBO, weekly 
• 
Treatment Arm X: 84 mg oral solution or matching PBO, weekly 
• 
Treatment Arm Y: 28 mg oral solution or matching PBO, weekly 
Treatment Arm assignment for an individual participant will be determined by which 
treatment arms are open at the time of the participant screening. For Treatment Arms 
C, X and Y, only one of the three will be initiated. PBO is embedded within each 
Treatment Arm. 
Efficacy 
assessments 
Efficacy assessments include the following: 
• 
Unified Huntington's Disease Rating Scales (UHDRS) components: 
• 
Total Functional Capacity (TFC) 
• 
Total Motor Scale (TMS) 
• 
Independence Scale (IS) 
 
 
 
 
 
 
 
 
Pharmacodynamic 
assessments  
• 
Volumetric MRI 
• 
Mutant Huntingtin Protein (mHTT) and total Huntingtin protein (HTT) in CSF, 
plasma 
Pharmacokinetic 
assessments  
PK samples from plasma and CSF will be obtained from all participants at all dose 
levels. Branaplam and its metabolite UFB112 will be determined in plasma and CSF 
by a validated LC-MS/MS method 
Key safety 
assessments 
Safety assessments include the following: 
Pre-USM: 
• 
Physical Examination 
• 
Vital signs 
• 
Height and weight 
• 
Electrocardiograms (ECGs) 




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25% missed doses (i.e., 4 doses for weekly dosing during DRF period) AND less 
than 2 consecutive weeks off treatment prior to the Week 17 visit LP. 
The summary measure: reduction (%) of mHTT protein in CSF from BL to Week 17 
visit for various doses (dose-response relationship). The justification is, that the primary 
estimand targets the treatment effect of branaplam for those who can tolerate it for  
16 weeks (with limited interruption/discontinuation) in order to inform the selection of 
an optimal dose. 
The primary estimand will only focus on the efficacy of branaplam on the reduction of 
mHTT in CSF (one of the primary objectives). The safety perspective will be evaluated 
in parallel. Dose selection for Open Label Extension and subsequent Phase 3 studies 
will be based on a combination of efficacy and safety results. However, estimands are 
not defined for the safety objective, safety analyses will be specified. No inferential and 
model based statistical analyses are planned for any safety or tolerability endpoints. 
Post USM: Refer to Section 12 Data Analysis and Statistical Methods 
Data 
Monitoring/Other 
Committee 
Yes 
Key words 
Huntington’s disease, branaplam, dose range finding, early manifest, LMI070, safety 
and tolerability 


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1 
Introduction 
1.1 
Background 
Huntington's disease (HD) is a fatal, neurodegenerative disorder for which no disease modifying 
therapies exist. The disease is characterized by a progressive worsening in motor and cognitive 
function and psychiatric symptoms (Walker 2007, Ross et al 2014). The current standard of 
care is limited to therapies for management of symptoms, which have no effect on the course 
of disease. The medical need for therapies that either slow progression or delay the onset of HD 
remains unmet (Caron et al 2018). 
HD is one of several inherited neurodegenerative diseases caused by trinucleotide repeat 
expansions in a gene (i.e., a "triplet repeat" disease) (MacDonald et al 1993). Inheritance of HD 
is autosomal dominant. The causative expansion in the coding region of the huntingtin gene is 
a series of cytosine-adenine-guanine (CAG) repeats that lead to incorporation of an abnormally 
long string of glutamine residues in the final protein (mutant huntingtin, (mHTT)), resulting in 
misfolding 
and 
toxic 
aggregation/accumulation 
(Shao and Diamond 2007,  
Ross and Tabrizi 2011). HD occurs when there are at least 40 CAG repeats in the HTT gene, 
but also occurs with a reduced penetrance in those with 36-39 repeats (McNeil et al 1997). 
Adult-onset HD is a slowly progressive neurodegenerative disease. The underlying pathogenic 
process begins at least 10-15 years before overt motor symptoms appear (Ross et al 2014). 
Clinical diagnosis is based on unequivocal, extrapyramidal motor symptoms and genetic or 
family history confirmation (Ross et al 2019). Once symptoms manifest, patients live another 
15-20 years. The age of onset of symptoms is inversely proportional to the length of the CAG 
repeat and is typically between 35 and 50 (Wexler et al 2004). Clinical decline is measured 
using the Unified Huntington’s Disease Rating Scale Total Functional Capacity Scale 
(UHDRS-TFC). Using this scale, which ranges from 0-13, patients progress from stage 1 (mild) 
through stage 5 (advanced). Prior to symptom onset, people with HD go through  
pre-symptomatic and prodromal stages. In the latter, subtle behavioral and cognitive symptoms 
develop, along with clear signs of brain atrophy (Tabrizi et al 2013). By the time of clinical 
diagnosis, about half of the striatum in the brain has atrophied, along with significant 
neurodegeneration in other parts. 
It is well established that mutant huntingtin protein (mHTT) is the proximal cause of disease 
onset and progression (Walker 2007, Ross and Tabrizi 2011). The goal of HTT-lowering 
therapies is to slow the decline in disease progression by reducing the levels of the toxic protein 
in the brain (Tabrizi et al 2019a). Complete knockout of HTT is lethal during embryogenesis, 
but people with only a single copy of the gene develop normally, and animal studies provide 
evidence that reducing the levels of mutant protein in the brain before or after symptom onset 
can delay or reduce the phenotypic expression of the disease (Kaemmerer and Grondin 2019). 
There is abundant pre-clinical evidence to support the idea that lowering HTT transcript and 
protein should lead to slowing of progression of HD (Kordasiewicz et al 2012, Stanek et al 2013, 
Southwell et al 2018, Zeitler et al 2019). Further, using multiple modalities (small molecules, 
ASOs, microRNAs, Zinc Finger Proteins (ZFPs)), it has been demonstrated that lowering the 
expression of total or mHTT in the brain is associated with a corresponding lowering of protein 
in the CSF. Lastly, lowering of total HTT following repeated intrathecal (IT) injections of an 


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ASO has been shown to be safe and tolerable at doses that lower HTT in the CSF by 40-50% 
(Tabrizi et al 2019b). 
Branaplam (LMI070) is a low molecular weight messenger ribonucleic acid (RNA) splicing 
modifier with clinically demonstrated efficacy in the treatment of infants with Type 1 spinal 
muscular atrophy (SMA). The efficacy in Type 1 SMA is due to promotion of inclusion of exon 
7 during transcription from Survival Motor Neuron 2 (SMN2). This leads to greater production 
of functional SMN protein from SMN2 and ameliorates the SMN protein deficiency that causes 
SMA. As of 15-Jan-2021, 38 patients with Type 1 SMA have been treated with weekly doses 
of branaplam up to 60 mg/m2 (3.125 mg/kg), several for more than 4 years (age at treatment 
start: 2-7 months). 
The increase in SMN protein is expected to result in improved motor neuron survival with 
consequent achievement of motor milestones, improved respiratory function and longer 
survival with less ventilation support and feeding tube dependence in SMA patients. 
Branaplam also promotes inclusion of a pseudoexon during transcription from the huntingtin 
gene (HTT). Because this pseudoexon contains a premature stop codon, this triggers 
degradation of the HTT messenger RNA (mRNA) before translation, resulting in a decrease in 
the production of full-length HTT protein. Nonclinical investigations of branaplam in BacHD 
transgenic mice expressing a neuropathogenic, full-length human mutant Huntingtin (fl-mHTT) 
gene revealed dose-dependent lowering of mHTT mRNA and mHTT protein concentrations in 
the brain, liver, and blood. Broad lowering of mHTT throughout the brain and periphery, 
including the cortex and striatum, suggests that oral dosing of branaplam may be an attractive 
approach for long-term HTT-lowering in patients with HD, and warrants further investigation 
of the potential therapeutic utility of branaplam in the treatment of HD. 
This Phase 2b dose range finding and proof of concept study will be conducted in early stage 
HD patients. HD is a slowly progressive neurodegenerative disease and generating dose-finding 
data based on slowing progression of clinical symptoms or biomarkers of neurodegeneration 
would require large sample sizes and long treatment durations. An alternative strategy utilizes 
a biomarker approach that is achievable with fewer patients and in a shorter time. Branaplam's 
expected efficacy is based on its ability to reduce the amount of mHTT protein produced in the 
brain. Based on animal studies, a reduction of mHTT and normal HTT protein in the brain of 
40-50% should be sufficient to slow disease progression without negative consequences from 
loss of normal HTT protein. The mHTT protein level in the CSF thus represents the best 
biomarker to measure target engagement, demonstrate proof of concept and select dose 
regimen(s) for further evaluation Phase 3 trials. 
1.2 
Purpose 
The purposes of this study are two-fold, reflecting the two treatment periods integrated in the 
study design: 
• The Core consists of a 17-week double-blind, placebo-controlled dose range finding (DRF) 
study followed by a Blinded Extension (BE) of variable duration (up to approximately  
12 months (dependent on recruitment rate)) to evaluate the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of various branaplam doses 
administered once weekly. The doses will be assessed to support the dose selection for the 


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OLE and any other future study. The DRF period will be analyzed using all available data 
collected at the time the last randomized patient in the study completes Week 17 visit 
assessments which, captures a full 16 weeks of treatment with study drug. Both reduction 
(%) of mHTT protein (change from Baseline (BL) after16 weeks of treatment) and 
safety/tolerability will be the primary endpoints. 
• The OLE is a one-year extension for participants on the selected dose(s) with the purpose 
to assess the long-term safety and efficacy of branaplam. 
2 
Objectives and endpoints 
As per the USM follow-up notification dated 06-Dec-2022, the original objectives are no 
longer applicable due to permanent discontinuation of study treatment. No statistical 
modelling will be done. All efficacy and safety data collected during the core (double-
blinded and unblinded) will be summarized descriptively based on cumulative data. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the dose-response relationship of 
branaplam administered over 16 weeks on 
mHTT protein change from baseline in CSF  
• 
Period: From baseline to Week 17 over the Dose 
Range Finding (DRF) 
• Reduction (%) of mHTT protein in CSF from 
baseline to Week 17. See Section 2.1 for 
Primary Estimand 
• 
To evaluate the safety and tolerability 
of branaplam when administered for 16 weeks 
or longer in participants with HD. 
• 
Safety and tolerability parameters/assessments 
including but not limited to adverse events, 
physical exam (including neurological 
examination), findings, clinical laboratory 
assessments, HTT lowering, etc. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the pharmacodynamics of branaplam 
in participants with HD on clinical, imaging, and 
biomarker endpoints relevant to HD. 
• 
The following endpoints will be assessed over 
three periods: 
1. DRF: change from baseline to Week 17 
compared to placebo 
2. Core: change from baseline to the end of Core 
compared to placebo 
3. Core + OLE: change from baseline and 
baseline-extension to week 53-extension 
• Ventricular, Caudate and Total Brain Volume 
as measured by structural magnetic 
resonance imaging (MRI) 
• Unified Huntington's Disease Rating Scale 
(UHDRS) Total Functional Capacity (TFC), 
UHDRS Total Motor Score (TMS), UHDRS 
Independence Scale (IS).  
• Concentrations of total HTT and mHTT protein 
in CSF and plasma 
• 
To assess pharmacokinetics of branaplam and 
its metabolite UFB112 in plasma and CSF 
• 
PK parameters (e.g. area under the curve 
(AUC)last, AUCtau, maximum concentration 
(Cmax), Tmax) of branaplam and its metabolite 








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using all available data collected at the time the last randomized patient in the study 
completes the Week 17 visit assessments which captures a full 16 weeks of treatment with 
study drug. 
• The OLE is a one-year open-label extension to assess both long term safety and tolerability, 
as well as the efficacy of the recommended optimal dose(s) for branaplam. If branaplam 
development in HD remains ongoing at the end of the OLE, the study will either be (a) 
amended to extend the OLE beyond a year, or (b) a separate extension study will be initiated 
to offer continued access to branaplam. Study participants from the OLE may be eligible to 
rollover into this separate extension study. 
The study design uses a staggered cohort approach, allowing safety and tolerability of lower 
doses to be assessed before randomizing subjects to higher doses. The Core Period consists of 
3 treatment arms; each treatment arm will enroll approximately 25 patients. Treatment arms are 
defined as: 
• Cohort 1: Treatment Arm A: Branaplam 56 mg oral solution or matching PBO, once 
weekly 
• Cohort 2: Treatment Arm B: Branaplam 112 mg oral solution or matching PBO, once 
weekly 
• Cohort 3: 
• Treatment Arm C: Branaplam 154 mg oral solution or matching PBO, once weekly or 
• Treatment Arm X: Branaplam 84 mg oral solution or matching PBO, once weekly or 
• Treatment Arm Y: Branaplam 28 mg oral solution or matching PBO, once weekly 
Randomization into treatment arms will be staggered into 3 Cohorts: 
1. Cohort 1 includes Treatment Arm A (56 mg or matching placebo) as noted in Figure 3-1. 
After the 10th participant in Arm A reaches Week 9 of the DRF Treatment Period, all 
available data, including relevant post-dose PK time points, will be reviewed from a safety 
and dose finding perspective by an independent Sponsor team to support the decision to 
open the next cohort. The independent Data Monitoring Committee (DMC) will review the 
data separately. The decision to open Cohort 2 at the Cohort Gating Assessment 1 (CGA 1) 
will be made by the Sponsor in consultation with the DMC. (Also, included in the review 
will be PK data, 
, from a safety and not efficacy 
perspective, to ensure that HTT lowering is not beyond the anticipated safety threshold.) 
During this time, recruitment will continue in Cohort 1. Based on the results from the review 
of the data during CGA 1, a decision will be made regarding the initiation of Cohort 2 
(Treatment Arm B, 112 mg or matching placebo). At this time, participants will be eligible 
to randomize into any open Treatment Arm if it has not yet been completed. Alternatively, 
if Cohort 1 recruitment is complete prior to the initiation of Cohort 2, participants will then 
only be eligible for randomization into Cohort 2. 
2. Cohort 2: If Cohort 2 is initiated, after approximately the 10th participant in Treatment Arm 
B has reached Week 9 of the DRF Treatment Period, all available data, including relevant 
post dose PK time points, will again be reviewed at CGA 2 by the independent Sponsor 
team and the DMC. Based on the results from the review of the data during CGA 2, a 
decision will be made to select the Treatment Arm in Cohort 3.  


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3. Cohort 3: If Cohort 3 is initiated, and based on the data review during CGA 2, the decision 
will be made to initiate the next higher dose (Treatment Arm C, 154 mg or matching placebo) 
or an intermediary dose (Treatment Arm X, 84 mg or matching placebo) or a lower dose 
(Treatment Arm Y, 28 mg or matching placebo). At this time, participants will be eligible 
to randomize into any open Treatment Arm if it has not yet been completed. Alternatively, 
if Cohort 1 and 2 recruitment is complete prior to the initiation of Cohort 3, participants will 
then only be eligible for randomization into Cohort 3. The interim analysis (IA) will then 
take place after the last randomized participant completes the DRF period (Week 17 visit). 
Participants will be randomized in an equal randomization rate among the open treatment arms, 
and then in a 4:1 ratio for active vs. placebo within each arm. Refer to Section 4.4. 
After a participant completes the DRF period (Week 17) he/she will seamlessly transition to the 
BE, by continuing on his/her blinded DRF treatment. All patients will remain in the BE until 
the results of the IA are available and the recommended optimal extension dose(s) is/are 
selected for OLE. Duration in the BE is therefore variable, longer for those that were 
randomized earlier in the study. 
After the last randomized participant in the study completes all the DRF (Week 17) assessments, 
an un-blinded IA will be conducted. All data available at this time, including, but not limited to 
safety/tolerability as well as PK, mHTT and total HTT lowering in CSF, plasma 
 
will be assessed to determine optimal dose(s) for OLE. After the IA and confirmation of selected 
dose(s), all patients from the blinded Core Period will roll over to OLE; patients will be re-
assigned from their blinded Core Period dosing onto the newly selected open label OLE dose(s). 
OLE is a one-year open label treatment and safety monitoring part of the study. 
The DMC may recommend to terminate treatment of any dose at any time. All participants will 
be followed for safety until 30 days after the last dose of study treatment.  
Core Period: Dose Range Finding & Blinded Extension. 
Following a 6-week Screening period, patients will complete a baseline assessment (can be 
performed over a 6 day time frame) and a multi-dose, treatment period (with duration varying 
across patients) at the assigned treatment arm. Safety, tolerability, PD biomarker (fluid and 
images), PK and clinical endpoints relevant to HD will be collected as outlined in the 
assessment schedule. 
The Screening period may be extended beyond 6 weeks in some cases. See Section 8.1. 
After confirming eligibility, participants will be randomized to an open cohort to receive either 
active or PBO treatment as an oral solution administered once weekly. Although a maximum 
of 3 treatment arms are planned, timing during the ongoing recruitment will determine which 
available treatment arms are actively recruiting (refer to Figure 3-1). In addition, not all 
treatment arms may be initiated, as it is dependent on the available safety profile, PK and mHTT 
lowering data. Participants will receive at least 16 weeks of treatment and will remain on the 
initially assigned treatment arm during the Core Period in the BE until IA is completed and 
optimal dose(s) selected for OLE. After dose selection, which may be more than one selected 
dose, patients will continue participation in OLE. 


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Post-USM: As per the USM follow-up notification dated 06-Dec-2022, the study treatment 
has been permanently discontinued and only Cohort 1 was enrolled. Participants who 
received active treatment (branaplam) will remain in the study for follow-up for 
approximately one year following initial treatment discontinuation. 
Open-Label Extension (OLE) 
OLE is no longer applicable due to permanent discontinuation of study treatment. 
Once the optimal dose(s) is/are selected, sites will be notified and active participants will roll 
over to OLE at a subsequent study visit. The specific timing for each patient will be determined 
based onsite readiness to conduct the OLE. Prior to commencing dosing in OLE, a series of 
assessments (re-baselining) may be collected, as outlined in the assessment schedule  
Table 8-2. If more than one dose is selected for the OLE, then patients will be re-assigned via 
IRT to one of the selected open label doses. 
Study visits will take place every 4 weeks in OLE period (approximately 52 weeks). If 
branaplam development in HD remains ongoing at the end of the OLE, the study will either be 
(a) amended to extend the OLE beyond a year, or (b) a separate extension study will be initiated 
to offer continued access to branaplam.  
4 
Rationale 
4.1 
Rationale for study design 
This is the first study of branaplam in adult HD patients. The study aims to explore a range of 
doses in order to select a safe and tolerable dose that lowers mHTT levels in the CSF to a degree 
expected to be efficacious over longer periods of time. As a slowing in progression of clinical 
symptoms or biomarkers of neurodegeneration require large sample size and treatment duration, 
reduction in the amount of mHTT, in line with branaplam's expected mechanism of action 
(MoA), is thought to be a relevant biomarker to measure target engagement and demonstrate 
proof of concept and guide dose selection for later phase confirmatory studies. 
Study participants will be randomly assigned to treatment arms in the Core Period, and once all 
randomized participants have completed the Week 17 visit, an IA will be performed to 
determine the appropriate dose(s) for the OLE. The decision for the OLE dose will be based on 
mHTT lowering in CSF at the end of the DRF period, as well as safety, tolerability and other 
biomarker data collected throughout the Core Period. All patients will then enter OLE, be 
assigned to the new dose, and continue to be assessed for safety and efficacy for approximately 
an additional year. 
Clinical and biomarker measures of HD will also be evaluated in this study. This includes 
volumetric MRI of brain, CSF and blood biomarkers, HD rating scales and clinical assessments. 


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Table 4-1 
Rationale for Study Design 
Study Design Aspect  
Rationale 
Placebo (PBO) controlled 
Use of PBO will help assess if any safety or tolerability findings might be 
attributed to branaplam and will enable interpretation of any clinical efficacy 
signal; PBO is justified in this patient population as no approved treatment is 
available 
Randomization 
This minimizes bias and helps to decrease the chance of an imbalance in 
baseline patient characteristics between groups 
Staggered cohort 
This allows for appropriate review of data at lower dose levels/regimens 
before proceeding to higher doses. 
Duration of study periods 
Core: approximately 53 weeks of treatment (minimum of 16 weeks of 
treatment for dose range finding is considered sufficient to assess preliminary 
safety, pharmacodynamics (PD) biomarker (mHTT), and PK) 
Open Label Extension: 1 year duration provides longer term assessment of 
safety, tolerability and efficacy, to support continued evaluation in larger 
Phase 3 confirmatory studies. If the interim database lock (iDBL) supports 
study objectives, the open-label period may extend beyond 12 months until a 
separate extension study is available.  
Blinding 
Double blind to mask active or PBO treatment to avoid bias including safety 
reporting. 
4.2 
Rationale for dose/regimen and duration of treatment 
The dose rationale for the present study is based on (i) safety information from Type 1 Spinal 
Muscular Atrophy (SMA) patients (CLMI070X2201) and from healthy volunteers 
(CLMI070A02102), (ii) target engagement information derived from the healthy volunteer 
study (CLMI070A02102) and (iii) predictions on reduction of mHTT protein in brain using 
non-clinical investigations in the humanized BacHD mouse model. 
To support the dose selection, steady state exposure values of branaplam in plasma were 
predicted using a preliminary PBPK model. The PBPK model of branaplam was based on the 
exploratory PK profiles of branaplam in plasma determined after single administration of 
branaplam (35 mg, 105 mg, 210 mg, and 420 mg) to healthy volunteers (CLMI070A02102) and 
the derived population-based PK parameters, physicochemical properties of branaplam, and 
assumptions on elimination pathways (approx. 74% elimination via CYP3A4, 8% of other 
enzymatic elimination, 9% of renal elimination, and 9% not-defined elimination pathways). 
Steady state exposure values were predicted for the selected weekly doses using the weekly 
dosing regimen and the estimated PK parameters. 
PK/PD Considerations 
Dosing frequency: Branaplam is proposed to be administered with a weekly dosing frequency. 
This is based on (i) the relatively long apparent terminal elimination T1/2 values of branaplam 
in plasma observed after single administration in healthy adult volunteers (preliminary T1/2: 
120h, 97.9h, 82.2h, and 104h at doses of 35 mg, 105 mg, 210 mg, and 420 mg, respectively, 
CLMI070A02102) and (ii) the observation, that the target engagement identified by lowering 
of the HTT mRNA from baseline in blood was maintained across the complete observation 
period up to 168h at doses of 105 mg, 210 mg, and 420 mg (CLMI070A02102). This 
maintenance of the target engagement in blood indicated that a weekly dosing frequency is 


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considered to be sufficient to prolong or to increase the target engagement with a weekly dosing 
frequency.  
Starting dose: The selection of the starting dose in Cohort 1 (56 mg) was based on the 
considerations to start the study (i) at an exposure range already investigated in Type 1 SMA 
patients (CLMI070X2201), in which safety and tolerability data have been collected for more 
than 4 years of treatment, and (ii) showed no safety signals after single dose of branaplam in 
healthy adult volunteers (CLMI070A02102). 
At the highest dose level in Type 1 SMA patients (nominal: 60 mg/m2 or 3.125 mg/kg, weekly 
dosing), the mean maximum concentration (Cmax) of branaplam was 96.5 +/- 32.7 ng/mL and 
the AUC 4280 +/-1030 h*ng/mL. No dose-limiting toxicities were observed and the maximum 
tolerated dose of branaplam was not determined in a total treatment duration for more than 4 
years. After single dose of 35 and 105 mg branaplam in healthy volunteers, no obvious adverse 
events were identified. The respective preliminary, mean Cmax values were 8.91 ng/mL and 
44.5 ng/mL and mean AUCinf values 1370 h*ng/mL and 5720 h*ng/mL. At the proposed 
lowest weekly dose of 56 mg in the Phase 2b study, the predicted median plasma Cmax at 
steady state (40.8 ng/mL) and AUCtau at steady state (3098 h*ng/mL) fulfill the considerations 
to start at an already investigated exposure range. 
Target engagement of branaplam (change in HTT mRNA levels from baseline) was investigated 
in blood following single administration of branaplam to healthy volunteers. Preliminary results 
showed that HTT mRNA levels were lowered from baseline at all dose levels with a maximum 
decrease of approximately 20% for the dose range of 35 to 105 mg. Whereas the HTT mRNA 
levels returned to baseline levels for the 35 mg dose, the lowering of HTT mRNA remained 
constant over the observation period of 168 h after single dose of 105 mg. Therefore, target 
engagement is already considered to occur at the starting dose of 56 mg/week with a more 
pronounced change of HTT mRNA from baseline expected after repeated dosing. 
Based on the predictions of the reduction of mHTT protein in brain using non-clinical 
investigations in the humanized BacHD mouse model, the mHTT protein in the brain was 
predicted to decrease from baseline at steady state by up to 16% at steady state AUC values of 
approximately 2500 h*ng/mL. These predictions suggest that already at the starting dose a 
benefit for HD patients is possible. 
Mid dose: At the mid dose of 112 mg, the predicted steady state exposure values (Cmax:  
87.5 ng/mL, AUCtau: 7059 h*ng/mL) are either within the already investigated exposure range 
(Cmax) or higher (AUCtau) compared to the exposure range observed in the Type 1 SMA 
population (Cmax: 96.5 +/- 32.7 ng/mL, AUC: 4280 +/-1030 h*ng/mL), but is still below the 
210 mg dose in the healthy volunteer study (preliminary means, Cmax: 118 ng/mL, AUCinf: 
11800 h*ng/mL, CLMI070A02102) where a trend of increase in liver enzymes was noted on 
Day 8 after branaplam administration. 
As discussed above, the target engagement of branaplam (change of HTT mRNA from baseline) 
and the predicted decrease of mHTT protein in the brain is considered to be more pronounced 
than at the starting dose. 
Highest dose: The weekly dose of 154 mg was selected as the highest dose. The predicted 
median Cmax and AUCtau values at steady state are 131 ng/mL and 10721 h*ng/mL, 


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respectively, being in the range of the 210 mg dose in the healthy volunteer study (preliminary 
means, Cmax: 118 ng/mL, AUCinf: 11800 h*ng/mL, CLMI070A02102) with a trend of liver 
enzyme increase. However, the liver enzyme levels generally remained within normal range or 
slightly above that and were considered as not clinically significant.  
Preliminary results showed that HTT mRNA in blood were lowered from baseline with a 
maximum decrease of approximately 40% after a single dose of 210 mg. The lowering of HTT 
mRNA in blood maintained constant over the observation period of 168 h. Therefore, target 
engagement at a weekly dose of 154 mg is considered to be more pronounced than in the two 
lower doses. 
In the event that the second cohort gating assessment indicates that doses above 112 mg are not 
recommended due to safety concerns, including having reached maximal peripheral HTT 
lowering levels, 84 mg will be selected as option in between the two lowest doses or 28 mg will 
be chosen as an option for a dose lower than the starting dose. 
Based on the predictions of the reduction of mHTT protein in brain using non-clinical 
investigations in the humanized BacHD mouse model, the mHTT protein in the brain was 
predicted to decrease from baseline at steady state by up to 41% at steady state AUC values of 
approximately 10600 h*ng/mL. This predicted decrease is considered to be sufficient for 
clinically meaningful slowing of disease progression without causing safety concerns by 
removing too much normal HTT protein. (Approximate 35-50% reduction in mHTT protein in 
the brain is needed (Kaemmerer and Grondin 2019; Caron et al 2018). 
Study duration: The 16-week timeframe was selected for the DRF because it allows for 
sufficient time for changes in mHTT protein to reach near steady-state-levels in CSF 
(Tabrizi et al 2019a). The additional treatment during the blinded and open-label extension 
allows for increased exposure to assess the safety and tolerability of repeated dosing of 
branaplam. 
4.3 
Rationale for choice of control drugs (comparator/PBO) or 
combination drugs 
Placebo will be used in a double-blind fashion. The use of PBO-control is considered essential 
to ensure study validity and allow for appropriate assessments of safety, tolerability and efficacy 
data. No active comparator is used in this study as there is no disease-modifying treatment 
currently available for early manifest HD patients. Current symptomatic standard of care, 
except those listed in Prohibited Medications Section 6.2.2, will be used as needed and allowed 
per protocol. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Staggered Cohort 
Staggering the cohorts allows for the time needed to evaluate the safety and tolerability of doses 
before exploring additional doses arms. The study will be initiated exploring a weekly dose of 
56 mg. 


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A minimum of 8 weeks of exposure is thought to be adequate to assess the initial safety and PK 
profile of repeated weekly dosing before proceeding to a higher weekly dose (112 mg) at the 
CGA 1. Similarly, the safety and PK profile of a weekly dose of 112 mg after 8 weeks of 
exposure will be assessed during CGA 2 before proceeding to a higher weekly dose (154 mg) 
or another intermediary dose (84 mg), or lower (28 mg), if warranted.  
Given the variable time needed to fully recruit the 10 participants, it is expected that some 
patients will have longer exposure at the time of the first Cohort Gating Assessment 1 (CGA 1). 
While the clinical data from the SMA program did not indicate safety risks, the preclinical 
toxicology data do indicate some potential safety concerns therefore reviewing data for the first 
10 patients with a minimum of 8 weeks treatment provides the opportunity to assess these 
potential risks and to determine initiation of subsequent dosing cohorts. The DMC will be 
reviewing the data approximately twice a year at a minimum. Since reduction of HTT protein 
in periphery by more than 80% is undesirable, this staggered approach also allows the decision 
to not open up the higher dose arms if sufficient HTT lowering is achieved with the lower dose 
arms. 
Interim Analysis 
Due to the USM, the timing and purpose of the interim Database Lock (iDBL) has changed. 
The iDBL will now occur once approximately 70% of the patients in Cohort 1 complete 
their Week 33 visit. The purpose of this IA is to confirm the CGA review leading to the 
USM recommendation and to allow earlier communication of interim study results with 
the broader scientific and HD communities.  
Pre-USM: An interim Database Lock (iDBL) was planned after the last randomized patient in 
the study had completed the Week 17 visit assessments which captures a full 16 weeks of 
treatment with study drug. Following the iDBL, an IA was planned as a review and evaluation 
of all available unblinded data (including but not limited to safety, all PK associated with the 
DRF period, PD, total HTT, mHTT, imaging, clinical and biomarker data) at the time the last 
randomized patient completes the Week 17 visit assessments, as well as for the overall exposure 
duration. The purpose of the IA was to identify the optimal dose(s) that would be introduced in 
the OLE, as well as for any future HD studies with branaplam. Dose selection for the OLE and 
future clinical development would be determined based on data generated from the 16-weeks 
DRF treatment period with branaplam. 
The dosing for OLE may begin after completion of the safety data review and confirmation of 
the dose selection. 
In addition to the unblinded review for IA, an independent DMC will meet at least twice a year 
at a minimum and will review safety data. See Section 10.2.4 for more information on the DMC. 
Guidance on decision rules for the above design adaptations will be outlined in the DMC charter. 
4.5 
Risks and benefits 
The USM Follow up Investigator Notification (06-Dec-2022) was issued by Novartis to 
inform investigators that Novartis has decided to discontinue development of branaplam 
as a potential treatment for people with Huntington’s disease. The decision followed a 
review of unblinded data from VIBRANT-HD indicating that the benefit:risk of 


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branaplam in Huntington’s disease is not positive. This decision was endorsed by the 
independent Data Monitoring Committee (DMC) as well as the VIBRANT-HD Steering 
Committee (SC).Evaluation of risk for branaplam in patients with HD is based on preclinical 
data and the current clinical development experience in Type 1 SMA study in young children 
and healthy adult volunteers. 
Table 4-2 summarizes the important potential risks from this experience. 
Table 4-2 
Summary of important 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 
Child Bearing Potential 
Genotoxicity 
(aneuploidy*) 
Potential 
Liver function effects 
Potential 
Cardiovascular effects 
Potential 
Renal toxicity 
Potential 
DDI 
- 
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. 
Branaplam causes stabilization of tubulin polymerization, resulting in cell cycle arrest within 
the range of doses that are pharmacologically active. Based on animal studies this cell cycle 
arrest can potentially present in various organ systems such as gastrointestinal, bone marrow, 
nervous system, retina, reproductive effects, organs and liver toxicities. The hematologic effects 
can include various forms of cytopenias such as neutropenia, anemia and thrombocytopenia. 
Gastrointestinal effects can present as emesis, loose stools, or malabsorption. 
Bone Marrow Effects 
In the ongoing study in Type 1 SMA patients some events of cytopenias (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 healthy volunteer study in healthy adult participants five subjects in Cohort 4 (420 mg or 
placebo) showed platelet count increases above the ULN (max increase up to 2x ULN) which 
were most pronounced in the 3 subjects with liver events and which have not been observed at 
lower dose levels. 


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Gastrointestinal effects 
In the 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 subjects in this cohort 
reported diarrhea (5 branaplam and 2 placebo-treated) on Day 1 with a spontaneous recovery 
by Day 2. 
Retinal 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 during the study. 
Nerve Fiber Degeneration 
As per the USM, the preliminary data from VIBRANT-HD was reviewed as part of the 
pre-planned CGA and DMC review. Following are some of the key findings: 
• Increased neurofilament light chain (NfL) levels in serum and/or CSF observed in 
the majority of the participants in active arm. 
• Changes in the neurological exam on two consecutive visits, predominantly new 
hypoactive and/or absent deep tendon reflexes (DTRs), observed in more than half of 
participants in the active arm, and the majority of participants with 12 weeks or 
more of treatment. 
• Almost half of the participants in the active arm reported symptoms of peripheral 
neuropathy, either through the neuropathy questionnaire or as an adverse event 
report. 
• Decreased amplitude (50%) in the sural nerve (SNAP) compared to baseline was 
observed in 7 participants in active arm. 
Following are some of the key findings that may be related to nerve fiber degeneration: 
• Preliminary MRI findings suggestive of an increased volume of the lateral ventricles 
were seen in majority of patients in active arm. 
Potential risk of neurotoxicity was identified based on a chronic juvenile dog toxicity study with 
daily dosing of branaplam. Neurotoxicity (axonal degeneration in peripheral nerves and spinal 
cord) was found in one species (dogs) after 17 weeks of daily administration of branaplam at 1 
and 2.5 mg/kg and at 0.25 and 0.75 mg/kg after 52 weeks of daily administration of branaplam. 
Mechanistic investigations (tubulin polymerization interaction) suggest that neurotoxicity may 
be a result of the known cell cycle inhibition properties of branaplam. A dose-dependent 
increase of NfL levels was observed in the CSF of monkeys treated twice weekly with 
branaplam for a duration of 6 weeks in the absence of histo-morphological findings in the brain, 
spinal cord, or peripheral nerves. Although an exploratory biomarker, elevations in NfL may be 


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a consequence of neurotoxicity. The ongoing study in Type 1 SMA has not identified any clear 
evidence of neurotoxicity in study participants.  
NfL levels in serum were monitored at several timepoints in the healthy volunteer 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 potential risk of branaplam-related neurotoxicity will be monitored closely via patient 
reported symptoms, comprehensive neurological examinations, serum and CSF NfL levels and 
nerve conduction studies when indicated. Furthermore, weekly dosing is expected to potentially 
mitigate this risk. 
Reproductive Toxicity  
Embryofetal toxicity studies have been conducted with branaplam in rats and rabbits. No 
teratogenic or embryo-toxic potential was observed in the rat. The exposure at the rat NOAEL 
(2.5 mg/kg/day) are approximately 1.9-fold higher than the predicted AUCweek at the starting 
dose of 56 mg (3098 h*ng/mL), 4.0-fold higher than predicted AUCweek at the lowest optional 
dose of 28 mg (1449 h*ng/mL), or 1.8-fold lower than the predicted AUCweek at the highest 
dose of 154 mg (10721 h*ng/mL). Maternal toxicity and embryo-fetal toxicity were observed 
in the rabbit pEFD study at high dose levels. The rabbit NOAEL (1.5 mg/kg/day) was associated 
with maternal exposure approximately 6.5-fold higher than the predicted AUCweek at the 
optional lowest dose of 28 mg or 1.1-fold lower than the predicted AUCweek of the highest 
dose of 154 mg. Metabolite UFB112 was not detected in pregnant rats and only to a minor 
extent in the pregnant rabbits. 
Huntingtin (HTT) protein is required for embryogenesis and early development, hence embryo-
fetal effects cannot be excluded in humans (Kaemmerer and Grondin 2019). An effect on the 
HTT transcript and protein is unlikely to occur in rat and rabbits based on mode of action of 
branaplam (HTT splicing effects and transcript lowering are human specific). 
In utero exposure to branaplam is therefore assumed to have serious risks of harm to a fetus 
including death. Exposure to branaplam in sexual partners of male study participants through 
contact with seminal fluids is also assumed to carry risks. These risks are mitigated by the 
contraception eligibility criteria (refer to Section 5.2). Women of child-bearing potential and 
sexually active males must be informed that taking the study treatment may involve unknown 
risks to the fetus if pregnancy were to occur during the study and must agree that in order to 
participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
Highly effective contraception will be required for all study participants and female partners of 
male participants as specified in the exclusion criteria. Oral contraception cannot be considered 
because the potential risk of decrease of efficacy due to DDI has not been investigated yet. 
Additionally, the cell cycle arrest properties of branaplam may also have an effect on male and 
female fertility. Study participants need to be counseled for fertility preservation measures.  


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Gonadal Effects: Testicular/Ovarian 
Testicular findings (degenerative changes involving seminiferous tubules of testes and 
testicular atrophy) were observed in a 52-week (juvenile) dog study with daily administration 
of branaplam (≥0.25 mg/kg/day) and in a 4-week wild type RasH2 mouse study with daily 
dosing of branaplam (≥10 mg/kg/day). Testicular findings in the mouse consisted of minimal 
to severe atrophy/degeneration of testis seminiferous tubules, including germ cells. This 
potential risk will be monitored by follicle-stimulating hormone (FSH) to identify potential 
seminiferous tubular injury. 
Ovarian findings (decrease of corpora lutea and follicles) were also observed in the wild type 
RasH2 mouse study with daily dosing of branaplam (≥10 mg/kg/day). No testicular or ovarian 
findings were observed in a prior 4-week study of branaplam (0, 1, 3, 4, and 10 mg/kg/day) in 
the same mouse strain or in any other toxicological studies conducted in the rat, dog or monkey. 
No adverse events relevant to ovarian findings have been reported in the ongoing study in Type 
1 SMA patients which enrolled only young children thus ovarian effects may not be evident. In 
the singe ascending dose (SAD) study in healthy adult volunteers, four post-menopausal female 
subjects (2 on active and 2 on placebo) were enrolled. No reproductive system-related adverse 
events were observed in these four subjects. 
Genotoxicity (Aneuploidy)  
Branaplam has a potential risk of aneugenicity with its potential clinical consequences of tumor 
formation.  
Since the aneugenic effect is considered to be a threshold effect, micronucleus formation was 
investigated in the healthy volunteer study to further understand the translatability of this risk 
and inform the balance of potential risks and benefits for the treatment of HD patients. Overall, 
the MNT results did not indicate a genotoxic potential of branaplam in any of the 4 cohorts. In 
light of these results, the risk of branaplam-related effects on cell cycle or risk of aneuploidy at 
the proposed weekly doses in this study are considered to be low. 
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 the ongoing study in Type 1 SMA patients there were some reported events of transient 
increases in aminotransferases. These events resolved without treatment while on study 
drug. There were no Hy’s Law cases. There were no liver related deaths or discontinuations. 
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 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 (hADME study). All observed ALT/AST increases 
in this study recovered spontaneously. 


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These findings are considered monitorable by safety labs, reversible by drug discontinuation 
and manageable by clinical care and intrinsic hepatocyte regeneration. Safety monitoring for 
liver function during ongoing clinical study includes measurement of clinical chemistries.  
The effect of branaplam treatment should be promptly reviewed and possibly discontinued if 
there should be a safety concern regarding liver function.  
Cardiovascular System 
Branaplam showed a concentration-related inhibition of hERG channel currents, with an IC50 
of 2.4 μM in a GLP-compliant assay and 15.7 μM in a non-GLP study. The 2.4 μM IC50 is 
27.9-fold higher than the predicted, free Cmax (33.9 ng/mL) at the highest dose of this study 
(154 mg). The specific risk from hERG inhibition in the Type 1 SMA and HD populations is 
unknown and considered low with a positive benefit-risk for both indications.  
No heart functional changes were observed in the dog safety pharmacology study or in the  
6 weeks monkey study with twice-weekly dosing. The Cmax at the highest dose in the monkey 
(436 ng/mL) were 4.5-fold higher compared to Cmax observed in Type 1 SMA patients and 
3.3-fold higher compared to predicted Cmax at the highest dose of this study.  
Microscopic findings (cardiomyocyte vacuolation) were observed only in one mouse study. The 
species specificity and mechanism underlying this finding will be further explored. 
In the 4 week wild type RasH2 mouse dose-range finding study with daily administration of 10, 
30, and 60 mg/kg/day of branaplam, histological findings of vacuolation of cardiomyocytes 
were noted. The estimated AUCweek at the highest dose in male and female mice without heart 
findings (4 mg/kg/day) was about 9345 h*ng/mL being approximately 3-fold and 0.86-fold 
higher than the predicted AUCweek at the starting and highest dose of this study, respectively. 
The heart was not identified as a target organ in previous animal safety studies in rat and dog 
with daily administration of branaplam up to 2.5 and 2 mg/kg/day in rat and dog, respectively. 
No heart findings were observed in a 6-week monkey study with twice weekly branaplam 
dosing up to 6 mg/kg/dose. 
In the ongoing study CLMI070X2201 in Type 1 SMA patients there have been 3 cardiovascular 
Suspected Unexpected Serious Adverse Reactions (SUSARs) reported in 3 patients, PTs were 
left ventricular hypertrophy and hypertension in one patient and PTs sinus tachycardia and left 
ventricular dysfunction in one patient and pericardial effusion in one patient. Overall, the 
majority of TEAEs in the cardiac and vascular disorders were Grade 1 and 2 and resolved on 
treatment. There were no clinically meaningful changes in any of the ECG parameters (PR, RR, 
QRS, QT, QTcB, and QTcF). 
In the SAD study in healthy subjects no abnormalities of clinical relevance and no trends were 
observed in standard safety electrocardiograms and no relevant arrhythmia events were detected 
in the 25-hour Holter ECG-based arrhythmia analysis in any of the subjects. Vital signs 
assessments did not show any abnormalities or trends of clinical relevance. Orthostatic vital 
signs assessment (supine and standing SBP, DBP and pulse rate) did not reveal any signs of 
orthostatic dysregulation/postural hypotension, except for 1 subject in the 420-mg group.  
Concentration-response analyses revealed a positive correlation between the branaplam plasma 
concentration and the placebo-adjusted mean change from baseline in QTcF (ΔΔQTcF), 


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characterized by the equation: ΔΔQTcF (ms) = 0.04912 x LMI070 plasma concentration 
(ng/mL). The estimated mean ΔΔQTcF exceeded 10 ms in the investigated exposure range 
while it appeared to be less than 5 ms at the Cmax of the 210 mg dose. In addition, a trend of 
mean ΔΔHR increase of approximately 2 bpm was observed in the investigated exposure range, 
which was not considered to be of clinical relevance. 
There was no apparent trend of clinical relevance in the concentration-response analyses of 
other ECG variables. Categorical outlier analyses revealed a single treatment-emergent new 
QTcF > 450 ms and an increase of QTcF from baseline > 30 ms at the 420-mg dose. There were 
no treatment-emergent QTcF values > 480 ms, no increase in QTcF or QT from baseline > 60 
ms and no ECG events or imbalance of clinical relevance for other ECG variables. 
Concentration-response analyses of branaplam plasma concentration and the placebo-adjusted 
mean change from baseline in systolic and diastolic blood pressure showed no clear correlation 
(slopes of prediction lines for the mean effect were 0.00404 and – 0.00714, respectively). 
The potential cardiovascular risks will be mitigated and monitored by following the appropriate 
exclusion criteria, adherence to protocol specified prohibited medications (Section 6.2.2), 
history and physicals including vital signs (HR, RR, BP), ECG, ECHO, and cardiac enzymes 
(Troponin and NT ProBNP) at protocol defined time points. Investigators should follow the 
guidelines in the protocol for detection and management of potential cardiac findings. 
Renal Toxicity 
Kidney findings were observed after chronic daily dosing only in the dog. In the current 
ongoing CLMI070X2201 study in Type 1 SMA no relevant renal adverse events have been 
identified. In the SAD and hADME studies in healthy subjects there have been no relevant 
abnormalities or changes in blood pressure, serum electrolyte levels or renal function 
variables or in the urinalysis assessments.  
Other potential risks 
Other potential risks of participation in this study include those related to procedures (e.g., 
venipuncture, LP) as well as those associated with study drug administration. The oral solution 
formulation contains a cyclodextrin (specifically hydroxyproply beta (HP-β)-cyclodextrin) to 
improve the aqueous solubility of branaplam. The matching placebo solution for this study will 
contain the same amount of cyclodextrin. Therefore, the potential risks of study drug 
administration include those associated with branaplam and cyclodextrin. 
High daily oral doses of HP-β-cyclodextrin (>16 g/day (270 mg/kg for 60 kg body weight)) 
may potentially cause digestive problems such as diarrhea and should be justified based on 
branaplam benefit-risk considerations (Stella and He 2008). 
The overall risk to HD patients in this study is expected to be low and manageable due to 
considerable risk mitigation strategies and planned safety monitoring. The risks are further 
minimized by the design of the study, including limiting accumulation of branaplam via weekly 
dosing, adherence to the inclusion/exclusion criteria, avoidance of prohibited concomitant 
medications, close clinical monitoring, a staggered dose escalation design requiring safety-


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driven cohort gating assessments and endorsement from an independent DMC before each dose 
escalation. 
See Section 10.2.4 for more information on the DMC. 
In addition, all available unblinded safety data will be regularly reviewed by an independent 
DMC for the duration of the trial. 
Given the safety profile of branaplam to date and positive data on HTT target engagement, an 
investigation of slowing the progression of symptoms and neurodegeneration in HD patients 
offers important benefits.  
The available safety information, combined with both the potential of branaplam to lower 
mHTT levels in patients with HD and the lack of therapies for these patients, suggests a 
favorable risk‑benefit ratio to evaluate branaplam in this population in a dose-finding study. 
Branaplam exposure beyond the initial DRF will continually be evaluated, individually and 
globally, and will inform the dose selection for Part 2 and future studies, and help establish the 
benefit/risk for branaplam in this population.  
4.6 
Rationale for Public health Emergency mitigation procedures 
In the event of a Public Health emergency as declared by Local or Regional authorities i.e. 
pandemic, epidemic or natural disaster, mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the Public Health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate. 
Potential risk associated with the COVID-19 Pandemic 
Novartis is committed to supporting the safety and wellbeing of our study participants, 
investigators and site staff. All local regulations and site requirements will be applied in the 
countries that are affected by the COVID-19 pandemic. 
The Novartis clinical trial team will review the situation in each participating country and work 
with investigators to continue to ensure the safety of participants during the conduct of the trial. 
As the COVID-19 situation evolves, investigators must use their best judgement to minimize 
risk to participate during the conduct of the study. Lastly, the COVID mRNA vaccines consist 
of processed, mature mRNA, which are not expected to be a substrate for branaplam. 
5 
Study Population 
As per the USM follow-up notification dated 06-Dec-2022, no further participants will be 
enrolled in this study. The inclusion and exclusion criteria in Section 5.1 and Section 5.2 
below, were applicable to those participants enrolled to Cohort 1. 
Approximately 75 male or female patients with confirmed Stage 1 or 2 HD and a UHDRS TFC 
score of >8 will be enrolled in this study to allow for of approximately 25 participants per 
treatment arm. Fewer participants will be enrolled if all treatment arms are not opened. Manifest 
patients with a TFC >8 are selected because they are late enough in the disease process so that 


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mHTT can be measured in their CSF and clinical symptoms can be readily assessed, and early 
enough in the disease process so that they can comply with the protocol defined schedule of 
assessments during Core blinded treatment period (DRF and BE) and be monitored for disease 
progression and safety throughout the OLE. Eligible patients starting at the age of 25 will be 
enrolled to avoid the very high CAG repeats associated with early disease onset as these patients 
could be considered to have a more rapidly progressing phenotype. An age cap of 75 years is 
employed to avoid age-related comorbidities that typically occur above this age. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Must be capable of providing informed consent (in the opinion of the Investigator) 
3. Clinically diagnosed Stage 1 or 2 Huntington's disease with a diagnostic confidence level 
(DCL) = 4 and a UHDRS Total Functional Capacity (TFC) >8 at screening  
4. Genetically confirmed Huntington's disease, with presence of ≥40 CAG repeats in the 
huntingtin gene. 
• For participants without prior documentation, a sample must be sent to the central study 
laboratory and confirmation of the CAG repeat length for these participants must be 
obtained prior to randomization 
• For participants with previously existing documentation of their CAG repeat length, it 
is acceptable to use this prior data to qualify for randomization. These participants must 
also submit a sample for CAG repeat testing to be conducted by the central study 
laboratory. 
5. Male and female participants between 25 to 75 years of age, inclusive, on the day of 
Informed Consent signature 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study: 
1. Use of other investigational drugs within 5 half-lives of the first dose of study drug, or 
within 30 days, whichever is longer. 
2. Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless 
participant received only placebo) 
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes. 
4a. Participants taking medications prohibited by the protocol (Table 6-2 Prohibited 
Medications). In addition, participants should be on a stable dose and regimen of permitted 
chronic concomitant medications for at least 6 weeks prior to receiving the first dose of 
study drug which in the medical judgement of the Investigator is not anticipated to change 
during the study. If new medications are initiated during Screening, laboratory evaluations 
must meet eligibility criteria before first dose of study drug. 
5. Any medical history, lumbar surgery or condition that would interfere with the ability to 
complete the protocol specified assessments, (e.g., history of brain or spinal injury that 


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would interfere with the LP or CSF circulation, implanted cerebrospinal shunt, conditions 
precluding MRI scans, herniated disc, etc.). 
6. History of malignancy of any organ system (other than localized basal cell carcinoma of the 
skin or in situ cervical cancer), treated or untreated, regardless of whether there is evidence 
of local recurrence or metastases. 
7. Participant has other severe, acute or chronic medical conditions including unstable 
psychiatric conditions, or laboratory abnormalities that in the opinion of the Investigator 
may increase the risk associated with study participation, or that may interfere with the 
interpretation of the study results. 
8. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this 
ideation occurred in the past 6 months from the Screening visit, or “yes” on any item of the 
Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious Behavior” (item also 
included in the Suicidal Behavior section), if this behavior occurred in the past 2 years. 
9. Pregnant or nursing (lactating) women. WOCB potential should not become pregnant 
during the study or within 7 months from stopping study medication. 
10a. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 120 days (4 months) after the last dose of the study treatment. A condom 
is required for all sexually active male participants even if they are surgically sterile with a 
vasectomy to prevent them from fathering a child AND to prevent delivery of study 
treatment via seminal fluid to their female partner. In addition, male participants must not 
donate sperm for the time period specified above. 
A condom is required to be used also by vasectomized men as well during intercourse with a 
male partner of the study participant.  
The branaplam exposure in body fluids is not known. Since branaplam is genotoxic, sexual 
partners are advised to avoid direct contact with semen of participants, to prevent exposure to 
the study drug. 
11a. Women of child-bearing potential, defined as all heterosexually active women 
physiologically capable of becoming pregnant, unless they are using one highly effective 
methods of contraception during dosing and for 7 months after stopping the study 
medication. Highly effective methods of birth control are those methods that have a less 
than 1% chance of an unwanted pregnancy for 1 year.  
In addition to one highly effective method of contraception, a condom is required for 
all male partners of female participants to prevent fathering a child AND to prevent 
exposure of study treatment via vaginal fluid to your partner, until at least 7 months 
following the last dose of study treatment. 
WOCB potential must not donate their eggs for 7 months after the last dose of study 
treatment. 
Oral contraception cannot be considered due to potential decreased efficacy as potential 
DDI with branaplam.  
Highly effective contraception methods include:  
• Total abstinence (when this is consistent with the preferred and usual lifestyle of the 
participant). [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 


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methods) and withdrawal are NOT acceptable methods of contraception for heterosexually 
active participants.] 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before 
taking investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization of partners (at least 6 months prior to screening). For female subjects 
on the study, the vasectomized male partner should be the sole partner. 
• Use of an intrauterine device (IUD) or intrauterine system (IUS) which is MRI 
compatible. 
In case local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF. 
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor 
symptoms). Women are considered not of childbearing potential if they are post-
menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), 
total hysterectomy or bilateral tubal ligation at least six weeks prior to Screening. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of childbearing potential. 
The branaplam exposure body fluids is not known. Since branaplam is genotoxic, sexual 
partners are advised to avoid direct contact with vaginal fluid of participants, to prevent 
exposure to the study drug. 
12a. 
History of: 
• Gene therapy or cell transplantation or any other experimental brain surgery 
• Hepatitis B or hepatitis C or serologic evidence for active viral hepatitis (HBsAg and 
HCVab test) 
• Immunodeficiency diseases, including a positive human immunodeficiency virus (HIV) 
test result 
• Current evidence of drug or alcohol abuse in the 12 months prior to screening, as 
defined by the DSM-V criteria for substance abuse. For former abusers, abstinence 
should be confirmed by laboratory tests (drug testing and/or CDT level in blood). 
• Use of Tetra-Hydro-Cannabinoid (THC)/ cannabinoid containing substances is allowed 
as per local regulations and/or local medical practice if in the opinion of the Investigator, 
use does not represent an exclusionary condition, does not constitute abuse and does 
not affect cognition, and provided that participants are currently treated with a stable 
regimen for at least 12 weeks prior to first dose of study drug. Note: If initiated during 
the study, use must be withheld for 72 hours prior to any cognitive and/or motor 
assessments. 
13a. 
Any surgical or medical condition which might put the participant at risk in case of 
participation in the study. The Investigator should make this determination in 
consideration of the participant’s medical history and/or clinical or laboratory evidence 
of any of the following at the Screening visit:  


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• Unstable chronic gastrointestinal (GI) condition such as history of Crohn’s disease, 
Ulcerative colitis, poorly controlled irritable bowel syndrome (IBS) or similar chronic 
GI conditions  
• Neurologic or neuromuscular conditions other than HD 
• History of or physical examination consistent with peripheral neuropathy or nerve 
conduction findings compatible with electrodiagnostic evidence of neuropathy 
• Participants who have a known diagnosis of diabetes mellitus or who do not have a 
known diagnosis of diabetes with a glycated hemoglobin (HbA1c) > 6.5% 
• Lipase, total bilirubin or amylase must not exceed the 1.5x ULN 
• Liver disease or liver injury as indicated by abnormal liver function tests  
• Any of the following single parameters in serum of ALT, AST, GGT, and alkaline 
phosphatase must not exceed 2.0 x upper limit of normal (ULN). 
• History of renal injury / renal disease or presence of severe impaired renal function as 
indicated by an estimated glomerular filtration rate (eGFR) using the modification of 
diet in renal disease (MDRD) equation < 30 (mL/min/1.73 m²) (allowing for age-related 
GFR decline in the mild to moderate range) or the presence >3+ proteinuria/ hematuria 
on a single (one time) repeated urinalysis. 
• Evidence of urinary obstruction potentially leading to an impaired renal function at 
screening 
• Diagnosis of testicular atrophy  
• Diagnosis of primary ovarian failure  
• Clinically significant retinal abnormalities on ophthalmologic examination by a local 
Ophthalmologist 
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed at least 3 days prior to first study drug administration (Day 1) 
• Any objects and/or implants in the body which may be contraindicated for MRI, such 
as pacemakers and some IUD 
• Diagnosis of chronic thrombocytopenia or a bleeding disorder  
14a. 
Cardiovascular exclusion criteria: 
• History or current diagnosis of ECG abnormalities indicating significant risk or safety 
concern for study participants such as: History of myocardial infarction, angina pectoris, 
heart failure, or coronary artery bypass graft (CABG).  
• Screening ECHO abnormalities per investigator’s medical judgement including but not 
limited to left ventricular ejection fraction (LVEF) <50%. 
• Screening or baseline not within normal range Troponin or NTproBNP values. 
• History or concomitant clinically significant cardiac arrhythmias (e.g., sustained 
ventricular tachycardia, atrial fibrillation, etc.), complete left bundle branch block, 
high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and 
third-degree AV block). 
• History of familial long QT syndrome or known family history of Torsade de Pointes 
risks for TdP including uncorrected hypokalemia or hypomagnesemia, history of 


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clinically significant/symptomatic bradycardia and a family history of idiopathic 
sudden death. 
• Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pretreatment [screening or 
baseline] (as mean of triplicate ECGs), or inability to determine the QTcF interval. 
• Use of agents known to prolong the QT interval or with a known or possible risk of 
Torsade de Pointes unless it can be permanently discontinued or replaced with a 
permitted medication (refer to Table 6-2). 
15a. 
Uncontrolled hypertension (average 3 systolic blood pressure [SBP]readings) at 
screening >140 mmHg or average diastolic blood pressure [DBP] > 90 mmHg 
excluding values related to white coat syndrome (anxiety-related), per Investigator’s 
judgement. Any clinically significant hematological abnormality as assessed by the 
Site Investigator at screening and/or laboratory evidence of any of the following: 
• INR, PT, or activated partial thromboplastin time (APTT) that are not within normal 
ranges 
• Hemoglobin <110 g/L (females) or <120 g/L (males) 
• Platelets ≤100 x 109/L 
• Platelets count >500 x 109/L 
• Neutrophil count <1.5 x 109/L 
• Leukocytes <3.0 x 109/L 
6 
Treatment 
6.1 
Study treatment 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment has been 
permanently discontinued; the last dose administered was 08-Aug-2022. 
The investigational treatment for this study is branaplam and matching placebo. Novartis will 
supply branaplam and matching placebo in 6 mL vials containing 5 mL of study treatment. The 
vials will be packed in boxes containing 4 vials each. All eligible participants will be 
randomized via Interactive Response Technology (IRT) to one of the available treatment arms. 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for preparation /dispensing, and administration of study treatment are outlined in 
the Instructions for Use. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
LMI070 
(branaplam) 17.5 
mg/5 mL 
Oral solution 
Oral use 
Double blind; vials 
Sponsor (global) 


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Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
matching placebo 5 
mL 
Oral solution 
Oral use 
Double blind; vials 
Sponsor (global) 
6.1.2 
Treatment arms/group 
At the Week 1 visit, participants will be randomized to one of the following treatment arms in 
a ratio of 4:1, active vs. PBO 
• Cohort 1: Treatment Arm A: Branaplam 56 mg oral solution or matching PBO, once 
weekly 
• Cohort 2: Treatment Arm B: Branaplam 112 mg oral solution or matching PBO, once 
weekly 
• Cohort 3: 
• Treatment Arm C: Branaplam 154 mg oral solution or matching PBO, once weekly or 
• Treatment Arm X: Branaplam 84 mg oral solution or matching PBO, once weekly or 
• Treatment Arm Y: Branaplam 28 mg oral solution or matching PBO, once weekly 
Treatment Arm assignment for an individual participant will be determined by which treatment 
arms are open at the time of the participant screening.  
For Treatment Arms C, X and Y, only one of the three will be initiated in Cohort 3. PBO is 
embedded within each Treatment Arm. 
6.1.3 
Treatment duration 
All participants who are randomized will enter the Core Treatment Period, receiving the 
investigational treatment or PBO for at least 16-weeks in the DRF portion. After the DRF period, 
all participants will continue on their assigned study treatment in the BE for up to approximately 
53 weeks in total. The participants who are randomized earlier will have longer treatment 
durations. This will be impacted by the recruitment rate as well as the time necessary to 
complete the IA to confirm the OLE dose(s) account for the estimated variable time range for 
the BE. The Core Period duration (Dose Range Finding + Blinded Extension) may be extended 
beyond the estimated 53 weeks if recruitment is slower than planned. 
Once the last randomized participant within all open Cohorts completes the DRF period, the 
data for the IA will be compiled while this last randomized participant continues to the BE. This 
timing will be closely monitored to assess the appropriate timing of the End of the Blinded 
Extension, and all sites will be notified in the preceding months so they can plan accordingly. 
All assessments for the End of Core visit will be completed as specified in Table 8-2,Table 8-3 
and Table 8-4. 
Treatment duration for OLE is for approximately 52 weeks, after which a subsequent extension 
study will be available for participants to roll into if this protocol was not previously amended 
to extend the OLE. 


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Participants may be discontinued from treatment with the study drug at any time due to 
unacceptable toxicity, disease progression and/or at the discretion of the investigator or the 
participant. 
6.2 
Other treatment(s) 
No additional treatment beyond investigational drug is provided in this trial. An overview of 
the prohibited medication is given in Table 6-2. 
6.2.1 
Concomitant therapy 
As per the USM, study treatment has been permanently discontinued after approximately 
4 months of temporary suspension; thus, there are no longer restrictions for concomitant 
drugs. Investigators should follow medical judgment and standard of care when 
prescribing new medications. 
All medications administered must be recorded on the Prior and Concomitant Medications 
electronic case report form (eCRF). All medications, procedures, and significant non-drug 
therapies (including physical therapy and blood transfusions) administered within 6 months 
prior to the Screening visit, and after the participant was enrolled into the study, must be 
recorded on the Prior and Concomitant Medications eCRF. Any medications, procedures, and 
significant non-drug therapies taken by the participant within the timeframe defined in the entry 
criteria prior to the start of the study should also be recorded. 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before randomizing a participant or allowing a new medication to be started. If the participant 
is already randomized and/or has received treatment with study drug, contact Novartis to 
determine if the participant should continue participation in the study. 
Pre-USM : In addition, participants should be on a stable dose and regimen of permitted chronic 
concomitant medications for at least 6 weeks prior to receiving the first dose of study drug 
which in the medical judgement of the Investigator is not anticipated to change during the study. 
If new medications are initiated during Screening, laboratory evaluations must meet eligibility 
criteria before first dose of study drug. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
THC /Cannabinoid containing substances are neither categorized as CYP3A4/5 substrates with 
narrow therapeutic index or as a sensitive CYP3A4/5 substrate nor as strong or moderate 
CYP3A4 inhibitors by e.g. FDA (see Table 6-2). However, interaction as substrate and/or 
inhibitor of CYP3A4 cannot completely be excluded. Therefore, the use of THC /Cannabinoid 
containing substances is allowed as per local regulations and/or local medical practice with 
caution if in the opinion of the Investigator, use does not represent an exclusionary condition, 
does not constitute abuse and does not affect cognition, and provided that participants are 
currently treated with a stable regimen for at least 12 weeks prior to first dose of study drug. If 
initiated during the study, use must be withheld for 72 hours prior to any cognitive and/or motor 
assessments. 


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6.2.1.2 
Concomitant SARS-CoV-2 / COVID-19 vaccines 
SARS-CoV-2 / COVID-19 vaccines are not prohibited and there is no requirement for specific 
timing of receiving a vaccine prior to or after branaplam. Any instructions provided in the 
package inserts for each vaccine should be followed. 
• Mechanistic studies have shown that branaplam acts as a glue between specific, un-spliced 
pre-mRNA sequences and the spliceosome Currently available COVID mRNA vaccines 
consist of processed, mature mRNA which are not expected to be a substrate for branaplam 
• Currently available non-replicating viral vector SARS-CoV-2 vaccines require further 
cellular processing of resulting mRNA to produce the Spike protein. The distinct sequence 
of the Spike mRNA and the known MoA of branaplam make it unlikely that branaplam 
would interfere with processing of Spike mRNA. 
•  Based on the MoA of SARS-CoV-2 DNA based / Naked plasmid DNA and Inactivated 
SARS-CoV-2, vaccines are not expected to interact with branaplam. 
Live attenuated SARS-COV-2 vaccines are not contraindicated unless patient is 
immunocompromised. 
6.2.2 
Prohibited medication 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment has been 
permanently discontinued, therefore the prohibited medications referenced below in 
Table 6-2 are no longer applicable.  
In vitro experiments showed that branaplam can be metabolized via Human Cytochrome P450 
3A4 (CYP3A4) and direct 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 or with strong systemic inducers such as examples 
provided in the table below. Use of weak to moderate inhibitors of CYP3A4 should be avoided 
unless absolutely necessary. 
Considering the direct glucuronidation pathway, there is a potential for inhibitors or inducers 
of UGT1A4, UGT1A7, and UGT1A9 to alter the clearance of branaplam in vivo if direct 
glucuronidation is the major clearance pathway of branaplam. However, no clinical relevant 
pan-UGT inhibitor is described in the literature and clinical relevant inhibition of all three 
identified UGTs is considered to be unlikely. Similar is true for the induction of UGTs. 
Therefore, potential UGT inhibitors/inducers are not prohibited and can be used with caution. 
In vitro, results indicated that branaplam has a potential perpetrator risk on MATE2-K and 
OCT1 transporters, which might alter the disposition of MATE2-K and OCT1 substrates. 
Therefore, co-administration should be considered with caution and be avoided if possible as 
described in Table 6-2. 
Branaplam is considered to have a minor-to-moderate potential to inhibit CYP3A4/5 in a time-
dependent manner impacting co-medications metabolized via CYP3A4/5 with a narrow 
therapeutic index. Due to the time-dependent inhibition, the decrease in enzyme activity may 
be amplified by administration of multiple doses. Therefore, use of known sensitive CYP3A4/5 
substrates should be considered with caution and be avoided if possible (Table 6-2).  


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Use of the treatments displayed in the Table 6-2 are not allowed after screening and at the time 
points specified. 
Table 6-2 
Prohibited Medications 
Medications 
Prohibition period 
Action taken 
Strong systemic inhibitors of 
CYP3A4 examples include, but are 
not limited to boceprevir, 
clarithromycin, cobicistat, 
conivaptan, grapefruit juice, 
idelalisib, indinavir, itraconazole, 
ketoconazole, mibefradil, 
nefazodone, nelfinavir, 
posaconazole, ritonavir, telaprevir, 
telithromycin, troleandomycin, 
voriconazole. 
As strong systemic inhibitors of 
CYP3A4 are also combination of 
ritonavir-boosted regimens 
considered: 
ombitasvir/paritaprevir/dasabuvir/rit
onavir (Viekira Pak), 
indinavir/ritonavir, 
tipranavir/ritonavir, 
danoprevir/ritonavir, 
elvitegravir/ritonavir, 
saquinavir/ritonavir, 
lopinavir/ritonavir, 
atazanavir/ritonavir, 
darunavir/ritonavir 
For a complete list and additional 
information, please visit the 
following FDA website on the 
respective table and discuss with 
Sponsor  
(Table 3-2) 
fda.gov/drugs/developmentapprov
alprocess/developmentresources/d
ruginteractionslabeling/ucm093664
.htm 
Within 14 days prior to 
first study dose administration or 
during the study 
If available, substitute with an 
alternative medication without 
CYP3A4 inhibition. If no alternative 
is available then it should be taken 
with caution based on the 
Investigator’s medical judgment 
Strong systemic inducers of 
CYP3A4 examples include, but are 
not limited to apalutamide, 
carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. 
John’s wort 
For a complete list and additional 
information, please visit the FDA 
website noted above, on the 
respective table and discuss with 
Sponsor  
(Table 3-3) 
Within 14 days prior to 
first study dose administration or 
during the study 
Prohibited. 
Alternative medication without 
CYP3A4 induction can be used, 
otherwise discontinue patient from 
study 
Co-medications metabolized via 
CYP3A4/5 with narrow 
therapeutic index examples 
include but are not limited to 
Within 14 days prior to 
first study dose administration or 
during the study 
If available, substitute with an 
alternative medication without 
CYP3A4 interaction, If no 
alternative is available then it 


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Medications 
Prohibition period 
Action taken 
alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus 
For a complete list of CYP3A4/5 
substrates and additional 
information, please visit the FDA 
website noted above, on the 
respective table and discuss with 
Sponsor 
(Table 3-1) 
should be taken with caution 
based on the Investigator’s 
medical judgment 
Co-medications eliminated via 
renal MATE2K transporter of 
clinical-relevant examples include, 
but are not limited to fexofenadine, 
glycopyrronium, metformin 
Co-medications substrate of 
OCT1 transporter of clinical-
relevant examples include, but not 
limited to cephalexin, dofetilde, 
pilsicainide, pindolol, 
procainamide, ranitidine, 
varenicline, umeclidinium, 
zidovudine. 
For a complete list and additional 
information, please visit the FDA 
website noted above, on the 
respective tables and discuss with 
Sponsor 
(in vitro: Table 4-1, clinics:  
Table 5-1). 
Within 14 days prior to 
first study dose administration or 
during the study 
If available, substitute with an 
alternative medication without 
MATE2K or OCT 1 transporter 
interaction, If no alternative is 
available then it should be taken 
with caution based on the 
Investigator’s medical judgment 
Medication(s) with a "Known 
Risk of Torsade de Pointes" per 
qtdrugs list (Woosley RL)These 
drugs include but are not limited to 
the following: escitalopram, 
citalopram, haloperidol, sulpiride, 
chlorpromazine, ondansetron, 
hydroxychloroquine ciprofloxacin, 
clarithromycin 
For a complete list and additional 
information, please visit 
www.CredibleMeds.org (website) 
and discuss with Sponsor 
Within 14 days prior to 
first study dose administration or 
during the study 
Discontinue the prohibited 
medication and substitute with an 
alternative medication without 
known or potential risk. See below 
for use of drugs with conditional 
risk of TdP 
After a patient has received study 
drug and if required due to life- 
threatening conditions or other 
exceptional circumstances 
indicating a high medical need for 
the use of these drugs the 
Investigator should use medical 
judgment carefully assessing 
benefit risk for an individual patient 
under consideration. However, 
ECG monitoring will be required 
before starting these drugs and 
repeated once again when steady 
state (5 half-lives) of this drug is 
achieved. In case of any 
abnormality on a single ECG (>480 
QTc) triplicate ECGs should be 
performed and mean values 
should be used for confirmation 
(mean QTc > 480 ms). 


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Medications 
Prohibition period 
Action taken 
Medication(s) with “Potential 
risk of TdP” per qtdrugs list 
(Woosley RL) These drugs include 
but are not limited to the following: 
aripiprazole, clozapine, 
deutetrabenazine, tetrabenazine, 
tiapride, levetiracetam, venlafaxine 
For a complete list and additional 
information, please visit 
CredibleMeds.org (website) and 
discuss with Sponsor 
Within 14 days prior to first study 
dose administration or during the 
study 
Discontinue the prohibited 
medication and substitute with an 
alternative medication without or 
with conditional risk of TdP (see 
recommendation for conditional 
TdP drugs below). 
After a patient has received study 
drug and if required due to life-
threatening conditions or other 
exceptional circumstances 
indicating a high medical need for 
the use of these drugs the 
Investigator should use medical 
judgment carefully assessing the 
benefit risk for an individual patient 
under consideration. However, 
ECG monitoring will be required 
before starting these drugs and 
repeated once again when steady 
state (5 half-lives) of this drug is 
achieved. In case of any 
abnormality on a single ECG (>480 
QTc) triplicate ECGs should be 
performed and mean values 
should be used for confirmation 
(mean QTc > 480 ms). 
Medication(s) with a 
“Conditional Risk of TdP” per 
qtdrugs list (Woosley RL) These 
drugs include but are not limited to 
the following: diphenhydramine, 
doxepin , fluoxetine, 
hydrochlorothiazide, furosemide, 
lansoprazole, metoclopramide, 
olanzapine, omeprazole, 
paroxetine, quetiapine,risperidone, 
sertraline, trazodone,ziprasidone 
For a complete list and additional 
information, please visit 
www.CredibleMeds.org website 
and discuss with Sponsor 
May participate in the study and 
continue medication if they have 
been on a stable dose (at least 6 
weeks, based on the medical 
judgement of the Investigator) of 
these drugs prior to the initiation of 
study drug. Furthermore, based on 
the opinion of the Investigator, the 
participant is anticipated to remain 
on the same dose/regimen 
throughout the duration of the 
study. 
If no alternative is available and 
medications in this category are 
felt to be necessary based on the 
medical judgment of the 
Investigator then they may be 
continued with caution. However, if 
initiated after the administration of 
study drug, ECG monitoring will be 
required before starting these 
drugs and repeated once again 
when steady state (5 half-lives) of 
this drug is achieved. In case of 
any abnormality on a single ECG 
(>480 QTc) triplicate ECGs should 
be performed and mean values 
should be used for confirmation 
(mean QTc > 480 ms).  
Antiplatelet or anticoagulant 
therapy including but not limited to 
aspirin (unless ≤ 81 mg/day), 
clopidogrel, dipyridamole, warfarin, 
heparinoids and direct coagulation 
factor inhibitors e.g. apixaban, 
dabigatran, rivaroxaban 
Within 14 days prior to screening 
and during study 
Discontinue the prohibited 
medication 
 


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6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a unique Participant Number (Participant No.), that 
is assigned when the participant is first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. The Participant 
No. consists of the Site Number (Site No.) (assigned by Novartis to the investigative site) with 
a sequential Participant Number suffixed to it, so that each participant is numbered uniquely 
across the entire database. The sequential numbers are assigned by the RAVE electronic data 
capture (EDC) system and are dependent upon when the site enters data into RAVE EDC. For 
example, Participant A signs the consent on 10-Jan-2021 and Participant B signs on 11-Jan-
2021; however if the site enters the data for Participant B first in RAVE, Participant B will be 
assigned the first sequential number #001 and Participant A will be assigned the next sequential 
number which is #002. 
6.3.2 
Treatment assignment, randomization 
At the randomization visit, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The Investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify unique medication numbers for the packages of 
investigational treatment to be dispensed to the participant. The randomization number will not 
be communicated to the Investigator staff.  
Patients should not be randomized in IRT nor receive study drug treatment until the baseline 
MRI scan has passed quality control (QC) at central vendor (expected turnaround time is 
approximately 3 days).  
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. A 
participant randomization list will be produced by the IRT supplier using a validated system 
that automates the random assignment of Participant Numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply using a validated system that automates the 
random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization will not be stratified in the study. The randomization scheme for participants 
will be reviewed and approved by a member of the Randomization Office. 
Randomization will begin first in Treatment Arm A. Within each Treatment Arm, a 
randomization ratio of 4:1 will be implemented, active vs. PBO. Since the study has a staggered 
design and new Treatment Arms are open only after decisions are made at the time of CGAs, it 
is possible that one or more Treatment Arms are open at the same time in case the sample size 
of 25 on a previously open arm has not been met (See Section 3). Therefore, eligible participants 
will be randomized via IRT with an equal randomization rate across arms in case more than one 
Treatment Arm is open at the same time. Again, the same randomization ratio of 4:1 (within 
each treatment arm) will be used, active vs. PBO. 


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6.4 
Treatment blinding 
Per the USM, the sites, Investigators and participants were unblinded on 07-Dec-2022. 
The Sponsor study team was unblinded on 02-Nov-2022. 
Pre-USM: For the Core Period, participants, Investigator staff, persons performing the 
assessments, and Sponsor study team will remain blind to the identity of the treatment within 
each cohort from the time of randomization until interim analysis for the Core Period using 
the following methods: Randomization data are kept strictly confidential until the time of 
unblinding and will not be accessible by anyone else involved in the study with the following 
exceptions: independent PK analyst, independent statistician and independent programmer 
supporting the Cohort Gating Decision Board and the DMC members. 
• The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor. 
• The randomization codes associated with participants from whom PK samples are taken 
will be disclosed to PK analysts who will keep PK results confidential until data base lock. 
• The data with a potential to unblind recipients (typically markers of the treatment effect) 
will be stored in a restricted area of the database until database lock. Although the 
randomization list and/or treatment allocation information will NOT be communicated to 
them, the following personnel will be considered as unblinded due to the results post-
baseline:  
• HD biomarker analysts (data including but not limited to HTT/mHTT in plasma 
(protein 
), 
and CSF (protein) 
• All other data with potential for unblinding i.e., tolerability data) will be treated similarly 
as randomization data with regards to blinding: the data will be loaded into a restricted area. 
Access will only be granted to members of the authorized independent unblinded team. 
Unblinding during the Core period will occur in the case of participant emergencies. 
In the open-label extension (OLE), treatment will be open to participants, Investigator staff, 
persons performing the assessments, and the Clinical Trial Team (CTT). 
6.5 
Dose escalation and dose modification 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment has been 
permanently discontinued, therefore this section is no longer applicable. 
Investigational or other study treatment dose adjustments are not permitted. 
6.5.1 
Definitions of dose limiting toxicities (DLTs) 
Not applicable. 
6.5.2 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions 
are permissible, in order to allow participants to continue the study treatment. 
Any changes in study treatment administration must be recorded on the Drug Administration 
Record eCRF. 


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If the administration of study treatment is temporarily interrupted for reasons other than toxicity, 
then treatment may be resumed at the same dose level and same dosing frequency. 
If the study treatment is withheld due to toxicity, refer to Safety Monitoring Section 10; 
scheduled visits and all assessments should continue to be performed (with the exception of the 
dosing of the withheld study drug), as described in the visit assessment schedule (Table 8-2, 
Table 8-3 and Table 8-4). 
Beyond the DRF period and upon consultation with the Sponsor, the Investigator may consider 
to permanently discontinue a participant from the study in cases of extended interruptions 
and/or suspected non-compliance with study treatment (e.g. extended interruptions of study 
treatment not described in Table 6-3 and in Safety Monitoring and Reporting Section 10).  
All participants will be followed for safety until 30 days after the last dose of study treatment. 
Deviations from mandatory dose interruptions are not allowed. Permanent study drug 
discontinuation is mandatory for specific events indicated in the Table 6-3. 
Table 6-3 
Investigator Guidance for Dose interruption/discontinuation, follow-up 
and re-initiation of study treatment for select Adverse Events 
Investigations (Hematologic) 
Neutropenia (absolute neutrophil count (ANC)) 
Mild (ANC < lower limit of normal (LLN) - 1500/mm3) 
Recommendation: May maintain dose 
Moderate (ANC < 1500 - 1000/mm3) 
Recommendation: May maintain dose 
Severe (ANC < 1000 - 500/mm3) 
Recommendation: Hold the study drug until resolved 
to mild or moderate, then maintain dose or consider 
every other week dosing after discussing with 
Sponsor 
Mandatory: If ANC < 500 mm3, hold the study drug 
until resolved to mild or moderate; if resuming dose 
use clinical judgement. 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.5°C) 
Recommendation: Hold the study drug and 
consider permanent discontinuation  
Thrombocytopenia 
Mild (platelets (PLT) < LLN - 75,000/mm3) 
Recommendation: May maintain dose 
Moderate (PLT < 75,000 - 50,000/mm3) 
Recommendation: May maintain dose 
Severe (PLT < 50,000 - 25,000/mm3) 
Recommendation: Hold the study drug until resolved 
to mild; 
• 
If resolved in ≤ 7 days, then maintain dose 
• 
If not resolved in ≤ 7 days, then may consider 
permanent discontinuation at  
• 
Investigator's discretion or if resolved > 7 days to 
mild consider every other week dosing after 
discussing with Novartis 
Mandatory: If platelets <25,000/mm3, Hold the study 
drug and permanently discontinue or if resolved > 7 
days to mild consider every other week dosing after 
discussing with Novartis 
Thrombocytosis 
Mild (PLT > 500,000-700,000/mm3) 
Recommendation: May maintain dose (monitor prior 
to next dose) 
Moderate (PLT >700,000 – 900,000/mm3) 
Recommendation: May hold dose until resolved to 
mild (monitor prior to next dose) 


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• 
If resolved in ≤7 days, then maintain dose 
• 
If not resolved in ≤7 days, hold dose until 
resolved to mild, may consider permanent 
discontinuation at Investigator's discretion or if 
resolved > 7 days to mild consider every other 
week dosing after discussion with Novartis  
Severe (PLT > 900,000/mm3) 
Recommendation: Hold the study drug until resolved 
to mild (monitor prior to next dose) 
• 
If resolved in ≤7 days, then maintain dose 
• 
If not resolved in ≤7 days, then may consider 
permanent discontinuation at Investigator's 
discretion or if resolved > 7 days to mild consider 
every other week dosing after discussion with 
Novartis 
Mandatory: If platelets >1,000,000/mm, permanently 
discontinue study drug. Manage per standard of care.  
Cardiovascular disorders 
Hypertension 
(Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg) 
Recommendation: Hold the study drug, treat per 
standard of care until resolved  
Mandatory: In case of life threatening consequences 
of hypertension e.g. malignant hypertension, transient 
or permanent neurologic deficit, hypertensive 
crisis, permanently discontinue study drug 
immediately. Manage per standard of care 
Cardiac Echocardiogram 
Left Ventricular Ejection Fraction (LVEF) <50% and/or 
Reductions in LVEF ≥10 % units and/or GLS ≥15 % 
units change from baseline 
Recommendation: Hold the study drug and 
continuing study treatment should be done in 
consultation with a cardiologist. Manage per standard 
of care. 
Clinically significant increase in cardiac enzymes 
(Troponin and NTproBNP) 
Recommendation: Hold the study drug, perform 
echocardiogram and ECG if not already done. 
Continuing study treatment should be done in 
consultation with a cardiologist. Manage per standard 
of care. 
Other cardiovascular events 
- 
Mild 
Recommendation: Maintain Dose  
Moderate  
Recommendation: Hold dose until resolved to mild 
Severe 
Recommendation: Hold the study drug and 
continuation of study treatment should be done in 
consultation with a cardiologist. Manage per standard 
of care 
Gastro intestinal 
Diarrhea 
Mild (Increase of <4 stools per day over baseline) 
Recommendation: May maintain dose 
Moderate (Increase of 4 - 6 stools per day over 
baseline) 
Recommendation: Hold the study drug until resolved 
to mild, then maintain dose 
If diarrhea returns as moderate to severe, then hold 
the study drug until resolved to mild. Manage per 
standard of care. Use clinical judgement before 
resuming study drug. 


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Severe (Increase of ≥7 stools per day over baseline) 
Recommendation: Hold the study drug until resolved 
to mild 
Mandatory: In case of life-threatening consequences; 
urgent intervention indicated. Permanently 
discontinue study drug immediately. Manage per 
standard of care. 
Investigation (metabolic) 
Amylase and/or lipase elevation 
Mild (> ULN - 1.5 x ULN) 
Recommendation: May maintain dose and monitor 
prior to next dose 
Moderate (> 1.5 - 2.0 x ULN) 
Recommendation: May maintain dose and monitor 
prior to next dose 
Severe (> 2.0 x ULN) 
A reflex amylase fractionation test is recommended. 
An exception to the recommendation on study drug 
will be made for cases of isolated amylase elevations 
in which amylase fractionation demonstrates that 
pancreatic amylase (isoenzymes) elevations are mild 
or normal 
Recommendation: Hold the study drug until resolved 
to mild or baseline (monitor prior to next dose), test 
weekly until resolution to mild/baseline. 
• 
If resolved in ≤7 days, then maintain dose 
• 
If not resolved in >7 days, then may consider 
permanent discontinuation at Investigator's discretion 
or if resolved > 7 days to mild/baseline consider every 
other week dosing after discussion with Novartis 
Mandatory: If >5.0x ULN and symptomatic hold the 
study drug and permanently discontinue. Manage per 
standard of care. 
Testicular 
 - 
Testicular atrophy 
Recommendation: If FSH level doubles from 
baseline and absolute value is above 5 IU/L then 
consult endocrinologist. Use clinical judgment for 
continuation of study drug; discuss with participant. 
Neurologic Findings 
Neurologic Findings suggestive of peripheral 
neuropathy 
Recommendation: Consider withholding study drug 
under the following conditions: 
• 
Any clinically significant neurologic finding on the 
comprehensive neurologic exam with or without a 
positive response on neurology questionnaire. 
The following should be actioned:  
• 
Perform Compound Motor Action Potential 
(CMAP)/ Sensory Nerve Action Potential 
(SNAP) 
Follow-up as per Investigators judgement 
• 
In case of inconclusive CMAP or SNAP results, 
Investigator may use clinical judgement regarding 
discontinuation or withholding study drug 
Mandatory: Discontinue study drug immediately and 
permanently under the following conditions: 
• 
Any clinically significant abnormality in the 
comprehensive neurology exam and CMAP or 
SNAP. Continue to follow patient (to resolution). 
Refer to Section 8.4.4 
Ophthalmological Findings 
 - 
Retinal Atrophy 
Recommendation: Any new retinal findings from 
baseline which in the opinion of the Investigator is 
related to the study drug, discontinue the study drug 
permanently. Manage as per standard of care. 


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Refer to Appendix 1 (Table 16-1 and Table 16-2) for guidance on hepatic events and  
Appendix 2 (Table 16-3 and Table 16-4) for guidance on renal events. 
This guidance does not provide an exhaustive list of AEs and Investigators should use their 
clinical judgement when assessing dose interruption for those AEs not mentioned in the table. 
Participants whose study treatment is temporarily interrupted or permanently discontinued due 
to an AE or abnormal laboratory value must be followed until resolution or stabilization of the 
event, whichever comes first, including all study assessments appropriate to monitor the event 
as described in this section. In the event study treatment has been temporarily interrupted  
(> 7 days) due to an AE or laboratory abnormality not listed in Table 6-3, study treatment may 
be re-challenged to an every other week dosing after discussing with the Novartis. 
6.5.2.1 
Dose adjustments for QTcF prolongation 
As dose adjustments are not allowed, this section describes criteria for participant treatment 
interruption and permanent treatment discontinuation in case of QTcF prolongation. The 
Investigator should discontinue study treatment for a given participant if, on balance, he/she is 
of the opinion that continuation is not in the best interest of the participant or would be 
detrimental to the participant's well-being. 
Clinically significant results or safety assessments that might put the participant at risk, 
including, but not limited to: 
• Absolute QTcF >500 msec, confirmed by repeat ECG measurements 
• Resting heart rate <30 or >120 bpm 
• QRS >120 msec and increase >25% from Baseline  
• Sustained ventricular tachycardia lasting 30 sec or more, ventricular fibrillation, or any 
hemodynamically compromising cardiac arrhythmia 
• New complete heart block (Grade III AV block) or second-degree AV block Mobitz type II 
In case of QTcF >500 msec (or QTcF prolongation >60 msec from baseline) 
• Assess the quality of the ECG recording and the QT value and repeat if needed 
• Interrupt study treatment 
• Determine the serum electrolyte levels (in particular hypokalemia and hypomagnesemia). 
If abnormal, correct abnormalities before resuming study treatment. 
• Review concomitant medication use for other causes for QT prolongation and for drugs 
with the potential to increase the risk of drug exposure related QT prolongation 
• Check the dosing schedule and treatment compliance 
• Consider collecting a time-matched PK sample and record time and date of last study 
treatment intake.  
After confirming ECG reading at site, if QTcF >500 msec 
• Interrupt study treatment 
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed >500 msec:  


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• Correct electrolytes, eliminate culprit concomitant treatments, and identify clinical 
conditions that could potentially prolong the QT as per the ECG and QTc Clinical 
Safety Standards Guidelines 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring twice weekly until normalization or stabilization of the 
ECG findings, until the QTcF returns to ≤480 msec 
• After resolution to ≤480 msec, consider permanent discontinuation of study drug treatment 
6.6 
Additional treatment guidance 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment has been 
permanently discontinued, therefore this section is no longer applicable. 
6.6.1 
Treatment compliance 
All doses of study treatment administration, including the weekly dosing not reflected on the 
visit assessment schedule (Table 8-2, Table 8-3 and Table 8-4), will be recorded on the 
appropriate Dosage Administration Record eCRF page. Compliance will be assessed by the 
Investigator and/or study personnel at each visit using empty medication packaging, and any 
other information provided by the participant. This information should be captured in the source 
document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log. Compliance will also be assessed and confirmed by a field monitor by drug 
accountability logs, by documentation and information provided by IRT and by the qualified 
site personnel that is responsible for treatment dispensation, administration and accountability. 
Cross-checks should be performed for home administrations and empty medication outer 
packing should be collected for compliance checks by field monitors. Site staff will review 
compliance with the participant at each visit including, if applicable, compliance with home 
administration of study treatment through weekly telephone contacts. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with branaplam, as detailed in the PK section (Section 8.5.2). 
6.6.2 
Recommended treatment of adverse events 
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs). Treatment of AEs should be according to the judgement of 
the Investigator and in accordance to local guidance. 
Medication used to treat AEs must be recorded on the appropriate eCRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks by site during the Core Period must only be undertaken when it is 
required in order to treat the participant safely. Most often, study treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study participant who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IRT. When the Investigator contacts the system to break a treatment code for a participant, 
he/she must provide the requested participant identifying information and confirm the necessity 
to break the treatment code for the participant. The Investigator will then receive details of the 


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investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide: 
• protocol number 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Participants requiring an emergency code break during the Core period should be discontinued 
from further study participation. 
6.7 
Preparation and dispensation 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment has been 
permanently discontinued, therefore this section is no longer applicable. 
The investigational drug, branaplam, and its matching placebo, identical in appearance, will be 
supplied to the site by Novartis. A unique medication number is printed on the study medication 
label. Each study site will be supplied with study drug in packaging as described under 
investigational and control drugs in Section 6.1.1. 
Investigator and/or designated site personnel will identify the study medication kits to dispense 
to the participant by contacting the IRT and obtaining the medication number(s). 
The study medication can be administered to the participant on site, or can be taken home for 
self-administration or administration with support from a home nurse or companion/care giver 
if needed (if allowed by Local or Regional Health Authorities and Ethics Committees as 
appropriate). If the study medication is taken home, the site will make necessary arrangements 
to supply the medication to the participant. 
Further details on the storage and management of study medication, instructions for dispensing 
and administering, and the return of study treatment to the site are outlined in the Instructions 
For Use. 
As per Section 4.6, 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. Delivery of 
Investigational Medicinal Product (IMP) directly to the participant's home may be permitted (if 
allowed by Local or Regional Health Authorities and Ethics Committees as appropriate). The 
dispatch of IMP from the site to the participant's home remains under the accountability of the 
Investigator, and is described in the Instructions For Use. 


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6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by monitors during site visits or remotely and at the completion of the trial. 
Participants will be asked to return all unused study treatment and packaging at the end of the 
study or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the Investigator 
folder at each site. 
6.7.1.2 
Handling of additional treatment 
No additional treatment beyond investigational drug and PBO control are included in this trial. 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Each study site will be supplied with study drug and matching placebo as described under 
the Section 6.1.1 (Investigational and control drugs). 
Participants should take the study treatment as instructed by the study staff. Study treatment 
may be administered to participants during site visits or on an outpatient basis (at the 
participant’s home) with support from a home nurse or companion/care giver if needed. 
Detailed instructions on drug preparation are included in the separate Instructions For Use. 
• Day 1 is defined as the first day where study treatment is administered to the participant 
• All participants should take study treatment once a week at the same day of the week and 
approximately the same time each day in the morning.  
• The window for study drug administration is ±1 days from the scheduled weekly dosing 
(with the exception of Day 1) 
• On days that PK samples are obtained, the participant will take study treatment during the 
site visit after the pre-dose PK samples and prior to post-dose PK samples, when instructed 
by the study staff. 


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• Participants should take study treatment on an empty stomach (i.e. fast from food and drink, 
except water) at least 1 hour before and 2 hours after taking the study treatment. Study 
medication can be taken with a glass of water. Entire dose should be taken within 5 minutes. 
• Participants should be instructed to drink the whole volume (in mL) of study drug according 
to the following table. 
Table 6-4 
Treatment Dose and Regimen Schedule 
Treatment Arm 
Investigational / Control 
Drug 
(Name and Strength) 
Dose and Regimen 
Volume 
 A 
branaplam 17.5 mg/5 mL 
or matching placebo 
56 mg weekly 
16 mL weekly 
 B 
branaplam 17.5 mg/5 mL 
or matching placebo 
112 mg weekly 
32 mL weekly 
C 
branaplam 17.5 mg/5 mL 
or matching placebo 
154 mg weekly 
44 mL weekly 
X 
branaplam 17.5 mg/5mL 
or matching placebo 
84 mg weekly 
24 mL weekly 
Y 
branaplam 17.5 mg/5mL 
or matching placebo 
28 mg weekly 
8 mL weekly 
• If vomiting occurs during the administration, or shortly thereafter, no re-dosing of the 
participant is allowed before the next scheduled dose. 
• Participants should be instructed not to make up missed doses (i.e. when the entire dose is 
not taken as instructed). A missed dose will be defined as a case when the full dose is not 
taken within 24 hours after the approximate time of the usually weekly dosing. That week’s 
dose should be omitted and the participant should continue treatment with the next 
scheduled dose on the following week. 
6.7.2.1 
Additional considerations for PK sampling 
• On days on which PK samples are obtained (refer to Section 16.3, PK Sample Log), the 
participant should wait until after the pre-dose PK sample is collected to take the assigned 
study medication. (The pre-dose PK sample represents the Ctrough concentration and, 
therefore, the last dose of branaplam should be 168 h (weekly dose regimen) before the pre-
dose PK sample.)  
• For the PK samples that are to be collected post dose, (refer to Section 16.3, PK Sample 
Log), the time of administration is defined as time 0 h; any post dose samples are to be taken 
as noted as per the visit assessment schedule (Table 8-2, Table 8-3 and  
Table 8-4) and Section 16.3. Actual time of samples must be recorded in the eCRF.  
• Day 1 - Study participants should avoid any food intake within at least 4 h prior to pre-dose 
triplicate BP, pulse and ECG assessments/PK sampling on the day of first study drug 
administration. Breakfast/snack can be served after dose administration. Food intake should 
further be avoided within at least 4 h prior to the triplicate ECG assessments/PK sampling 
at 12 hours post dose. 
• Week 9 (+/- 1 week) - Food intake should be avoided within at least 4 h prior to the pre-
dose triplicate BP, pulse and ECG assessments/PK sampling on week 9 (+/- 1 week) 


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(breakfast/snack should be served after dose administration). Food intake should further be 
avoided within at least 4 h prior to the triplicate ECG assessments/PK sampling at 12 hours 
post dose. 
• If the participant has skipped the dose the week prior to the scheduled lumbar puncture, 
guidance will be provided to the Investigator to clarify which biomarker/pk samples may 
be deferred to ensure alignment with the planned lumbar puncture. See also Section 8.5.4.1. 
7 
Informed consent procedures 
Per the USM follow-up notification dated 06-Dec-2022, sites are required to update and 
submit for approval an addendum to the Informed Consent that takes into account the 
changes described in this protocol amendment. 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative and answer all questions 
regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of FDA 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 90 days from the previous ICF signature date unless otherwise indicated per local 
regulations. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
(e.g. collected as per protocol as described in the visit evaluation schedule) for optional 
additional research (e.g. research beyond what is described in the study protocol). The 
Investigator or authorized designee will explain to each participant the objectives of the 
additional research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant’s agreement to allow any remaining 
specimens to be used for additional research. Participants who decline to participate in this 
optional additional research will document this.  
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation) Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved informed consent.  




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8 
Visit schedule and assessments 
As per the USM, participants were to continue with their original VES up to and including 
Week 29. A new VES was created for Weeks 33, 53 and 69 (see Table 8-5). 
The assessment schedule (Table 8-2, Table 8-3 and Table 8-4) lists all of the assessments and 
when they are performed. All data obtained from these assessments must be supported in the 
participant’s source documentation, as appropriate. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule or 
as close to the designated day/time as possible. Refer to Table 8-1 for allowable visit windows. 
Missed or rescheduled visits should not lead to automatic discontinuation. 
If the end of the Blinded Extension has not been triggered by the time participants reach week 
53 (i.e., because the results of the DRF are not available), the BE will continue beyond week 
53. Participants beyond Week 53 will remain on the assigned dose until the End of Blinded 
Extension is triggered. Refer to Table 8-3. 
The Baseline visit in the OLE is equivalent to the End of Treatment (EOT)-Blinded Extension 
visit for participants who are still ongoing at the time the End of the BE is declared. Investigators 
will be notified ahead of time in preparation for transition to OLE. Since the duration of the BE 
may be different for individual participants, and in order to minimize participant burden, 
guidance will be provided to Investigators to clarify what BE assessments may be deferred at 
the final regular BE visit to ensure that they are performed only once as part of the OLE baseline 
visit, such as LP and MRI. 
If the COVID-19 or similar pandemic limits or prevents on-site study visits, alternative methods 
of providing continuing care may be implemented. Phone calls, virtual contacts  
(e.g. teleconsult) or visits by site staff/home nursing service to the participant´s home depending 
on local regulations and capabilities, may replace on-site study visits, for the duration of the 
pandemic until it is safe for the participant to visit the site again. If the Investigator delegates 
tasks to an off-site healthcare professional, the Investigator must ensure the individual(s) is/are 
qualified and appropriately trained to perform assigned duties. The Investigator must oversee 
their conduct and remain responsible for the evaluation of the data collected. 
If such situation emerges, the Investigator should consult the Novartis to evaluate the suitability 
of remote options and the potential impact on study outcomes. 
All visits are to be scheduled according to the appropriate number of calendar days from Day 1 
of study drug administration, and not from the previous visit date. 
Table 8-1 
Allowable Visit Windows 
Post-USM visits are +/- 2 weeks. The below visit windows are no longer applicable. 
Visit Name 
Window 
DRF visits  
± 1 day 
Blinded Extension visits 
± 1week 
Open Label Extension visits 
± 1 week 
Imaging (MRI) for all visits excluding Baseline* 
± 7 days 


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Visit Name 
Window 
Study drug administration for all weekly dosing 
(excluding Day 1)** 
± 1 day 
*allowable visit window for Baseline visit is Day -14 to -3 
** If study drug administration is adjusted to ± 1 day for any given Scheduled visit, all associated PK and 
biomarker samples for that visit should be adjusted accordingly using the same window. 
 


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Table 8-2 
Assessment Schedule, Part 1 - Core (DRF and BE) 
Period 
Screening 
Baseline 
Dose Range Finding 
Visit Name 
Screening 
Baseline 
Wk 1 
Wk 2 Wk 3 Wk 5 Wk 9 
Wk 
13 
Wk 171 
Days 
-42 to -7 
-6 to -1 
1 to 7 
8 
15 
29 
57 
85 
113 to 116 
Weeks 
-6 to -1 
-1 
1 
2 
3 
5 
9 
13 
17 
Time (post-dose) 
- 
- 
0h 
4h 
7h 
12h2 22h 
72h 
- 
- 
- 
0h 
4h 
12h2 22h 
- 
0h 
4h 
7h 
12h2 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pharmacogenetic 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History of Huntington's 
Disease 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Smoking and Alcohol 
history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CAG repeat length 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HIV and Hepatitis screen X3 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Examination4,5 
S3 
S 
S 
  
  
  
  
  
S 
S 
S 
S 
  
  
  
S 
S 
  
  
  
Neurological Examination X3 
X 
X 
  
  
  
  
  
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Body Height6 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight7 
X 
X 
X 
  
  
  
  
  
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Vital Signs 
X 
X 
X8 
X8 
  
  
  
  
X 
X 
X 
X8 
X8 
  
  
X 
X 
  
  
  
Electrocardiogram (ECG) X 
X 
X9 
X  
  
X9 
  
  
X 
X 
X 
X9 
X  
X9 
  
X 
X 
  
  
  
Hematology 
X3 
X 
  
  
  
  
  
X 
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Clinical Chemistry 
X3 
X 
  
  
  
  
  
X 
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Thyroid Function 
X 
X 
  
  
  
  
  
 
  
  
  
X 
  
  
  
  
X 
  
  
  


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Protocol No. CLMI070C12203 
 
Period 
Screening 
Baseline 
Dose Range Finding 
Visit Name 
Screening 
Baseline 
Wk 1 
Wk 2 Wk 3 Wk 5 Wk 9 
Wk 
13 
Wk 171 
Days 
-42 to -7 
-6 to -1 
1 to 7 
8 
15 
29 
57 
85 
113 to 116 
Weeks 
-6 to -1 
-1 
1 
2 
3 
5 
9 
13 
17 
Time (post-dose) 
- 
- 
0h 
4h 
7h 
12h2 22h 
72h 
- 
- 
- 
0h 
4h 
12h2 22h 
- 
0h 
4h 
7h 
12h2 
HbA1c 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
NTproBNP, Troponin 
X 
X 
  
  
  
  
  
X  
X  
  
X 
 X 
  
  
  
X 
X  
  
  
  
Coagulation Panel 
X3 
X 
  
  
  
  
  
X 
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Follicle stimulating 
hormone - FSH10 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Serum Bile Acid11 
  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
Pregnancy Test - Serum X 
X 
  
  
  
  
  
  
  
  
X 
X 
  
  
  
X 
X 
  
  
  
Pregnancy Test (urine)12   
  
X 
  
  
  
  
  
X 
X 
  
  
  
  
  
  
  
  
  
  
Urinalysis13 
X3 
X 
  
  
  
  
  
X 
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Fasting glucose 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Columbia-Suicide 
Severity Rating Scale (C-
SSRS) 
X3 
X 
  
  
  
  
  
  
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Serum Biomarkers (NfL 
and others)14,21 
X 
X 
  
  
  
  
  
  
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Echocardiogram15 
X 
  
  
  
  
  
  
  
  
  
 X 
  
  
  
  
X 
  
  
  
  
Nerve Conduction 
Studies (tibial nerve 
CMAP/sural nerve 
SNAP) 
X 
  
Only performed if positive findings on neurologic exam or per Investigator judgement 
Ophthalmologic 
examination16 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Brain MRI17,18 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  


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Protocol No. CLMI070C12203 
 
Period 
Screening 
Baseline 
Dose Range Finding 
Visit Name 
Screening 
Baseline 
Wk 1 
Wk 2 Wk 3 Wk 5 Wk 9 
Wk 
13 
Wk 171 
Days 
-42 to -7 
-6 to -1 
1 to 7 
8 
15 
29 
57 
85 
113 to 116 
Weeks 
-6 to -1 
-1 
1 
2 
3 
5 
9 
13 
17 
Time (post-dose) 
- 
- 
0h 
4h 
7h 
12h2 22h 
72h 
- 
- 
- 
0h 
4h 
12h2 22h 
- 
0h 
4h 
7h 
12h2 
UHDRS - TFC, TMS, IS, 
17 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
Plasma (mHTT/total 
HTT)20 
  
X22 
X21 
  
  
  
X 
X 
X21 
X21 
X21 
X21 
  
  
X 
X21 
X21 
  
  
  
PK blood collection 
  
  
X21,9 X 
X 
X9 
X 
X 
X21 
X21 
X21 
X21,9 X 
X9 
X 
X21 
X21 
X 
X 
X 
mRNA20 
  
X22 
X21 
X 
X 
  
X 
X 
X21 
X21  
X21  
X21 
 
  
 X 
 X21 
X21 
X 
X 
  
Lumbar puncture (
 
 NfL, 
)21 
  
  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
Lumbar puncture - PK21 
  
  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Protocol No. CLMI070C12203 
 
Period 
Screening 
Baseline 
Dose Range Finding 
Visit Name 
Screening 
Baseline 
Wk 1 
Wk 2 Wk 3 Wk 5 Wk 9 
Wk 
13 
Wk 171 
Days 
-42 to -7 
-6 to -1 
1 to 7 
8 
15 
29 
57 
85 
113 to 116 
Weeks 
-6 to -1 
-1 
1 
2 
3 
5 
9 
13 
17 
Time (post-dose) 
- 
- 
0h 
4h 
7h 
12h2 22h 
72h 
- 
- 
- 
0h 
4h 
12h2 22h 
- 
0h 
4h 
7h 
12h2 
Period 
completion/disposition 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug dispensation23 
  
  
X 
  
  
  
  
  
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Drug administration 
record24 
  
  
X 
  
  
  
  
  
X 
X 
X 
X 
  
  
  
X 
X 
  
  
  
Prior and concomitant 
medications 
X 
X 
  
  
  
  
  
  
Update as necessary 
Serious Adverse 
Events25 
X 
X 
X 
  
  
  
  
  
Update as necessary 
Adverse Events25 
X 
X 
X 
  
  
  
  
  
Update as necessary 
 
Period 
Dose Range Finding 
Blinded Extension 
Visit Name 
Wk 171 
Wk 21 
Wk 25 
Wk 29 
Wk 33 
Wk 37 
Wk 41 
Wk 45 
Wk 49 
Wk 53 - EOT 
Blinded26,27, 28 
Days 
113 to 116 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Weeks 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Time (post-dose) 
22h 
72h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Informed consent 
  
  
  
  
  
  
  
  
  
  
  
Pharmacogenetic Informed Consent   
  
  
  
  
  
  
  
  
  
  
Demography 
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
  
  
  
  
  
  
  
  
  
  
  


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Protocol No. CLMI070C12203 
 
Period 
Dose Range Finding 
Blinded Extension 
Visit Name 
Wk 171 
Wk 21 
Wk 25 
Wk 29 
Wk 33 
Wk 37 
Wk 41 
Wk 45 
Wk 49 
Wk 53 - EOT 
Blinded26,27, 28 
Days 
113 to 116 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Weeks 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Time (post-dose) 
22h 
72h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history/current medical 
conditions 
  
  
  
  
  
  
  
  
  
  
  
History of Huntington's Disease 
  
  
  
  
  
  
  
  
  
  
  
Smoking and Alcohol history 
  
  
  
  
  
  
  
  
  
  
  
CAG repeat length 
  
  
  
  
  
  
  
  
  
  
  
HIV and Hepatitis screen 
  
  
  
  
  
  
  
  
  
  
  
Physical Examination4,5 
  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
Neurological Examination 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Height6 
  
  
  
  
  
  
  
  
  
  
  
Body Weight7 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG) 
  
  
X 
X 
X 
X 
X 
X 
X 
X26 
X 
Hematology 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid Function 
  
  
  
X 
  
X 
  
X 
  
X 
X 
HbA1c 
  
  
  
  
  
  
  
  
  
  
  
NTproBNP, Troponin 
  
  
 X 
X 
X  
X 
X 
X 
X 
X 
X 
Coagulation Panel 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follicle stimulating hormone - FSH10   
  
  
X 
  
  
X 
  
  
  
X 
Serum Bile Acid11 
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Test - Serum 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (urine)12 
  
  
  
  
  
  
  
  
  
  
  
Urinalysis13 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting glucose 
  
  
  
  
  
  
  
  
  
  
  


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Protocol No. CLMI070C12203 
 
Period 
Dose Range Finding 
Blinded Extension 
Visit Name 
Wk 171 
Wk 21 
Wk 25 
Wk 29 
Wk 33 
Wk 37 
Wk 41 
Wk 45 
Wk 49 
Wk 53 - EOT 
Blinded26,27, 28 
Days 
113 to 116 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Weeks 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Time (post-dose) 
22h 
72h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Biomarkers (NfL and 
others)14, 21 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram15 
  
  
 X 
 
X  
  
X 
  
 X 
  
X 
Nerve Conduction Studies (tibial 
nerve CMAP/sural nerve SNAP) 
Only performed if positive findings on neurologic exam or per Investigator judgement 
Ophthalmologic examination16 
  
  
  
  
  
  
X 
  
  
  
X 
Brain MRI17,18 
  
  
  
  
  
X 
  
  
  
  
X 
UHDRS - TFC, TMS, IS, 
17 
  
  
  
  
  
X 
  
  
  
  
X 
Plasma (mHTT/total HTT)20 
X 
X 
  
X21 
  
X21 
  
X21 
  
  
X21 
PK blood collection 
X 
X 
  
X21 
  
X21 
  
X21 
  
  
X21 


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Protocol No. CLMI070C12203 
 
Period 
Dose Range Finding 
Blinded Extension 
Visit Name 
Wk 171 
Wk 21 
Wk 25 
Wk 29 
Wk 33 
Wk 37 
Wk 41 
Wk 45 
Wk 49 
Wk 53 - EOT 
Blinded26,27, 28 
Days 
113 to 116 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Weeks 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Time (post-dose) 
22h 
72h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
mRNA20 
X 
X 
  
X21 
  
X21 
  
X21 
  
  
X21 
Lumbar puncture (
 
NfL
)21 
  
  
  
  
  
X 
  
  
  
  
X 
Lumbar puncture - PK21 
  
  
  
  
  
X 
  
  
  
  
X 
Randomization 
  
  
  
  
  
  
  
  
  
  
  
Period completion/disposition 
  
  
  
  
  
  
  
  
  
  
  
Drug dispensation23 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug administration record24 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
Update as necessary 
Serious Adverse Events25 
Update as necessary 
Adverse Events25 
Update as necessary 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Week 17 is the last visit within the dose range finding part of the study. Therefore, a full 16 weeks of treatment data are captured. 
2 For patients staying overnight at site/hospital 
3 If required, assessment may be repeated during the initial screening phase 
4 Findings must be recorded on the appropriate Medical History or Adverse Events eCRF 
5 A complete physical exam is done at screening and baseline  
6 Only at Screening 
7 In indoor clothing, but without shoes 
8 Triplicate blood pressures - 1) pre-dose after 10 minutes supine rest and 2) repeated in the same manner after 4 hours post dose  
9 After 4 hours of fasting and 10 minutes supine rest 10 Male patients only 
11 Participants must be fasting 
12 Urine dipstick for pregnancy performed at site. Positive urine dipstick result must be confirmed with a central laboratory serum pregnancy test. Refer to Section 8.4.3 


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Protocol No. CLMI070C12203 
 
Period 
Dose Range Finding 
Blinded Extension 
Visit Name 
Wk 171 
Wk 21 
Wk 25 
Wk 29 
Wk 33 
Wk 37 
Wk 41 
Wk 45 
Wk 49 
Wk 53 - EOT 
Blinded26,27, 28 
Days 
113 to 116 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Weeks 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Time (post-dose) 
22h 
72h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
13 Urine dipstick done at site; if findings then send urine to central lab for microanalysis 
14 Serum Biomarkers, including NFL. See Biomarkers Assessments in Blood and CSF, Section 8.5.3 
15 Echocardiogram with GLS 
16 Indirect with scleral indentation (if necessary) and Direct ophthalmoscopy  
17 To minimize burden to patients, it is recommended that Post-baseline MRI and UHDRS assessments are done up to 1 day prior to the planned study drug dosing 
date at any given visit. If done same day as Lumbar Puncture, MRI and UHDRS should be done first. 
18 Patients should not be randomized and receive study drug treatment until the baseline MRI scan has passed QC at central vendor 
20 For visits where samples are collected only once a day, they must always be collected at approximately the same time of the day 
21 Pre-dose 
22 The baseline sample may be collected at any time during Day -6 to -1. This sample is different from the 0 hr pre-dose sample to be collected before the first dose of 
study drug on Day 1 
23 IRT call and drug preparation by site personnel 
24 Weekly dosing, not reflected on the VES, should be confirmed with weekly telephone calls to the participant and will be collected on the eCRF. 
25 Adverse Events and Serious Adverse Events are collected after the Informed Consent Form is signed by the participant 
26 Participants beyond Week 53 in the Blinded Extension will follow visit structure as per Table 8-3 remain on the assigned dose until End of Blinded Extension is 
triggered. 
27 If a participant prematurely discontinues study treatment before or at Week 17 visit during the DRF period (for reasons other than withdrawal of consent), all 
assessments corresponding to all visits during the DRF period should still be completed up to and including Week 17 as described in the VES. If a participant 
prematurely discontinues study treatment during the blinded extension after the Week 17 visit during the Core period (for reasons other than withdrawal of consent) and 
therefore does not continue in the OLE, all assessments as described under the EOT/Week53 visit in the VES should be completed during the last visit. Participants that 
prematurely discontinue blinded study treatment during the Core period and do not continue in the OLE study period must be followed up for safety for 30 days after the 
last dose of blinded study drug is administered. 
28 Participants who discontinue study treatment should be scheduled for an EOT Blinded visit at which time all of the assessments listed for the EOT Blinded visit will be 
performed.  
 


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Table 8-3 
Assessment Schedule, Part 2 - BE beyond 53 weeks  
Period 
Blinded Extension Beyond 53 Weeks 
Visit Name 
Wk 57 
Wk 61 
Wk 65 
Wk 69 
Wk 73 
Wk 77 
Wk 81 
Wk 85 
Wk 89 
Wk 93 
Wk 97 
Wk 101 
Days 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
701 
Weeks 
57 
61 
65 
69 
73 
77 
81 
85 
89 
93 
97 
101 
Physical Examination1 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Neurological Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid Function 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
NTproBNP, Troponin 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follicle stimulating hormone - FSH3 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test - Serum 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram4 
  
X  
 
  
X  
 
  
 X 
 
  
X  
X 
Nerve Conduction Studies (tibial 
nerve CMAP/sural nerve SNAP) 
Only performed if positive findings on neurologic exam or per Investigator judgement 
Ophthalmologic examination5 
  
  
  
  
  
X 
  
  
  
  
  
X 
Brain MRI6 
  
  
  
X 
  
  
  
X 
  
  
  
X 
UHDRS - TFC, TMS, IS, 
  
  
  
X 
  
  
  
X 
  
  
  
X 


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Period 
Blinded Extension Beyond 53 Weeks 
Visit Name 
Wk 57 
Wk 61 
Wk 65 
Wk 69 
Wk 73 
Wk 77 
Wk 81 
Wk 85 
Wk 89 
Wk 93 
Wk 97 
Wk 101 
Days 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
701 
Weeks 
57 
61 
65 
69 
73 
77 
81 
85 
89 
93 
97 
101 
Serum Biomarkers (NfL and 
others)7, 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood collection11 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
mRNA8, 11 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Lumbar puncture (
NfL, 
)11 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Lumbar puncture – PK11 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Drug dispensation9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug administration record10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
Update as necessary 
Adverse Events 
Update as necessary 
Serious Adverse Events 
Update as necessary 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Findings must be recorded on the appropriate Medical History or Adverse Events eCRF 
2 In indoor clothing, but without shoes 


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Period 
Blinded Extension Beyond 53 Weeks 
Visit Name 
Wk 57 
Wk 61 
Wk 65 
Wk 69 
Wk 73 
Wk 77 
Wk 81 
Wk 85 
Wk 89 
Wk 93 
Wk 97 
Wk 101 
Days 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
701 
Weeks 
57 
61 
65 
69 
73 
77 
81 
85 
89 
93 
97 
101 
3 Male patients only 
4 Echocardiogram with GLS 
5 Indirect with indentation (if necessary) and direct ophthalmoscopy  
6 To minimize burden to patients, it is recommended that Post-baseline MRI and UHDRS assessments are done up to 1 day prior to the planned study drug dosing date 
at any given visit. If done same day as Lumbar Puncture, MRI and UHDRS should be done first. 
7 Serum Biomarkers, including NFL. See Biomarkers Assessments in Blood and CSF, Section 8.5.3 
8 For visits where samples are collected only once a day, they must always be collected at approximately the same time of the day 
9 IRT call and drug preparation by site personnel 
10 Weekly dosing, not reflected on the VES, should be confirmed with weekly telephone calls to the participant and will be collected on the eCRF 
 
Table 8-4 
Assessment Schedule, Part 3 - Open Label Extension  
Period 
Open Label Extension 
Visit Name 
Baseline-Ext1 Wk 5-
Ext 
Wk 9-
Ext 
Wk 13-
Ext 
Wk 17-
Ext 
Wk 21-
Ext 
Wk 25-
Ext 
Wk 29-
Ext 
Wk 33-
Ext 
Wk 37-
Ext 
Wk 41-
Ext 
Wk 45-
Ext 
Wk 49-
Ext 
EOT 
open-
label2 
EOS 
Days 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
999 
Weeks 
1 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
143 
Physical Examination3 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
Neurological Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Body Weight 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Electrocardiogram (ECG) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Thyroid Function 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
  
NTproBNP, Troponin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  


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Period 
Open Label Extension 
Visit Name 
Baseline-Ext1 Wk 5-
Ext 
Wk 9-
Ext 
Wk 13-
Ext 
Wk 17-
Ext 
Wk 21-
Ext 
Wk 25-
Ext 
Wk 29-
Ext 
Wk 33-
Ext 
Wk 37-
Ext 
Wk 41-
Ext 
Wk 45-
Ext 
Wk 49-
Ext 
EOT 
open-
label2 
EOS 
Days 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
999 
Weeks 
1 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
143 
Coagulation Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Follicle stimulating hormone 
- FSH4 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
X 
  
Pregnancy Test - Serum5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Echocardiogram7 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
X 
  
Nerve Conduction Studies 
(tibial nerve CMAP/sural 
nerve SNAP) 
Only performed in case of positive findings on neurologic exam or per Investigator judgement 
  
Ophthalmologic examination X 
  
  
  
  
  
X 
  
  
  
  
  
  
X 
  
Brain MRI15 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
X 
  
UHDRS - TFC, TMS, IS, 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
X 
  


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Period 
Open Label Extension 
Visit Name 
Baseline-Ext1 Wk 5-
Ext 
Wk 9-
Ext 
Wk 13-
Ext 
Wk 17-
Ext 
Wk 21-
Ext 
Wk 25-
Ext 
Wk 29-
Ext 
Wk 33-
Ext 
Wk 37-
Ext 
Wk 41-
Ext 
Wk 45-
Ext 
Wk 49-
Ext 
EOT 
open-
label2 
EOS 
Days 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
999 
Weeks 
1 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
143 
Plasma (mHTT/total HTT)8, 10 X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Serum Biomarkers (NfL and 
others)9, 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
PK blood collection10 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
mRNA8, 10 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Lumbar puncture (
 NfL
)10 X 
  
  
  
X 
  
  
  
X 
  
  
  
  
X 
  
Lumbar puncture - PK10 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
X 
  
Randomization11 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study completion information   
  
  
  
  
  
  
  
  
  
X 
  
  
X 
  
Drug dispensation12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Drug administration record13 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Prior and concomitant 
medications14 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serious Adverse Events14 
X 
Update as necessary 
  
Adverse Events14 
X 
Update as necessary 
  
End of Study Disposition 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 The Baseline visit in the OLE is equivalent to the EOT-Blinded Extension visit for participants who are still ongoing at the time the End of the Blinded Extension is 
declared. Investigators will be notified ahead of time in preparation for transition to OLE. Since the duration of the BE may be different for individual participants, and in 
order to minimize participant burden, guidance will be provided to Investigators to clarify which BE assessments may be deferred at the final regular BE visit to ensure 


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Period 
Open Label Extension 
Visit Name 
Baseline-Ext1 Wk 5-
Ext 
Wk 9-
Ext 
Wk 13-
Ext 
Wk 17-
Ext 
Wk 21-
Ext 
Wk 25-
Ext 
Wk 29-
Ext 
Wk 33-
Ext 
Wk 37-
Ext 
Wk 41-
Ext 
Wk 45-
Ext 
Wk 49-
Ext 
EOT 
open-
label2 
EOS 
Days 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
999 
Weeks 
1 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
143 
that they are performed only once as part of the OLE baseline visit, such as LP and MRI.  
2 Participants who discontinue study treatment should be scheduled for an EOT Open-label visit at which time all of the assessments listed for the EOT open-label visit 
will be performed. A 30-day safety follow up period after the last open label study treatment dose was taken must be observed. 
3 Findings must be recorded on the appropriate Adverse Events eCRF 
4 Male patients only 
5 Serum pregnancy test is collected as part of the blood chemistry. Refer to Section 8.4.3 for positive result follow up action 
6 Urine dipstick done at site; if findings then send urine to central lab for microanalysis 
7 Echocardiogram with GLS 
8 For visits where samples are collected only once a day, they must always be collected at approximately the same time of the day 
9 Serum Biomarkers, including NFL. See Biomarkers Assessments in Blood and CSF, Section 8.5.3 
10 Pre-dose 
11 Randomization will be done if there is more than one dose chosen 
12 IRT call and drug preparation by site personnel 
13 Weekly dosing, not reflected on the VES, should be confirmed with weekly telephone calls to the participant and will be collected on the eCRF. 
14 Update as necessary 
15 To minimize burden to patients, it is recommended that Post-baseline MRI and UHDRS assessments are done up to 1 day prior to the planned study drug dosing date 
at any given visit. If done same day as Lumbar Puncture, MRI and UHDRS should be done first 
The table below (see Table 8-5) reflects the changes in the USM follow-up notification dated 06-Dec-2022.  
Participants randomized to placebo do not require additional safety assessments and can be discontinued from the study at the Week 
33 visit or immediately if this visit was already completed. The End of Treatment and End of Study (EOS) dispositions can be declared. 
Participants that had already permanently discontinued study treatment and had scheduled an EOT and/or follow up assessments at 
the time of the USM follow-up notification dated 06-Dec-2022 should have follow up (FU) assessments as closely as possible to 
Assessment Table 8-5.  


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Table 8-5 
Assessment Schedule Urgent Safety Measure 
Period 
Revised follow-up assessment schedule3 
Visit Name 
Wk 33 
Wk 53 
Week 69  
EOS 
Days 
225 
365 
477 
477 
Weeks 
33 
53 
69 
69 
Physical Examination 
S 
S 
S 
  
Neurological Examination 
X 
X 
X 
  
Vital signs (including body weight) 
X 
X 
X 
  
Electrocardiogram (ECG) 
X 
 
 
  
Hematology 
X 
X1 
X1 
 
Clinical Chemistry 
X 
X1 
X1 
 
Thyroid Function 
X 
X1 
X1 
 
NTproBNP, Troponin 
X 
X1 
X1 
 
Pregnancy Test - Serum 
X 
X 
X 
 
Urinalysis 
X 
X1 
X1 
 
Columbia- Suicide Severity Rating Scale (C-SSRS) X 
X 
X 
 
Serum Biomarkers (NfL) 
X 
X 
X 
 
Nerve Conduction Studies (tibial CMAP/sural 
nerve SNAP)2 
X 
X 
X 
 
Brain MRI 
X 
X 
X 
 
UHDRS – TFC, TMS, IS, 
X 
 
X 
 
Adverse Events  
X 
X 
X 
 
Serious Adverse Events 
X 
X 
X 
 
Prior and concomitant medications or therapies 
X 
X 
X 
 
End of Study Disposition 
 
 
 
X 


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Period 
Revised follow-up assessment schedule3 
Visit Name 
Wk 33 
Wk 53 
Week 69  
EOS 
Days 
225 
365 
477 
477 
Weeks 
33 
53 
69 
69 
1 To minimize burden to participants, it is recommended that safety labs/urinalysis are performed only if required for Adverse Events or follow up of an AE. 
2 NCS must be performed in triplicate and recommended bilaterally. However, if performed unilaterally, then it should be conducted on the same side as 
per the screening visit 
3 Visit window for Week 33 onwards is ±2 weeks. 
 


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8.1 
Screening 
As per the USM, no further enrollment is allowed. 
Written Informed Consent must be obtained before any study specific procedures are performed. 
During the screening assessment period, inclusion and exclusion criteria will be evaluated and 
all screening assessments to confirm eligibility must be performed prior to randomization. 
For details of assessments required during screening please refer to Table 8-2.  
Participants will be required to have all screening assessments within 42 days of randomization 
with the exception of CAG repeat and height. However, participants may remain in screening 
for greater than 42 days in the following cases:  
• If recruitment (i.e. randomization) is paused (e.g. enrollment is complete for open treatment 
arms and pending opening of additional treatment arms following the cohort gating 
assessment), 
• In cases where a switch in concomitant medication is considered by the Investigator 
following the guidance in Table 6-2, participants should be on a stable dose and regimen of 
permitted chronic concomitant medications for at least 6 weeks prior to receiving the first 
dose of study drug which in the medical judgement of the Investigator is not anticipated to 
change during the study. If new medications are initiated during Screening, laboratory 
evaluations must meet eligibility criteria before first dose of study drug. 
• In order to minimize patient burden and upon consultation with the Novartis, the screening 
period may also be extended beyond 42 days to accommodate the scheduling of baseline 
assessments. 
A participant who has laboratory test results that do not satisfy the entrance criteria may have 
the tests repeated. These tests may be repeated as soon as the Investigator believes the re-test 
results are likely to be within the acceptable range to satisfy the entrance criteria, but should be 
completed within the screening period. In this instance, the participant will not be required to 
sign another Informed Consent Form (ICF), and the original Participant Number assigned by 
the Investigator will be used. In the event that the laboratory tests cannot be performed within 
the screening visit window, or the re-tests do not meet the entrance criteria, or other eligibility 
criteria have changed and are not met anymore, the participant is considered a screen failure, 
and must be discontinued from the study. 
At this time, participants will be eligible to randomize into any open Treatment Arm if it has 
not yet been completed.  
At that time, and depending on the overall recruitment rate and number of participants in active 
screening, guidance will be provided to Investigators regarding screening new potential patients. 
All visits are to be scheduled according to the appropriate number of calendar days from Day 1 
of study drug administration, and not from the previous visit date. 
It is permissible to re-screen a participant if she/he fails the initial screening; however, each 
case must be discussed and agreed with the Novartis on a case-by-case basis. 


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8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible, 
for any reason, prior to randomization will be considered as screen failures. The reason for 
screen failure should be recorded on the appropriate eCRF. The demographic information, 
informed consent, and Inclusion/Exclusion pages must also be completed for screen failure 
participants. No other data will be entered into the clinical database for participants who are 
screen failures, unless the participant experienced a serious adverse event during the screening 
period (Section 10.1.3). If the participant fails to be randomized, the IRT must be notified within 
2 days of the screen fail that the participant was not randomized. Data and samples collected 
from participants prior to screen failure may still be analyzed. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason should be recorded on the appropriate eCRF. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Participant demographics and baseline characteristics collected will include the following: age 
of participant, gender (and childbearing potential for female), education level, race and ethnicity, 
height, weight, smoking and alcohol history, all relevant medical history including HD history, 
CAG repeat length, (for participants with previously existing source documentation, prior and 
current concomitant medication. For full list of assessments at screening and BL, please refer 
to Table 8-2. 
BL assessments may be completed over a 6-day period.  
Patients should not be randomized and receive study drug treatment until the baseline MRI scan 
has passed quality control (QC) at central vendor (expected turnaround time 3 days). 
The LP should be performed on a different day than both the MRI and HD assessments; 
however if it cannot be, then the MRI and/or HD assessments must be completed prior to the 
LP.  
8.3 
Efficacy/Pharmacodynamics 
Efficacy assessments include the following: 
• Unified Huntington's Disease Rating Scales (UHDRS) components:  
• Total Functional Capacity (TFC) 
• Total Motor Scale (TMS) 
• Independence Scale (IS) 
 
 
 
 
 
 
 
 








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8.4 
Safety/Tolerability 
To minimize burden to participants, it is recommended that safety labs/urinalysis are for 
performed only if required for Adverse Events or follow up of an AE. See VES Table 8-5 
for list of safety assessments to be performed following the USM. 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE/SAE collection and reporting, refer to Section 10. 
Table 8-6 
Assessments & Specifications 
Assessment 
Specification 
Physical 
examination 
A complete physical examination including the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological will be performed at Screening and Baseline visits. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. 
A short physical exam will include vital signs (temperature, blood pressure [SBP and DBP] 
and pulse) examination of general appearance, head, eyes, ears, nose, throat, neck, skin, 
lungs, heart and abdomen. Evidence of possible bleeding tendency such as bruises or 
petechial rash should be noted. 
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed consent 
must be recorded on the appropriate eCRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs include temperature (method of body temperature (i.e. oral) is up to site local 
practices), BP and pulse measurements. After the participant has been supine for ten 
minutes, systolic and diastolic blood pressure will be measured three times using an 
automated validated device, e.g. OMRON, with an appropriately sized cuff. The repeat 
measurements will be made at 1 - 2 minute intervals. In case the cuff sizes available are not 
large enough for the participant's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
Height and 
weight 
Height and body weight (in indoor clothing, but without shoes) will be measured 
Neurological 
Neurological examination includes at a minimum the following: mental status, cranial nerves 
I- XII, motor system, deep tendon reflexes, sensory system including touch and vibration, 
coordination, gait. In addition, a detailed motor, deep tendon reflexes and sensory system 
examination will be completed and recorded on the appropriate eCRF at screening and at 
each visit to monitor for any abnormalities. Nerve conduction studies consisting of tibial 
CMAP and sural SNAP will be done at screening and during study if indicated clinically. 
Cardiac 
Full PK profile with digital standard 12-lead triplicate ECGs, PK samples and vital signs at 
the same time points (vital signs = pulse rate, supine systolic and diastolic blood pressure) 
will be performed. ECHO with GLS will be performed as per assessment schedule. Specific 
visits will require fasting prior to pre-dose ECGs as specified in the visit schedule and in 
Section 8.4.2.  
Ophthalmologic 
An ophthalmologic examination without sedation using dilated direct and indirect 
ophthalmoscopy with scleral indentation if necessary will be performed at the time points 
defined in the Assessment Schedule by an Ophthalmologist. 
8.4.1 
Laboratory evaluations 
Central laboratories will be used for the analysis of scheduled hematology, biochemistry and 
other blood specimens collected as part of safety monitoring (as detailed Table 8-7). Dipstick 
urinalysis will be performed locally (unless local institution policies dictate otherwise), except 


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in the case of any out of range parameter on scheduled local urinalysis, when a urine sample 
will be sent to central laboratory for further analysis. Laboratory values obtained during the 
Screening phase will be used to assess patient’s eligibility. The time windows granted for 
laboratory evaluations are identical to the corresponding visit time windows for each visit (refer 
to Table 8-1, Table 8-2, Table 8-3,  Table 8-4, and Table 8-5 (post-USM). 
The site does not need to wait for the results of centrally-analyzed laboratory assessments when 
an immediate clinical decision needs to be made and in those cases locally unscheduled testing 
may be performed. 
Details on the collection, shipment of samples and reporting of results by the central laboratory 
are provided to Investigators separately. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
Table 8-7 
Laboratory evaluations 
Test Category 
Test Name 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Chloride, Sodium, Potassium, 
Phosphate, Creatinine, estimated Glomerular filtration rate (eGFR), Creatine kinase (CK), 
Total Bilirubin, Total Cholesterol, Low density lipoproteins (LDL), High density lipoproteins 
(HDL), Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, 
Lipase, Glucose, (fasting and non-fasting), high sensitivity C-reactive protein (CRP), fasting 
bile acids; glycated hemoglobin (HbA1c) (screening visit only) 
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated. 
In the event ALT/AST is above 3 times upper limit of normal, reflex testing will be performed 
by the central laboratory for GLDH (glutamate dehydrogenase) 
In the event CK is above ULN then reflex testing of isoenzymes will be performed by the 
central laboratory 
In case of severe amylase/lipase elevations (> 2x ULN), a reflex fractionation amylase test 
is recommended (local testing acceptable) 
Hematology 
Hematocrit, Hemoglobin, mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), Platelets, Mean 
Platelet volume* (MPV), Red blood cells RBC), White blood cells, RBC Morphology, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other 
(absolute value preferred, %s are acceptable), reticulocytes 
* In event the platelet count is out of range (both upper and lower limits) MPV reflex testing 
will be performed by the central laboratory 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity ) 
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial 
cells); done only if findings on urine dipstick. In addition the central laboratory will perform 
analysis of the urine protein and blood. 
Coagulation 
Prothrombin time (PT), International normalized ratio [INR]), Activated partial thromboplastin 
time (APTT)  
Additional tests 
FSH, Troponin T, NTproBNP, T3 Triiodothyronine [free], T4 Thyroxine [free], Thyroid-
Stimulating Hormone (TSH) 
Pregnancy Test 
Serum / Urine pregnancy test 


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8.4.2 
Cardiac assessments 
Electrocardiogram (ECG) 
As per USM: Refer to Table 8-5 for schedule of ECG assessments. Participants do not 
require to be fasting prior to the ECG. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable BL, 
according to the ECG Investigator Manual. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions.  
Triplicate 12-lead resting ECGs are to be collected, with ECG machines as supplied by central 
ECG vendor, at all timepoints pre-specified in the visit and assessment schedule and should be 
performed with a 2-4 minutes interval between each ECG. Details on the triplicate ECG 
collection procedure and its specific requirements and restrictions for the participant are 
provided in an ECG Investigator Manual. Specific visits will require fasting prior to pre-dose 
ECGs as specified in Table 8-8, and in Section 6.7.2. For PK sampling timepoints, please see 
Appendix 16.3. 
Table 8-8 
Central ECG Collection Plan 
Period 
Visit Name 
Days 
Timepoint  
Timing of Triplicate ECGs  
Screening 
Screening 
-42 to -7 
- 
Anytime 
Baseline 
Baseline 
-6 to -1 
- 
Anytime 
DRF 
Wk 1 
1 
0 hr 
Pre-dose after 4 hr fasting  
DRF 
Wk 1 
1 
4 hr 
Post-dose  
DRF 
Wk 1 
1 
12 hr 
Post-dose after 4 hr fasting 
DRF 
Wk 2 
8 
- 
Pre-dose  
DRF 
Wk 3 
15 
- 
Pre-dose 
DRF 
Wk 5 
29 
- 
Pre-dose 
DRF 
Wk 9 
57 
0 hr 
Pre-dose after 4 hr fasting 
DRF 
Wk 9 
57 
4 hr 
Post-dose  
DRF 
Wk 9 
57 
12 hr 
Post-dose after 4 hr fasting 
DRF 
Wk 13 
85 
- 
Pre-dose 
DRF 
Wk 17 
113 
0 
Pre-dose  
BE & OLE  
Wk 21 until 
EOT OLE 
141 to EOT 
OLE 
- 
Pre-dose  
For any ECGs with participant safety concerns, the Investigator should treat based on standard 
of care. 
In the event that a clinically significant ECG abnormality is identified at the site at the time of 
ECG collection (e.g. severe arrhythmia, conduction abnormality of QTcF >500 msec), an 
expedited review by the central reader may be requested if applicable, and the ECG should be 
repeated to confirm the diagnosis. If the participant is hemodynamically compromised, the 
Investigator or a medically qualified person must initiate appropriate safety procedures without 
delay (for example cardioversion). 


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Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
Echocardiogram with Global Longitudinal Strain (GLS) 
Echocardiogram with GLS is no longer required per the USM follow-up notification dated 
06-Dec-2022. 
Pre-USM: Echocardiogram with GLS will be performed per the assessment schedule. An 
echocardiogram is a test that uses high frequency sound waves (ultrasound) to make a cardiac 
image and provides information regarding cardiac structure and function. GLS is an additional 
parameter used to assess myocardial contractility.  
Two dimensional echocardiography measurements will be assessed during the study. The 
images will be transmitted to a central reading vendor for independent review. Sites will receive 
appropriate training as well as an Echocardiography Manual that includes detailed instructions 
and data transfer procedures. 
A Left Ventricular Ejection Fraction (LVEF) <50% (calculated using the biplane Simpson 
method) is considered reduced and clinically relevant. Reductions in LVEF ≥10 % units and/or 
GLS ≥15 % units change from baseline are considered clinically relevant following consensus 
guidelines for abnormal cardiac response (Plana et al 2014). 
Echocardiograms should be locally reviewed by the Investigator for incidental findings. For the 
purpose of the study only clinically relevant abnormalities noted should be recorded as AE. All 
other echocardiography assessments will be done by central reading vendor. The central reading 
vendor will only send alert notifications to sites when the LVEF and GLS thresholds defined 
above are met. 
Eligibility at screening will be confirmed by the Investigator based on the local 
echocardiography assessment as reported by a cardiologist. Recordings at screening will be sent 
to the central reader to serve as reference measurement for future comparison. All recordings 
will be sent to the central reader. 
Aligned with recommendations of the American Society of Echocardiography concerning the 
use of echocardiography in clinical trials (Gottdiener et al 2004), the following standard 
parameters - pertinent to the assessment of changes in cardiac muscle mass and/or contractile 
function - will be monitored during the study: 
• Left ventricular wall (anterior and posterior) and septal thickness 
• Left ventricular mass and mass index 
• Left ventricular end-diastolic volume 
• Left ventricular end-systolic volume 
• Left ventricular ejection fraction 
• Left ventricular diastolic and systolic diameter 
• Left atrial size and volume 
• Left Ventricular Global Longitudinal Strain 


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Cardiac Enzymes 
Troponin and NTproBNP levels will be assessed at BL and timepoints outlined in the 
assessment schedule. These blood tests are to monitor cardiac injury and cardiac failure. 
8.4.3 
Pregnancy and assessments of fertility 
As per the USM follow-up notification dated 06-Dec-2022, the study treatment has been 
permanently discontinued; oral contraception is now permitted as a highly effective 
contraception method given that there is no longer a potential for a Drug-Drug Interaction 
(DDI). 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy or urine 
pregnancy test at the visits specified in the assessment schedule (Table 8-2, Table 8-3 and  
Table 8-4). Additional serum pregnancy testing might be performed if required by local 
requirements or if urine pregnancy is positive. If the result of urine pregnancy test is positive: 
i) treatment should be put on hold and ii) confirmation is necessary by serum test. 
A positive serum pregnancy test requires immediate discontinuation from the study drug. The 
patient must be followed to understand the outcome of the pregnancy. 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm for 120 days (4 months) after the last dose of study 
treatment. In addition, a condom is required by male partners of participants in the study in 
order to prevent exposure to the study drug. 
If participants cannot visit the site to have serum pregnancy tests 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, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 
Assessments of Fertility 
A woman is considered of childbearing potential from menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Medical documentation of 
bilateral oophorectomy, hysterectomy, or bilateral tubal ligation must be retained as source 
documents.  
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In the absence of medical documentation, confirming permanent sterilization, or if the post-
menopausal status at screening/baseline is not clear, the Investigator should use his medical 


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judgment to appropriately evaluate the fertility state of the woman and document it in the source 
document.  
8.4.4 
Neurological assessments 
Neurological Examination 
In addition to a standard neurological examination (mental status, cranial nerves I- XII, motor 
system, deep tendon reflexes, sensory system including touch and vibration, coordination, gait), 
a more detailed neurological examination comprised of motor system, deep tendon reflexes and 
sensory system will be completed and reported on a corresponding eCRF at BL and any 
clinically significant abnormalities will be noted at each visit. 
Nerve conduction study (NCS) 
As per the USM of 05-Aug-2022, if a repeat NCS is required due to findings suggestive of 
peripheral neuropathy, it is recommended that this be performed bilaterally with three separate 
readings. If it is performed unilaterally then it must be the same side as it was performed at 
screening. 
Nerve Conduction Studies (NCS) are medical diagnostic tests to evaluate the function, of motor 
and sensory nerves by measuring electrical conduction. NCSs will be conducted at screening 
and repeated in the event there are any new clinically significant findings during the 
neurological exam that might suggest peripheral neuropathy. The screening NCS results will be 
interpreted locally and should be normal without of any electrodiagnostic evidence of 
neuropathy. 
This study will be assessing both the motor and sensory electrophysiological functions by 
testing the tibial and sural nerves respectively. The study will be performed unilaterally and the 
same side should always be assessed with three separate readings performed. The CMAP is 
recorded by electrical stimulation of a motor nerve. Its amplitude is measured in millivolts (mV). 
The SNAP is obtained by electrically stimulating a sensory nerve. Its amplitude is measured in 
microvolts (μV). In addition, nerve conduction velocity (NCV) is taken during both tests. NCV 
indicates how quickly electrical impulses move along a nerve. It is measure in meters per second 
(m/s). 
These tests will be performed by medical specialists at the site such as clinical 
neurophysiologists, or neurologists who subspecialize in electrodiagnostic medicine and who 
will be responsible in providing the final results and their interpretation.  
The following tests will be assessed as safety parameters: 
Table 8-9 
Nerve conduction study safety parameters 
Maximum of 3 measures performed per nerve 
1a Sural SNAP Measurement #1 #2 #3 
1b Sural Sensory NCV measurement #1 #2 #3 
2a Tibial CMAP measurement #1 #2 #3 
3b Tibial Motor NCV measurement #1 #2 #3 
Numbers with a/b refer to the fact that these measurements are yielded from one and the same stimulation. 




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obtained at baseline and then at regular intervals during the course of the study. If FSH levels 
double from the patient’s BL and is above 5 IU/mL consultation with an endocrinologist is 
recommended. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are included due to potential risks associated with branaplam. 
Neurological Investigations: Potential risk of neurotoxicity (axonal degeneration of peripheral 
nerves and spinal cord) was identified based on two dog studies. In order to assess this, a 
comprehensive neurologic exam will be conducted. In addition, nerve conduction evaluations 
with CMAP and sensory nerve action potential (SNAP) will be conducted at the Screening visit 
to ensure no existing peripheral neuropathy is present. These tests may be repeated if, in the 
opinion of the Investigator, there is potential peripheral neuropathy based on participant self-
report, abnormal findings on neurological examination indicative of a potential peripheral 
neuropathy (see Section 8.4.4). 
8.5 
Additional assessments 


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8.5.2 
Pharmacokinetics 
As per the USM, PK and blood biomarkers including mHTT/HTT (plasma 
) 
 should only be collected in all randomized participants up to 6 weeks 
after the last dose of study drug .  
Pharmacokinetic (PK) samples will be collected at the visits defined in the assessment schedule. 
Follow instructions for fasting as outlined in Section 6.7.2.1 and sample collection, numbering, 
processing, and shipment in the Lab Manual. Refer to Appendix 16.3 for PK sample log. PK 
samples should be collected as close to the scheduled timepoints as feasible. 
An additional blood sample will be collected in the event that a patient experiences an AE which 
requires premature termination from the study medication. 
PK samples from plasma and CSF will be obtained from all participants at all dose levels. 
Bioanalytical analysis of PK samples will be executed if participant is treated with branaplam 
and no bioanalysis will be executed in plasma samples if participant is treated with placebo. 
Branaplam and its metabolite UFB112 will be determined in plasma and CSF by a validated 
LC-MS/MS method. The anticipated Lower Limit of Quantification (LLOQ) is 0.500 ng/mL. 
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. 
PK samples remaining after completion of the determination of parent and/or UFB112 may be 
used for exploratory assessment of metabolites, plasma protein binding or other bioanalytical 
purposes (e.g. cross check between different sites, stability assessment). Given the exploratory 
nature of the work, the analytical method used for those assessments will not be validated. 
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol. If feasible, the following pharmacokinetic parameters will be 
determined in plasma after first dosing and at the Week 17 visit using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 8 or 
higher): the maximum concentration (Cmax), the time it takes to reach Cmax (Tmax), AUClast, 




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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
As per the USM follow-up notification dated 06-Dec-2022 study treatment is permanently 
discontinued for all patients. 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
Investigator. 
The Investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant (or legal representative, if needed) decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
• Following emergency unblinding 
• Emergence of the following adverse events: Consider any adverse events that in the 
judgment of the Investigator, taking into account the participant’s overall status, prevent the 
participant from continuing participation in the study. Refer to Table 6-3 and protocol 
Section 6.5.2.1 Dose adjustments for QTcF prolongation. 
• Any laboratory abnormalities that in the judgment of the Investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study. 
If discontinuation of study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant's premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). Where possible, 


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participants in the DRF Treatment Period should return for the remaining DRF assessments (off 
study drug) indicated in the Assessment Schedule (Table 8-2, Table 8-3 and Table 8-4). 
If participants fail to return for these assessments for unknown reasons, every effort  
(e.g. telephone, e-mail, letter) should be made to contact the participant/pre-designated contact 
as specified in the lost to follow-up section. This contact should preferably be done according 
to the study visit schedule. 
After study treatment discontinuation, the participant should be followed for a period of 30 days. 
The following data should be collected at unscheduled site visits (if needed) or via telephone 
contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The Investigator must also contact the IRT to register the participant's discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
Premature discontinuation of study treatment during Core Period: 
• If a participant prematurely discontinues study treatment before or at Week 17 visit during 
the DRF period (for reasons other than withdrawal of consent), all assessments 
corresponding to all visits during the DRF period should still be completed up to and 
including Week 17 as described in the visit evaluation schedule Table 8-2, Table 8-3 and 
Table 8-4). 
• If a participant prematurely discontinues study treatment during the blinded extension after 
the Week 17 visit during the DRF period (for reasons other than withdrawal of consent) and 
therefore does not continue in the OLE, all assessments as described under the EOT/Week 
53 visit in the VES should be completed during the last visit. 
Any participant that discontinues study drug treatment at any given timepoint during the Core 
period should complete the EOT-Core Disposition CRF.  
• Participants that prematurely discontinue blinded study treatment during the Core period 
and do not continue in the OLE study period must be followed up for safety for 30 days 
after the last dose of blinded study drug is administered.  
• Participants that complete the blinded study treatment during the Core period and continue 
in the OLE study period, will be monitored for safety during the OLE while taking the 
selected open label dose. 
9.1.2 
Withdrawal of informed consent and exercise of participants’ data 
privacy rights 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent/opposition to use of data and/or biological samples occurs in 
countries where the legal justification to collect and process the data is consent and when a 
participant: 
• Explicitly requests to stop use of their data  


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and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contact). 
 This request should be as per local regulations (e.g., in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs discontinuation based on the 
protocol definitions of these terms. 
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 their consent/ 
exercise data privacy rights and record this information. The Investigator shall clearly document 
if the participant has withdrawn his/her consent for the use of data in addition to a study 
discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant's withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table (refer 
to Section 8). 
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. No new Personal Data (including biological samples) 
will be collected following withdrawal of consent. 
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g., dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed.  
9.1.4 
Early study termination by the Novartis 
The study can be terminated by Novartis at any time. 


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This may include reasons related to the benefit/ risk assessment of participating in the study, 
practical reasons (including slow enrollment), or for regulatory or medical reasons. In taking 
the decision to terminate, Novartis will always consider the participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible for the End 
of Treatment visit and treated as a prematurely withdrawn participant. The Investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The Investigator or Novartis depending 
on the local regulation will be responsible for informing IRBs/IECs of the early termination of 
the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
In the event of an early study termination decision, a 30-day safety follow-up is required after 
the last administration of study treatment. Alternatively, if an umbrella extension study is 
opened, the study may be concluded early and participants rolled into the new study where they 
will receive continued treatment; in this case, the 30-day safety follow-up is not required. 
All randomized and/or treated participants should have a safety follow-up call conducted  
30 days after last administration of study treatment. The information collected is kept as source 
documentation. All serious adverse events (SAEs) reported during this time period must be 
reported as described in Section 10.1.3. Documentation of attempts to contact the participant 
should be recorded in the source documentation. 
Continuing care should be provided by the Investigator and/or referring physician based on 
participant availability for follow-up. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.1.1 and Section 10.1.2.  
AEs will be reported by the participant (or, when appropriate, by a companion/caregiver, 
surrogate, or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs and SAEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.1.3 SAE 
reporting. 


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10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The Investigator has the responsibility for managing the safety of individual participants and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Drug interrupted/increased 
• Dose interrupted/permanently discontinued 
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Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be not recovered/not resolved (e.g., continuing at the end of the study), and assessment must be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
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 must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease.  
10.1.2 
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: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• 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 signing the informed consent 


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• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• Is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the electronic 
Serious Adverse Event Report Form; all applicable sections of the form must be completed in 
order to provide a clinically thorough report. 
SAE reporting timeframes 
1. Screen Failures: SAEs occurring after the participant has provided informed consent until 
the time the participant is deemed a Screen Failure must be reported to Novartis. 
2. Randomized OR Treated participants: SAEs collected between time participant signs ICF 
until 30 days after the participant has discontinued or stopped study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances that than within 24 hours of the 
Investigator receiving the follow-up information. (Note: If more stringent, local regulations 


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regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the Investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
Investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries. 
Any SAEs experienced after the 30-day period following the last administration of study 
treatment should only be reported to Novartis Safety if the Investigator suspects a causal 
relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Officer and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided the pregnancy reporting will occur up to one year after the estimated 
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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Misuse/Abuse 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. Abuse corresponds to the persistent or sporadic, intentional 
excessive use of a medicinal product, which is accompanied by harmful physical or 
psychological effects.  
All reports of misuse and abuse of the product are also considered serious adverse events 
irrespective of whether a clinical event has occurred and should be reported in the safety 
database within 24 hours of Investigator’s awareness. 
Medication errors 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant, or 
consumer (European Medicines Agency (EMA) definition). 
• Study treatment errors and uses outside of what is foreseen in the protocol will be 
recorded on the appropriate eCRF irrespective of whether or not associated with an 
AE/SAE.  
• In addition, study treatment errors and uses outside of what is foreseen in the protocol if 
associated with an AE/SAE and misuse or abuse will also be collected and reported in the 
safety database within 24 hours of Investigator’s awareness.  
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.  
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate eCRFs 
Please refer to Table 16-1 in Section 16.1 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver event defined in Table 16-1 should be followed up by the Investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Section 16.1. Repeat liver chemistry tests (i.e., ALT, AST, total 


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bilirubin (TBL), prothrombin time/international normalized ratio (PT/INR), alkaline 
Phosphatase (ALP) and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, 
any local liver chemistry tests previously conducted that are associated with this event 
should have results recorded on the appropriate eCRF.  
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption or every other week dosing after 
discussion with Novartis if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
Section 9.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases 
• Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
• Exclusion of underlying liver disease, as specified in Section 5.2 
• Imaging such as abdominal ultrasound, CT or MRI, as appropriate 
• Obtaining a history of exposure to environmental chemical agents 
• Considering gastroenterology or hepatology consultations 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
Follow up on potential drug-induced liver injury (DILI) cases  
An increase in transaminase combined with total bilirubin increase may be indicative of 
potentially severe DILI, and should be considered as clinically important events and assessed 
appropriately to establish the diagnosis. The required clinical information, as detailed below, 
should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. The threshold for potential DILI may depend on the participant’s 
baseline AST/ALT and total bilirubin value; participants meeting any of the following criteria 
will require further follow-up as outlined below 
For participants with normal ALT and AST and total bilirubin value at baseline: AST or ALT > 
3.0 x ULN combined with total bilirubin > 2.0 x ULN 


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As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. A 
detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, and history of any pre-
existing liver conditions or risk factors should be collected. Laboratory tests should include 
ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, prothrombin time (PT)/INR, 
alkaline phosphatase, albumin, and creatine kinase. If available, testing of Glutamate 
Dehydrogenase (GLDH) is additionally recommended. (In the event ALT/AST is above 3 times 
upper limit of normal, reflex testing will be performed by the central laboratory for GLDH). 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule-out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). Note: The R value is calculated by dividing the ALT by the 
ALP, using multiples of the ULN for both values. It denotes whether the relative pattern of ALT 
and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and 
< 5) liver injury. For children, there are caveats to calculating the R-ratio as normal levels of 
ALP are higher than in adults with standard ranges varying by developmental age. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury. Table 10-2 Table 10-1 provides guidance on 
specific clinical and diagnostic assessments which can be performed to rule -out possible 
alternative causes of observed LFT abnormalities. These labs may be done locally. 
Table 10-1 
Guidance on specific clinical and diagnostic assessments 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV 
DNA; anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV 
RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle 
Antibody (ASMA) titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic congestive heart 
failure, hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
 
Other causes should also be considered based upon participant’s medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes mellitus / glycogenic hepatitis). 


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Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” (i.e., >50% likely,), if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as a SAE using the 
term “potential treatment-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 
10.2.2 
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• Urine protein-creatinine ratio (PCR) ≥1 g/g or ≥113 mg/mmol, OR new onset dipstick 
proteinuria ≥ 3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation, 
urinary tract infection (UTI), extreme exercise, or trauma) 
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment. 
Every renal laboratory trigger or renal event as defined in Table 10-2 should be followed up by 
the Investigator or designated personnel at the trial site as summarized in Section 16.2. 
Since this is an early phase study baseline serum creatinine is determined as the mean of two 
serum creatinine measurements (e.g. at screening and pretreatment). 


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Table 10-2 
Renal Events and Definition and Diagnosis 
A renal event is defined as the presence of any of 
the following 
Confirm Finding 
GFR Event 
Serum creatinine increase ≥ 25% versus baseline 
Note: Dependent on NORMAL hydration status, 
see the list below 
Confirm assessment 24 - 48 h after first assessment 
Urine Event 
Protein-creatinine ratio > or = 1 g/g Cr or ≥113 
mg/mmol 
New onset dipstick proteinuria ≥ 3+New onset dipstick 
hematuria ≥ 3+* 
  
*Exclude menstruation, urinary tract infection (UTI), extreme exercise or trauma, and bleeding from the distal 
urinary tract/bladder 
When assessing (Drug Induced Nephrotoxicity (DIN) renal events, also consider other causes 
of renal events and/or altered serum creatinine and BUN:  
• Hypovolemia  
• Major operations  
• Severe infections and sepsis  
• Co-medications affecting creatinine secretion (e.g., trimethoprim, cimetidine) 
• Change of antihypertensive treatment regimens  
• Acute or worsening heart failure  
• Rhabdomyolysis (monitor for increase in CPK) 
10.2.3 
Prospective suicidality assessment 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses suicidal ideation and suicidal behavior. The C-SSRS must be administered at each visit, 
including unplanned visits. 
The C-SSRS, which uses a semi-structured interview to probe participant responses, will be 
administered by an individual who has received training and certification in its administration. 
At the first study visit, the “baseline/screening” version of the C-SSRS will be administered. 
This version assesses suicidal ideation and suicidal behavior during the participant's lifetime 
and during a predefined period. At subsequent visits, the “since last visit” version will be 
administered 
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
suicidal ideation section of the C-SSRS or “yes” on any item of the suicidal behavior section, 
the participant must be referred to a mental health care professional for further assessment 
and/or treatment. The decision on whether the study treatment should be discontinued is to be 
taken by the Investigator in consultation with the mental health professional to whom the 
participant is referred. 
In addition, all life-threatening events must be reported as SAEs. For example, if a participant 
answers “yes” to one of the questions in the suicidal behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 


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(question also included in the suicidal behavior section) should be reported as AEs and assigned 
the appropriate severity grade. 
10.2.4 
Data Monitoring Committee 
As per the USM follow-up notification dated 06-Dec-2022, after DMC recommendation to 
permanently discontinue study drug administration, Novartis will continue to engage with 
the DMC, until conclusion of the study or as mutually agreed by the DMC and Novartis. 
This study will include an external Data Monitoring Committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site Investigators participating in the study. The primary goal of the DMC is to perform an 
ongoing review of safety and tolerability data, and critical efficacy variables during the course 
of the clinical study, and recommend to Novartis whether to continue, modify, or terminate the 
trial. 
The DMC will consist of external experts, with experience in management and monitoring of 
clinical trials and/or disease area expertise but without direct involvement in any activities 
related to branaplam studies. The DMC will be assisted by an independent statistician and 
statistical programmer provided by Novartis; however Novartis study personnel will not have 
access to treatment codes or any unblinded data or data summaries prepared for the DMC. 
The DMC is responsible for monitoring the safety of the trial participants, ensuring that the 
branaplam studies are being conducted with the high scientific and ethical standards and making 
appropriate recommendations based on data reviewed. The DMC will conduct full unblinded 
safety reviews of cumulative safety and tolerability data, as well as participant narratives for 
deaths and SAEs, discontinuations due to AEs and cases of special interest at regular intervals. 
In addition, unblinded safety review by the DMC will be implemented to stagger participant 
exposure to cohorts with higher doses. The DMC will be updated on an ongoing basis regarding 
any new preclinical safety data as well. 
The DMC may also assess any potential relationship between CSF and/or PBMC mHTT data 
and dose/dose regimen with respect to signs and signals of safety concerns. 
The DMC could make the following recommendations: 
• Requesting changes or adjustments that may be required to ensuring participant safety and 
preserve trial integrity. 
• Suggesting modification to protocol, including but not limited to changes in eligibility 
criteria, alteration of dosing regimen frequency of visits/safety assessments, or 
discontinuation of one or more Treatment Arms. 
• Recommending continuation of the trial according to current version of the protocol OR to 
discontinue trial 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the Novartis and the DMC. 
At the time of the CGAs, all available data will be reviewed from a safety and dose finding 
perspective by an independent Novartis team to support the decision to open the next cohort. 


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The independent Data Monitoring Committee (DMC) will review the data separately. The 
decision to open a new cohort will be made by the Novartis in consultation with the DMC. 
10.2.5 
Steering Committee 
A Steering Committee (SC) comprised of Investigators or experts in HD management will be 
formed prior to initiation of the trial. The purpose of the SC is to provide overall guidance 
regarding design, conduct and execution of the trial to include (but not limited to) safety, accrual 
and contribution to scientific input for publications. Responsibilities of the SC and 
communication flow between SC and Novartis will be included in the SC charter document. 
11 
Data Collection and Database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-2, Table 8-3 , Table 8-4 and Table 8-5 (post-USM)) and can be recorded 
directly on the eCRFs. All other data captured for this study will have an external originating 
source (either written or electronic) with the eCRF not being considered as source. 
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 Code of Federal Regulations (CFR) Part 11 requirements. 
Investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data (recorded on eCRFs) (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 instructions for generating copies of the 
participant's 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. 
11.2 
Database management and quality control 
Novartis personnel (or designated contract research organization (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 


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adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
Investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis/Clinical Research Associate (CRA) organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The Investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant’s file. The Investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 


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12 
Data analysis and statistical methods 
As per the USM, the original planned analyses of primary, secondary and exploratory 
endpoints to demonstrate efficacy are no longer applicable. No statistical modelling will 
be done. As specified earlier, the primary IA will take place once the majority of 
participants in cohort 1 complete their Week 33 visit Efficacy and safety endpoints will be 
summarized descriptively in an unblinded way as all the parties have been unblinded. 
More details will be documented in the Statistical Analysis Plan. 
As per the USM, there is only one Cohort initiated and the OLE period is no longer 
applicable. No analysis based on OLE will be performed.  
This section will mainly describe the IA that will take place once all randomized participants 
have completed their assessments at Week 17. 
Data will be reported by treatment group and by visit as applicable. This study will include 3 
treatment arms A, B, and C (or X or Y), which consists of 6 treatment groups (3 active dose 
groups and 3 matching placebo groups that are embedded within each treatment arm with a ratio 
of 4:1 active vs. placebo). Note that, in the analysis all participants assigned to placebo in 
different treatment arms will be pooled together as one placebo group. Hence, there are 4 
treatment groups in total (3 active, 1 placebo). Assessment of potential bias due to pooling of 
placebo from different Cohorts will be described in the SAP. 
Unless specified differently, descriptive analysis for categorical data will be summarized as 
frequencies and percentages and continuous data will be summarized with the mean, standard 
deviation (SD), median, minimum, and maximum. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Randomized Analysis Set (RAS) will consist of all participants who received a 
randomization number, regardless of whether participants received study medication. 
The Full Analysis Set will consist of all randomized participants who received at least one dose 
of study drug. Efficacy analysis will be conducted on the Full Analysis Set. 
The Safety Set (SAF) will consist of all participants who received at least one dose of study 
drug. Participants will be analyzed according to the treatment received. Safety analyses for the 
Core Period will be conducted on participants from SAF. 
Pre-USM: Open Label Analysis Set (OLS) will consist of all participants who received at least 
one dose of study drug in OLE. The OLS will NOT be used for IA and will be used after OLE 
is completed. 
Open label Safety Analysis Set (OLSAF) will consist of all participants who received at least 
one dose of study drug in OLE. Participants will be analyzed according to the treatment received. 
Safety analyses on OLE data will be conducted on participants from OLSAF. 


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12.2 
Participant demographics and other baseline characteristics 
Demographic variables and other baseline data including disease characteristics will be 
summarized for each treatment group and for all participants (total) for the Full Analysis Set. 
In addition, all relevant medical history at baseline will be summarized following the same 
strategy. 
12.3 
Treatments 
The SAF will be used for the below analyses for Core Period (and cumulatively: Core + OLE). 
The OLSAF will be used for analyses for OLE Period.  
The duration of exposure in days to each treatment group will be summarized by means of 
descriptive statistics. Concomitant medications and significant non-drug therapies prior to and 
after the start of the study treatment will be summarized according to the Anatomical 
Therapeutic Chemical (ATC) classification system. The number of participants who 
permanently discontinued from randomized treatment and the reasons will be summarized. 
In addition, the number of participants whose dose interruption/discontinuation is within the 
acceptable limits as described in Section 2.1 primary estimand (i.e., missed dose less than 25% 
in the first 16 week and not missed 2 or more consecutive weeks prior to LP at week 17) will 
be summarized. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
As per the USM, the primary estimand and statistical modelling for dose-response 
relationship are no longer applicable. Primary endpoint of mHTT in CSF will be 
summarized descriptively.  
The primary data analysis, so called the IA, will be performed at the end of DRF, when 
all randomized participants have completed their last assessment of this DRF period (Week 17, 
after 16 weeks on treatment). The analysis may include 4 treatment groups (3 active, 1 placebo). 
There are two primary objectives in this study: 
1. To assess the dose-response relationship of branaplam administered over 16 weeks on 
mHTT protein change from baseline in CSF.  
2. To evaluate the safety and tolerability of various doses of branaplam over 16 weeks or 
longer in patients with HD. 
The second primary objective safety and tolerability evaluation of the study drug will be 
addressed in safety Section 12.5.2. No inferential and model based statistical analyses are 
planned for any safety or tolerability endpoints. Hence, the rest of Section 12.4 mainly outlines 
the analysis plans for the first primary endpoint: reduction of mHTT in CSF for dose finding 
purpose. 
The dose finding objective is associated with the two goals below: 
• To confirm an overall dose response (DR) signal, versus placebo, based on data of 16 weeks 
of treatment 
• To identify the dose(s) that correspond(s) to the optimal treatment effect based on the 
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12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The primary estimand is defined in Section 2.1 of this protocol. 
The efficacy primary endpoint is the % change from baseline of mHTT concentrations in CSF 
after 16 weeks of treatment, which is expressed as:  
(mHTTwk17- mHTTbaseline)/mHTTbaseline*100%. 
The primary endpoints of the safety and tolerability objective will comprise main safety data, 
including but not limited to AEs/SAEs, physical exam (including neurological examination) 
findings, clinical laboratory assessments, and HTT lowering. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The Multiple Comparison Procedure - Modelling (MCP-Mod) methodology (Bretz et al 2005, 
Pinheiro et al 2014) will be employed to test for an overall DR signal and to estimate the DR 
curve. MCP-Mod method is able to utilize all available data from the continuum of active doses 
and placebo to estimate a parametric DR curve which allows for interpolation of treatment effect 
across a range of doses. It is a hybrid approach that combines hypothesis testing and modeling 
to analyze Phase IIb dose-ranging studies with the purpose of finding suitable dose(s) for future 
trials. The first step of the procedure (MCP-step) is to assess presence of a DR signal using a 
trend test deducted from a set of pre-specified candidate dose-response shapes. The second step 
(Mod-step) relies on parametric modeling to estimate the DR curve and target doses of interest. 
An overview of the steps for the MCP-Mod methodology is outlined below. Details will be 
provided in the Statistical Analysis Plan (SAP). 
MCP-Mod is a two-step procedure: 
Step 1 (Testing an overall dose-response signal - MCP part): 
The (covariate) adjusted mean responses at each individual dose at week 17 will be obtained 
from a mixed-effect linear model for repeated measures (MMRM) with the following baseline 
covariates considered, as appropriate: treatment, visit, age, CAG repeat length (the large allele), 
education level, baseline TFC, baseline CSF mHTT, treatment-by-visit interaction. To allow 
adjustment for correlations between time-points within participants, an unstructured variance-
covariance structure will be used, if applicable. 
The generalized MCP-Mod procedure (Pinheiro et al 2014) will be performed based on the 
adjusted treatment means obtained from the MMRM analysis for Week 17 data. The null 
hypothesis of a flat DR relationship for the mHTT lowering at a one-sided significance level of 
5% will be tested against the alternative hypothesis of a non-constant DR curve. The testing 
will be performed with a multiple contrast test. 
A wide range of possible DR relationships will be pre-specified to take model uncertainty into 
account based on the range of the doses.  
A set of candidate models with five candidate sigmoid maximum effect (Emax) DR curves will 
be used to derive the optimal model contrasts for the multiple contrast tests assuming a 
monotonic DR relation. The parameters of the five candidate sigmoidal maximum effect (Emax) 
models (median effect dose (ED50), h) will be (5, 1), (20, 2), (50, 1), (50, 3), and (80, 6), where 
ED50 are the values the dose at which half of the maximum effect is reached, and h is the Hill 


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parameter that determines the steepness of the dose-response shape. For each of the five 
candidate DR curves, a contrast test statistic will be derived (Bretz et al 2005). The overall null 
hypothesis of no DR relationship is rejected if the multiplicity adjusted p-value for at least one 
contrast test is < 0.05 (one sided). 
Step 2 (Estimation of the dose-response curve and target dose – Mod part): 
A Sigmoid Emax model will be used to estimate the DR relationship in the Mod step. The dose-
response curve will be estimated using bootstrap. A large number of bootstrap samples from 
the multivariate normal distribution will be drawn with adjusted means from the MMRM and 
corresponding covariance matrix. For each draw generalized least squares is used to fit the 
draws from the multivariate normal distribution. The final DR curve estimate is the median of 
these predictions while confidence intervals will be calculated from the quantiles. The final DR 
curve estimate with the model-based two-sided 90% confidence interval will be presented 
graphically.  
Step 2 might be skipped and replaced by ANOVA if data is not sufficient to support the 
modelling step. 
All data related to safety, efficacy and other assessments including PK exposure will be taken 
into consideration to propose a dose for further studies. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
Intercurrent events of primary estimand will be addressed with hypothetical strategy: 
• Treatment discontinuations for any reason or interruptions of dosing beyond acceptable 
limits: the treatment effect will be imputed as if the treatment had continued or dosing had 
not been interrupted and participant behaved like other participants from the same treatment 
group whose treatment discontinuation/interruption is within the acceptable limits. The 
limits are reached if one or both of the criteria below are met: 
1. >25% missed doses (i.e., >4 doses missed during DRF) 
2. 2 or more consecutive weeks off treatment prior to the Week 17 visit (LP) 
• Intake of prohibited medications without discontinuation of study drug: the treatment effect 
will be imputed as if the prohibited medications had not been taken and participant behaved 
like other participants from the same treatment group who did not take prohibited 
medications 
• AE/SAE/Death or any other intercurrent events leading to endpoint missing: the treatment 
effect will be imputed as if the intercurrent events had not occurred and participant behaved 
like other participants from the same treatment group who did not experience such 
intercurrent events. 
12.4.4 
Handling of missing values not related to intercurrent event 
As stated in the primary estimand, the question of interest is the treatment effect in participants 
who, had treatment continued over 16 weeks with limited dose interruption/discontinuation. 
Participants with primary endpoint missing for any other reason not related to intercurrent event, 
will have the value(s) imputed using multiple imputation (MI) methods under a missing at 
random (MAR) assumption. The proportion of participants with missing primary endpoint at 


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week 17 will be compared among different doses and placebo. More implementation details of 
the multiple imputation (MI) will be specified in the SAP.  
12.4.5 
Supportive analyses 
• Modelling of DR relationship will be repeated by including additional covariate CAG age 
product (CAP) score which is derived from age and CAG length 
• Modelling of DR relationship will be performed as an additional primary supportive 
analysis by Disease stage (1 and 2). 
12.4.6 
Sensitivity analyses for primary endpoint/estimand 
Sensitivity analyses will be specified in the SAP. 
12.4.7 
Supplementary analysis 
Supplementary analysis will be specified in the SAP (including investigating the robustness of 
the MCP-Mod). 
12.5 
Analysis of secondary endpoints/estimands 
Safety endpoints as one of the primary endpoints will be described in Section 12.5.2. 
Secondary variables are: 
• Clinical endpoints: Unified Huntington's Disease Rating Scale (UHDRS) Total Functional 
Capacity (TFC), UHDRS Total Motor Score (TMS), UHDRS Independence Scale (IS) 
• Volumetric MRI (vMRI): Ventricular, Caudate and Total Brain Volume 
Other biomarkers: total HTT and mHTT protein in CSF and plasma. 
In addition to the above listed efficacy and biomarker outcomes, the following are secondary 
PK outcome parameters: 
• PK parameters (e.g. AUClast, AUCtau, Cmax, Tmax, Ctrough) of branaplam and its 
metabolite UFB112 in plasma across the study duration 
• Concentrations of branaplam and its metabolite UFB112 in CSF and concentration ratio 
CSF/plasma of the analytes 
No multiplicity adjustment will be carried out for secondary analyses. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
As per the USM, the original planned statistical modelling and OLE period are no longer 
applicable. Secondary efficacy endpoints will be summarized descriptively. 
UHDRS Total Functional Capacity (TFC). The TFC consists of five items and ranges from 0 
to 13. A higher TFC score indicates better functional capacity. 
UHDRS Total Motor Score (TMS). The range of TMS is 0 to 124, with higher scores indicating 
more severe motor impairment. 
UHDRS Independence Scale (IS). The IS measures the level of independence by one single 
score between 10 and 100. 


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For the three efficacy secondary endpoints, data will be reported over three periods as follows: 
1. DRF: An analysis of change from baseline to week 17 will be performed using ANCOVA 
model with treatment group as factor and adjusting for important covariates for DRF period 
at the time of IA (based on Full Analysis Set). 
2. Core: descriptive statistics of the change from baseline to the end of Core will be presented 
by treatment group and compared to placebo (based on Full Analysis Set) 
3. Core + OLE: descriptive statistics of the change from baseline and baseline-extension (EXT) 
to week 53-EXT will be presented by treatment group originally assigned during core and 
by selected dose(s) for OLE (based on OLS) 
12.5.2 
Safety endpoints 
As per the USM, the OLE period is no longer applicable. Safety analyses will be carried 
out based on the SAF cumulatively. 
As one of the primary endpoint, safety analyses will be carried out based on the SAF for 
summaries including Core Period data, OLSAF for summaries using only OLE data: 
• IA: all safety data from baseline to a cut-off date (a date pre-specified for iDBL) will be 
reviewed by treatment group. 
• End of study: all safety data will be reported cumulatively (Core + OLE) and by two periods 
separately: 
1. Core period (DRF + BE: this would partially overlap with IA, plus the data from BE 
that were not reported at IA) by treatment group 
2. OLE period by treatment group (only if more than one dose is selected for OLE) and 
by treatment group originally assigned in the core period 
Adverse events 
The number (and percentage) of participants with treatment emergent AEs will be summarized 
in the following ways: 
• By primary system organ class and preferred term. 
• By primary system organ class, preferred term and maximum severity. 
• By Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for SAEs, deaths, and study medication related AEs, AEs 
leading to study discontinuation and AEs leading to study drug interruption/discontinuation. 
Vital signs 
Number and percentage of participants with clinically notable vital signs will be presented. 
Participants with clinically notable vital signs will be defined in the SAP. 
Cardiac assessments 
Cardiac assessments will include 12-lead ECG, Echocardiogram (ECHO) with GLS, and 
cardiac enzymes (Troponin and NTproBNP). For each assessment, summary statistics will be 


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provided for each individual parameter, as appropriate. Number and percentage of participants 
with clinically significant abnormalities will be calculated. 
Clinical laboratory evaluations 
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (to be defined in the SAP) will be 
summarized by laboratory parameter. The most extreme post-dose value is considered. For 
selected laboratory tests (e.g., liver enzyme abnormalities), summary statistics of change from 
BL laboratory results will be presented by laboratory test category, visit and treatment group.  
12.5.3 
Pharmacokinetics 
As per the USM, dosing in the study includes only for the 56 mg/week branaplam dose. 
All planned activities will be executed as described below with exception of the dose 
linearity of branaplam for PK plasma parameters. The latter cannot be executed since 
only one dose was tested and, therefore, the analysis is deleted from the analysis plan. 
Branaplam and UFB112 concentrations will be expressed in mass per volume. The plasma and 
CSF concentrations of both analytes will be listed by analyte, treatment, participant, and 
visit/sampling time point. Descriptive summary statistics will be provided by analyte, treatment 
and visit/sampling time point, including the frequency (n, %) of concentrations below the 
LLOQ and reported as zero. 
Summary statistics of plasma and CSF concentrations of branaplam and UFB112 will include 
mean (arithmetic and geometric), SD, coefficient of variation (CV) (arithmetic and geometric), 
median, minimum, and maximum. 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. 
Pharmacokinetic parameters will be calculated as described in Section 8.5.2. Pharmacokinetic 
parameters will be listed by analyte, treatment and participant. Descriptive summary statistics 
of pharmacokinetic parameters will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented. The dose linearity of 
branaplam for PK plasma parameters such as Cmax and AUClast/AUCtau will be explored after 
first and last treatment within the DRF part of the study if data allows. Accumulation ratios of 
branaplam will be assessed for PK plasma parameters such as Cmax and AUClast/AUCtau by 
comparison of PK parameters determined after first and last treatment within the DRF if data 
allows. 
12.5.4 
Biomarkers 
As per the USM notifications of 05-Aug-2022 and 06-Dec-2022, the original planned 
statistical modelling and OLE period are no longer applicable. Secondary endpoint vMRI 
will be summarized descriptively. Due to the limitation of the assay, biomarker data may 
be reported separately except primary endpoint mHTT in CSF.  






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12.7 
Interim analyses 
Cohort Gating Assessments (CGAs) 
Prior to the IA (primary analysis) to select the dose for the OLE and future studies, there will 
be up to two CGAs during the Core Period to determine whether to initiate additional dose 
Cohorts. As described in Section 3, additional Cohorts will be opened up sequentially based on 
safety data review in consultation with the DMC. No inferential and model based statistical 
analyses are planned for CGAs. 
12.8 
Sample size calculation 
Sample size is determined by feasibility and is evaluated using the primary endpoint mHTT 
reduction in CSF from baseline to Week 17. 
12.8.1 
Primary endpoint(s) 
In the analysis, all participants assigned to matching placebo in different treatment arms will be 
pooled together as one placebo group. Bias because of pooling is not expected due to the nature 
of the biomarker endpoint. 
The Multiple Comparison Procedure – Modelling (MCP-Mod) methodology (Bretz et al 2005 
and Pinheiro et al 2014 and Pinheiro et al 2014) will be employed to test for an overall dose 
response (DR) signal and to estimate the DR curve. Five candidate sigmoidal Emax models will 
be used for the testing step with parameter (ED50, h) being (5, 1), (20, 2), (50, 1), (50, 3), and 
(80, 6). 
For the primary endpoint of mHTT reduction in CSF, the planned sample size of N = 75 for 3 
dose arms (3 active treatment groups with n = 20 each and a placebo group with n = 15) will be 
sufficient to reach > 80% power on average for detecting DR signal using MCP-Mod 
methodology (under the MCP step) with one-sided significance level of 5%. The calculations 
are based on assumption of 35% mHTT lowering in CSF (for the highest dose) and 0% mHTT 
lowering for placebo. The assumptions on SD were based on Tabrizi et al 2019a. An inflation 
factor of 50% has been applied to the SD of both the active groups (SD = 0.195) and placebo 
group (SD = 0.471) in order to be conservative leading to an overall treatment effect size of 1 
approximately. The sample size calculation is performed in RStudio 3.6.1 using package 
"DoseFinding". 


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For the safety endpoint, no formal sample size calculation is performed. In general, AEs/SAEs 
with higher incidence rate will be identified more likely. Low incidence AEs/SAEs are less 
likely to be observed until later in the study when there are more participants recruited.  
Table 12-1 presents the likelihood to identify AEs/SAEs at different timing of the cohort gating 
assessments and interim analysis. 
Table 12-1 
Likelihood of Identifying AEs/SAEs with Hypothetical Incidence Rate 
Time of Assessment 
Expected # in active 
group  
Incidence rate 
Likelihood to observe 
at least one AE/SAE 
Cohort Gating 
Assessment 1 
minimum 8 
1% 
8% 
5% 
34% 
10% 
57% 
Cohort Gating 
Assessment 2 
minimum 16 
1% 
15% 
5% 
56% 
10% 
81% 
Interim analysis 
60 
1% 
45% 
5% 
95% 
10% 
99% 
12.8.2 
Secondary endpoint(s) 
The study is not powered for secondary endpoint. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Council on Harmonization (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC,, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis/Novartis 
clinical trial results website and all required Health Authority websites (e.g. Clinicaltrials.gov, 
or EudraCT etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial IInvestigator 
meetings. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 


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Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
13.3 
Quality Control and Quality Assurance 
Novartis/Novartis maintains a robust Quality Management System (QMS) that includes all 
activities involved in quality assurance and quality control, to ensure compliance with written 
Standard Operating Procedures as well as applicable global/local GCP regulations and ICH 
Guidelines. 
Audits of IInvestigator 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 standard operating procedures (SOPs), and are performed according to 
written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an IInvestigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the IInvestigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the IInvestigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 








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16 
Appendices 
16.1 
Appendix 1: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-1 
Liver event and laboratory trigger definitions 
- 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
• 
3 x ULN < ALT / AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
- 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
- 
• 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
- 
• 
ALT or AST > 3 × ULN and INR > 1.5 
- 
• Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN) 
- 
• 
Any clinical event of jaundice (or equivalent term) 
- 
• ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia 
- 
• 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total 
bilirubin; ULN: upper limit of normal 
Table 16-2 
Follow up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 
> 3 × ULN and INR > 1.5 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, continue 
follow-up monitoring 
• 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 
> 3 to ≤ 5 × ULN (participant is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, initiate 
close observation of the 
participant and hold study drug 
until ULN < 3 
• 
Consider every other week 
dosing if ULN <3 after 
discussion with Novartis 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
ALP (isolated) 
- 
- 
> 2 × ULN (in the absence of 
known bone pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish 
causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
TBL (isolated) 
- 
- 
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 


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Criteria 
Actions required 
Follow-up monitoring 
> 1.5 to ≤ 2 × ULN (participant is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, initiate 
close observation of the 
participant 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at IInvestigator 
discretion) 
Any AE potentially indicative of a 
liver toxicity* 
• 
Consider study treatment 
interruption, every other week 
dosing after discussion with 
Novartis or discontinuation of 
study drug  
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN b(General) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia cResolution is defined as an 
outcome of one of the following: (1) return to baseline values, (2) stable values at three subsequent monitoring 
visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, 
and (5) death. 
Based on IInvestigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.  


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16.2 
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-3 
Specific Renal Alert Criteria and Actions 
Renal Event 
Actions 
Confirmed serum creatinine increase 25 – 49% 
• Consider causes and possible interventions 
• Follow up within 2-5 days 
Serum creatinine increase 50 % + 
• Consider causes and possible interventions 
• Repeat assessment within 24-48h if possible 
• Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
• Consider participant hospitalization and specialized 
treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or ≥ 113 
mg/mmol equivalent as converted by the measuring 
laboratory) 
• Consider causes and possible interventions 
• Assess serum albumin & serum total protein 
• Repeat assessment to confirm 
• Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
New onset hematuria ≥ 3+ on urine dipstick 
• Repeat assessment to confirm 
• Distinguish hemoglobinuria from hematuria 
• Urine sediment microscopy 
• Assess sCr 
• Exclude UTI, trauma, bleeding from the distal 
urinary tract/bladder, menstruation and extreme 
exercise 
• Consider bleeding disorder 
+ Corresponds to KDIGO criteria for Acute Kidney Injury 
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.) 
Whenever a renal event is identified, a detailed participant history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event: 
• Blood pressure assessment (after 5-minute rest, with an appropriate cuff size) 
• Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema 
• Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis 


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Table 16-4 
Renal Event Follow Up 
FOLLOW-UP OF RENAL EVENTS 
• 
Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells (dysmorphic/glomerular 
vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells 
• 
Blood pressure and body weight 
• 
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid 
• 
Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) in the eCRF. 
• 
Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr),  
OR 
• 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization 
at a new level with ±50% variability over last 6 months. 
• 
Analysis of urine markers in samples collected over the course of the DIN event 
16.3 
Appendix 3: PK sample log - Time schedule for blood and CSF 
sampling for PK assessments 
Table 16-5 
Plasma PK samples for Core DRF and Blinded Extension 
Day 
Time point 
Dose reference 
ID#  
PK sample # 
(LMI070+UFB112) 
Blood volume 
(mL) 
1 
0 h (pre-dose)(a) 
1(b) 
101 
3 
1 
4 h (±30 min) post-
dose 
1(c) 
102 
3 
1 
7 h (±30 min) post-
dose 
1(c) 
103 
3 
1 
12 h (±30 min) 
post-dose 
1(c) 
104 
3 
2 
22 h (±60 min) 
post-dose 
1(c) 
105 
3 
4 
72 h (±120 min) 
post-dose 
1(c) 
106 
3 
8 
0 h (pre-dose)(a)(g) 
1(c) 
107 
3 
15 
0 h (pre-dose)(a) 
2(b) 
108 
3 
29 
0 h (pre-dose)(a) 
3(b) 
109 
3 
57 
0 h (pre-dose)(a) 
4(b) 
110 
3 
57  
4 h (±30 min) post-
dose 
4(c) 
111 
3 
57 
12 h (±30 min) 
post-dose) 
4(c) 
112 
3 
58 
22 h (±60 min) 
post-dose 
4(c) 
113 
3 
85 
0 h (pre-dose)(a) 
5(b) 
114 
3 
113 
0 h (pre-dose)(a) 
6(b) 
115 
3 
113 
4 h (±30 min) post-
dose 
6(c) 
116 
3 
113 
7 h (±30 min) post-
dose 
6(c) 
117 
3 


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Day 
Time point 
Dose reference 
ID#  
PK sample # 
(LMI070+UFB112) 
Blood volume 
(mL) 
113 
12 h (±30 min) 
post-dose 
6(c) 
118 
3 
114 
22 h (±60 min) 
post-dose 
6(c) 
119 
3 
116 
72 h (±120 min) 
post-dose 
6(c) 
120 
3 
169 
0 h (pre-dose)(a) 
7(b) 
121 
3 
225 
0 h (pre-dose)(a) 
8(b) 
122 
3 
281 
0 h (pre-dose)(a) 
9(b) 
123 
3 
365 (e) 
0 h (pre-dose)(a) 
10(b) 
124 
3 
421 (f) 
0 h (pre-dose)(a) 
11(b) 
125 
3 
477 (f) 
0 h (pre-dose)(a) 
12(b) 
126 
3 
533 (f) 
0 h (pre-dose)(a) 
13(b) 
127 
3 
589 (f) 
0 h (pre-dose)(a) 
14(b) 
128 
3 
645 (f) 
0 h (pre-dose)(a) 
15(b) 
129 
3 
701 (f) 
0 h (pre-dose)(a) 
16(b) 
130 
3 
999 (e) 
EOT 0 h (pre-
dose)(a) 
17(b) 
149 
3 
Plasma PK samples for Open Label Extension 
Day 
Time point 
Dose reference 
ID# 
PK sample # 
(LMI070+UFB112) 
Blood volume 
(mL) 
1 
0 h (pre-dose)(a) 
18(b) 
151 
3 
57 
0 h (pre-dose)(a) 
19(b) 
152 
3 
113 
0 h (pre-dose)(a) 
20(b) 
153 
3 
169 
0 h (pre-dose)(a) 
21(b) 
154 
3 
225 
0 h (pre-dose)(a) 
22(b) 
155 
3 
281 
0 h (pre-dose)(a) 
23(b) 
156 
3 
365 
0 h (pre-dose)(a) 
24(b) 
157 
3 
- 
Unscheduled(d) 
- 
1001+ 
3 
(a) Take sample immediately prior to administration of study drug (within approximately 3 hours prior to dosing) 
(b) For pre-dose PK samples, dose reference # refers to the first dose the subject received immediately after 
collection of the PK sample with exception of sample 107. 
(c) For post-dose PK samples, dose reference # refers to the last dose the subject received prior to collection 
of the PK sample. 
(d) PK samples to be uniquely, sequentially numbered as #001, #002, #003, etc.; the time of unscheduled 
sample has to be recorded accurately in the DRF, BE or OLE study parts. 
(e) Day 365 corresponds to Week 53/EOT in the BE. In the event the BE for the participant is extended beyond 
365 days, the last sample taken in the BE is described as day 999 and is defined as EOT.  
(f) Days of sample collection are scheduled in the event the BE is extended beyond the planned EOT at day 
365 
(g) The sample equals to 168 h after first dosing and pre-dose to second dosing. 


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Table 16-6 
Time schedule for CSF sampling for PK assessments (all patients) 
CSF PK samples for Core DRF and Blinded Extension 
Day 
Time point 
Dose reference 
ID#  
PK sample # 
(LMI070+UFB112) 
volume (mL) 
1 
0 h (pre-dose)(a) 
1(b) 
301 
2 x 0.6 
57 
0 h (pre-dose)(a) 
4(b) 
302 
2 x 0.6 
113 
0 h (pre-dose)(a) 
6(b) 
303 
2 x 0.6 
225 
0 h (pre-dose)(a) 
8(b) 
304 
2 x 0.6 
365 (d) 
0 h (pre-dose)(a) 
10(b) 
305 
2 x 0.6 
477 (e) 
0 h (pre-dose)(a) 
12(b) 
306 
2 x 0.6 
589 (e) 
0 h (pre-dose)(a) 
14(b) 
307 
2 x 0.6 
701 (e) 
0 h (pre-dose)(a) 
16(b) 
308 
2 x 0.6 
999 
0 h (pre-dose)(a) 
17(b) 
349 
2 x 0.6 
CSF PK samples for Open Label Extension  
1 
0 h (pre-dose)(a) 
18(b) 
351 
2 x 0.6 
113 
0 h (pre-dose)(a 
20(b) 
353 
2 x 0.6 
225 
0 h (pre-dose)(a 
21(b) 
355 
2 x 0.6 
365 
0 h (pre-dose)(a 
24(b) 
357 
2 x 0.6 
- 
Unscheduled(c) 
- 
3001+ 
2 x 0.6 
(a) Take sample immediately prior to administration of study drug (within approximately 3 hours prior to dosing) 
(b) For pre-dose PK samples, dose reference # refers to the first dose the subject received immediately after 
collection of the PK sample. 
(c) PK samples to be uniquely, sequentially numbered as #001, #002, #003, etc.; the time of unscheduled 
sample has to be recorded accurately in the DRF, BE or OLE study parts 
(d) *Day 365 corresponds to Week 53/EOT in the BE. In the event the BE for the participant is extended 
beyond 365 days, the last sample taken in the BE is described as day 999 and is defined as EOT. (e) Days 
of sample collection are scheduled in the event the BE is extended beyond the planned EOT at day 365 
 
16.4 
Appendix 4: Biomarker sample log - Time schedule for 
blood/CSF sampling for Biomarker assessments 
Table 16-7 
Blood and CSF Biomarkers 
Core DRF and Blinded Extension 
  
  
  
Day 
Time point 
Dose 
referenc
e ID# 
CSF 
(mHTT/tHTT
) 
CSF 
Biomarker
s (NfL, 
others) 
Plasma 
(mHTT 
/tHTT) 
Baselin
e 
- 
- 
- 
- 
700 
1 
0 h (pre-
dose)(a) 
1(b) 
201 
401 
701 
1 
4 h (±30 min) 
post-dose 
1(c) 
- 
- 
- 
1 
7 h (±30 min) 
post-dose 
1(c) 
- 
- 
- 
1 
12 h (±30 min) 
post-dose 
1(c) 
- 
- 
- 


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Core DRF and Blinded Extension 
  
  
  
Day 
Time point 
Dose 
referenc
e ID# 
CSF 
(mHTT/tHTT
) 
CSF 
Biomarker
s (NfL, 
others) 
Plasma 
(mHTT 
/tHTT) 
2 
22 h (±60 min) 
post-dose 
1(c) 
- 
- 
705 
4 
72 h (±120 
min) post-
dose 
1(c) 
- 
- 
706 
8 
0 h (pre-
dose)(a)(g) 
1(c) 
- 
- 
707 
15 
0 h (pre-
dose)(a) 
2(b) 
- 
- 
708 
29 
0 h (pre-
dose)(a) 
3(b) 
- 
- 
709 
57 
0 h (pre-
dose)(a) 
4(b) 
202 
402 
710 
57  
4 h (±30 min) 
post-dose 
4(c) 
- 
- 
- 
57 
12 h (±30 min) 
post-dose) 
4(c) 
- 
- 
- 
58 
22 h (±60 min) 
post-dose 
4(c) 
- 
- 
713 
85 
0 h (pre-
dose)(a) 
5(b) 
- 
- 
714 
113 
0 h (pre-
dose)(a) 
6(b) 
203 
403 
715 
113 
4 h (±30 min) 
post-dose 
6(c) 
- 
- 
- 
113 
7 h (±30 min) 
post-dose 
6(c) 
- 
- 
- 
113 
12 h (±30 min) 
post-dose 
6(c) 
- 
- 
- 
114 
22 h (±60 min) 
post-dose 
6(c) 
- 
- 
719 
116 
72 h (±120 
min) post-
dose 
6(c) 
- 
- 
720 
169 
0 h (pre-
dose)(a) 
7(b) 
- 
- 
721 
225 
0 h (pre-
dose)(a) 
8(b) 
204 
404 
722 
281 
0 h (pre-
dose)(a) 
9(b) 
- 
- 
723 
365 (e) 
0 h (pre-
dose)(a) 
10(b) 
205 
405 
724 
421 (f) 
0 h (pre-
dose)(a) 
11(b) 
- 
- 
725 
477 (f) 
0 h (pre-
dose)(a) 
12(b) 
206 
406 
726 


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Core DRF and Blinded Extension 
  
  
  
Day 
Time point 
Dose 
referenc
e ID# 
CSF 
(mHTT/tHTT
) 
CSF 
Biomarker
s (NfL, 
others) 
Plasma 
(mHTT 
/tHTT) 
533 (f) 
0 h (pre-
dose)(a) 
13(b) 
- 
- 
727 
589 (f) 
0 h (pre-
dose)(a) 
14(b) 
207 
407 
728 
645 (f) 
0 h (pre-
dose)(a) 
15(b) 
- 
- 
729 
701 (f) 
0 h (pre-
dose)(a) 
16(b) 
208 
408 
730 
999 (e) 
EOT 0 h (pre-
dose)(a) 
17(b) 
249 
449 
749 
Blood and CSF Biomarkers for Open Label Extension 
  
Day 
Time point 
Dose 
referenc
e ID# 
CSF 
(mHTT/tHTT
) 
CSF 
Biomarker
s (NfL, 
others) 
Plasma 
(mHTT/tHTT
) 
1 
0h (pre-
dose)(a) 
18(b) 
251 
451 
751 
57 
0 h (pre-
dose)(a) 
19(b) 
- 
- 
752 
113 
0 h (pre-
dose)(a) 
20(b) 
253 
453 
753 
169 
0 h (pre-
dose)(a) 
21(b) 
- 
- 
754 
225 
0 h (pre-
dose)(a) 
22(b) 
255 
455 
755 
281 
0 h (pre-
dose)(a) 
23(b) 
- 
- 
756 
365 
0 h (pre-
dose)(a) 
24(b) 
257 
457 
757 
- 
Unscheduled(d
) 
- 
2001+ 
4001+ 
7001+ 
(a) Take sample immediately prior to administration of study drug (within approximately 3 hours prior to dosing) 
(b) For pre-dose PK samples, dose reference # refers to the first dose the subject received immediately after 
collection of the PK sample with exception of sample 107. 
(c) For post-dose PK samples, dose reference # refers to the last dose the subject received prior to collection 
of the PK sample. 
(d) Unscheduled samples to be uniquely, sequentially numbered as #001, #002, #003, etc.; the time of 
unscheduled sample has to be recorded accurately in the DRF, BE or OLE study parts. 
(e) Day 365 corresponds to Week 53/EOT in the BE. In the event the BE for the participant is extended beyond 
365 days, the last sample taken in the BE is described as day 999 and is defined as EOT.  
(f) Days of sample collection are scheduled in the event the BE is extended beyond the planned EOT at day 
365 
(g) The sample equals to 168 h after first dosing and pre-dose to second dosing. 


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Table 16-8 
Blood Biomarkers continued 
Core DRF and Blinded Extension 
 
Day 
Timepoint 
Serum biomarkers 
(NfL, Others) 
Screening 
- 
800 
Baseline 
- 
801 
8 
0 h (pre-dose)(a) 
802 
15 
0 h (pre-dose) (a) 
803 
29 
0 h (pre-dose) (a) 
804 
57 
0 h (pre-dose) (a) 
805 
85 
0 h (pre-dose) (a) 
806 
113 
0 h (pre-dose) (a) 
807 
141 
0 h (pre-dose) (a) 
808 
169 
0 h (pre-dose) (a) 
809 
197 
0 h (pre-dose) (a) 
810 
225 
0 h (pre-dose) (a) 
811 
253 
0 h (pre-dose) (a) 
812 
281 
0 h (pre-dose) (a) 
813 
309 
0 h (pre-dose) (a) 
814 
337 
0 h (pre-dose) (a) 
815 
365 
0 h (pre-dose) (a) 
816 
393 
0 h (pre-dose) (a) 
817 
421 
0 h (pre-dose) (a) 
818 
449 
0 h (pre-dose) (a) 
819 
477 
0 h (pre-dose) (a) 
820 
505 
0 h (pre-dose) (a) 
821 
533 
0 h (pre-dose) (a) 
822 
561 
0 h (pre-dose) (a) 
823 
589 
0 h (pre-dose) (a) 
824 
617 
0 h (pre-dose) (a) 
825 
645 
0 h (pre-dose) (a) 
826 
673 
0 h (pre-dose) (a) 
827 
701 
0 h (pre-dose) (a) 
828 
999 
0 h (pre-dose) (a) 
849 
Open Label Extension 
 
 
Day 
Timepoint 
Serum biomarkers 
(NfL, others) 
1 
0 h (pre-dose) (a) 
851 
29 
0 h (pre-dose) (a) 
852 
57 
0 h (pre-dose(a)) 
853 
85 
0 h (pre-dose) (a) 
854 
169 
0 h (pre-dose) (a) 
857 
197 
0 h (pre-dose) (a) 
858 
281 
0 h (pre-dose) (a) 
861 
309 
0 h (pre-dose) (a) 
862 
337 
0 h (pre-dose) (a) 
863 


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Protocol No. CLMI070C12203 
 
Core DRF and Blinded Extension 
 
Day 
Timepoint 
Serum biomarkers 
(NfL, Others) 
365 
0 h (pre-dose) (a) 
864 
Unscheduled 
- 
8001+ 
(a) Take sample immediately prior to administration of study drug (within approximately 3 hours prior to dosing) 
 

SAP_001.pdf: 


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SAP Amendment 1 
Study No LMI070C12203 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
30-
Nov-
2021 
Prior 
to 
FPFV 
Creation of first 
version 
First version 
NA 
20-
Oct-
2023 
Prior 
to 
LPLV 
Protocol 
amended 
Analysis 
will 
be 
done 
descriptively. 
No 
inferential 
statistical testing or statistical 
modelling will be implemented. 
All sections 
26-
Oct-
2023 
Prior 
to 
LPLV 
Protocol 
amended 
PK analysis is added. 


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SAP Amendment 1 
 
Study No LMI070C12203 
 
 
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 design ............................................................................................................ 7 
1.1.1 
Primary estimand(s) ................................................................................ 7 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 14 
2.3.2 
Demographics and other baseline characteristics ................................. 14 
2.3.3 
Medical history...................................................................................... 15 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
A listing showing exposure in doses and days. Prior, concomitant 
and post therapies .................................................................................. 16 
2.5 
Analysis supporting primary objective(s) .............................................................. 16 
2.5.1 
Primary endpoint(s) ............................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.5.3 
Handling of intercurrent events ............................................................. 17 
2.5.4 
Handling of missing values not related to intercurrent event ............... 17 
2.6 
Analysis supporting secondary objectives ............................................................. 17 
2.6.1 
Secondary endpoint(s) ........................................................................... 17 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.6.3 
Handling of intercurrent events ............................................................. 21 
2.6.4 
Handling of missing values not related to intercurrent event ............... 21 
2.7 
Safety analyses....................................................................................................... 22 
2.7.1 
Adverse events (AEs) ............................................................................ 22 
2.7.2 
Deaths .................................................................................................... 24 
2.7.3 
Laboratory data ..................................................................................... 24 


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SAP Amendment 1 
 
Study No LMI070C12203 
 
 
2.7.4 
Other safety data ................................................................................... 25 
2.8 
Pharmacokinetic endpoints .................................................................................... 30 
2.9 
PD and PK/PD analyses ........................................................................................ 30 
 
 31 
2.11 
Biomarkers ............................................................................................................. 31 
2.11.1 
NFL in serum and CSF ......................................................................... 31 
2.11.2 
mHTT in CSF ........................................................................................ 32 
 
 32 
 
 33 
2.13 
Interim analysis (IA) .............................................................................................. 33 
3 
Sample size calculation ..................................................................................................... 33 
3.1 
Primary endpoint(s) ............................................................................................... 33 
3.2 
Secondary endpoint(s) ........................................................................................... 34 
4 
Change to protocol specified analyses .............................................................................. 34 
5 
Appendix ........................................................................................................................... 35 
5.1 
Imputation rules ..................................................................................................... 35 
5.1.1 
Study drug ............................................................................................. 35 
5.1.2 
AE date imputation ............................................................................... 35 
5.1.3 
Concomitant medication date imputation ............................................. 36 
5.1.4 
Values below LLOQ ............................................................................. 36 
5.2 
AEs coding/grading ............................................................................................... 36 
5.3 
Laboratory parameters derivations ........................................................................ 36 
5.4 
Visit windows ........................................................................................................ 36 
5.5 
Notable and abnormality criteria ........................................................................... 41 
5.6 
Rule of exclusion criteria of analysis sets.............................................................. 44 
6 
Reference ........................................................................................................................... 45 


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SAP Amendment 1 
 
Study No LMI070C12203 
 
 
 
List of tables 
Table 1-1 
Original objectives and related endpoints ............................................... 8 
Table 2-1 
 BSI measuring atrophy by region ........................................................ 18 
Table 2-2 
Plasma PK samples schedule for week 1 and week 17 ......................... 20 
Table 2-3 
 AEs indicative of neuro toxicity / peripheral neuropathy .................... 22 
Table 2-4 
 Example of consecutive worsening and recovery for Neuro Exam ..... 28 
Table 2-5 
Nerve Conduction Safety Parameters ................................................... 29 
Table 3-1 
Likelihood of Identifying AEs/SAEs with Hypothetical Incidence 
Rate ....................................................................................................... 34 
Table 5-1 
Imputation of start dates ........................................................................ 35 
Table 5-2 
Visit windows for Neurological Exams, nerve conduction studies, 
weight, urinalysis, C-SSRS, 
 ...................................... 37 
Table 5-3 
Visit window for vital Signs, ECG, Hematology, chemistry, 
NTproBNP, Troponin ........................................................................... 37 
Table 5-4 
Visit windows for echocardiogram ....................................................... 37 
Table 5-5 
Visit windows for ophthalmologic examination ................................... 38 
Table 5-6 
Visit windows for UHDRS scores (TFC, TMS, IS, 
), 
 
 and brain MRI .............................................................. 39 
 
 39 
Table 5-8 
Visit windows for biomarker collected via lumbar puncture 
(
, Nfl
) ..................................................... 40 
Table 5-9 
Clinically notable criteria for vital signs ............................................... 41 
Table 5-10 
Abnormal ranges for ECG .................................................................... 41 
Table 5-11 
Clinically notable criteria for selected hematology tests ...................... 42 
Table 5-12 
Clinically notable criteria for selected chemistry tests ......................... 42 
Table 5-13 
Clinically notable criteria for selected Other Lab parameters .............. 42 
Table 5-14 
Clinically notable criteria for Echocardiogram with GLS .................... 43 
Table 5-15 
Clinically notable liver function test values .......................................... 43 
Table 5-16 
Subject Classification ............................................................................ 44 
 
List of figures 
Figure 1-1 
Study Design Overview .......................................................................... 7 
 


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List of abbreviations 
AE 
BE 
BL 
CRF 
CSF 
CSR 
DMS 
DR 
DRF 
EoS 
Adverse Event 
Blinded extension 
Baseline 
Case Report Form 
Cerebrospinal fluid 
Clinical Study Report 
Document Management System 
Dose response 
Dose range finding 
End of Study 
FAS 
Full Analysis Set 
HD 
Huntington’s disease 
HTT 
Huntingtin  
IA 
Interim Analyses 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mHTT 
Mutan huntingtin 
MI 
Multiple imputation 
OLE 
PBO 
PK 
Open-label extension 
Placebo 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
RAP 
Reporting & Analysis Process 
SAP 
SAS 
SD 
Statistical Analysis Plan 
Statistical Analysis System 
Standard deviation 
TFLs 
UHDRS 
Tables, Figures, Listings 
Unified Huntington's Disease Rating Scales 
 Vol 
Volumetric 
WHO 
World Health Organization 




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Table 1-1 
Original objectives and related endpoints 
Original objective(s) 
Original endpoint(s) 
Will be reported in CSR 
Primary objective(s) 
Endpoint(s) for primary 
objective(s) 
 
• 
To assess the dose-
response relationship of 
branaplam administered 
over 16 weeks on mHTT 
protein change from 
baseline in CSF  
• 
Period: From baseline to 
Week 17 over the Dose 
Range Finding (DRF) 
• Reduction (%) of 
mHTT protein in 
CSF from baseline to 
Week 17. See 
Section 2.1 for Primary 
Estimand 
• 
mHTT protein in CSF 
• 
To evaluate the safety and 
tolerability of branaplam 
when administered for 16 
weeks or longer in 
participants with HD. 
• 
Safety and tolerability 
parameters/assessments 
including but not limited 
to adverse events, 
physical exam (including 
neurological examination), 
findings, clinical laboratory 
assessments, HTT 
lowering, etc. 
• 
AEs 
• 
Neurological exams and 
nerve conduction studies 
• 
Labs, vital signs, ECG and 
etc (details in Section 2.7) 
 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
 
• 
To assess the 
pharmacodynamics of 
branaplam in participants 
with HD on clinical, 
imaging, and biomarker 
endpoints relevant to HD. 
• 
The following endpoints 
will be assessed over 
three periods: 
1. DRF: change from 
baseline to Week 17 
compared to placebo 
2. Core: change from 
baseline to the end of 
Core compared to 
placebo 
3. Core + OLE: change 
from baseline and 
baseline-extension to 
week 53-extension 
• Ventricular, Caudate 
and Total Brain Volume 
as measured by 
structural magnetic 
resonance 
imaging (MRI) 
• Unified Huntington's 
Disease Rating Scale 
(UHDRS) Total 
Functional Capacity 
(TFC), UHDRS Total 
Motor Score (TMS), 
UHDRS Independence 
Scale (IS).  
• 
VolMRI ventricular, caudate 
and total brain volume 
• 
UHDRS TFC, TMS and IS 








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Study day = Assessment date – Day 1 + 1; 
• for dates prior to Day 1: 
Study day = Assessment date – Day 1. 
Baseline  
The baseline value is defined as the last assessment performed prior to start of study treatment. 
In this study, baseline values will be the values obtained during screening, the week of Baseline 
or on Day 1. If the Baseline visit is missing or the assessment was not done at Baseline, the last 
assessment of an earlier visit (scheduled or unscheduled) which is the closest to the Baseline 
visit will be used as Baseline. In case an assessment is repeated at a later visit during the 
screening/baseline epoch, the latest one will be used as Baseline.  Note: Assessments on the day 
of randomization are assumed to have been taken as per protocol, i.e. if the assessment should 
be performed before dosing, the assessment will be treated as pre-dose as per protocol. 
Practically, i.e. that the time part of the date/time entry will be ignored. Exception: In case there 
is a protocol deviation or a comment that specifically indicates that the assessment has been 
taken post-dose, the assessment will not be treated as pre-dose. 
Post-baseline measurement  
Post-baseline measurements are defined as those assessments after the first dose of treatment.   
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available except for 
volumetric (vol) MRI: 
Change from baseline = post-baseline value – baseline value. 
Percent (%) change from baseline= (post-baseline value – baseline value)/baseline value*100%. 
Annualized change from baseline=365.25*change from baseline/ time interval (in days). 
Annualized percent change from baseline=365.25*percent change from baseline/time interval 
(in days). 
Time interval = (date of current assessment – date of baseline assessment + 1). 
Note for MRI data, change is derived via BSI technique, the changes are already provided in 
source data (calculation of change and % change for MRI is available in Section 2.6.2.2).  
Prior and Concomitant Medication 
Prior medication will be defined as any non-study medication taken prior to the first dose of the 
study drug, irrespective of whether the medication continued into the treatment period.  
Any non-study medication administered at least once between the day of first dose of study 
drug and end of the study will be a concomitant medication.  
Therefore, some medications can be categorized as both, prior and concomitant medication.  
Age at clinical HD diagnosis 
It should be estimated from date of clinical HD diagnosis and age at screening as follows: 


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Age at screening+ rounded (down) difference in years between date of clinical HD diagnosis 
and screening date. If partial date is available for HD diagnosis, impute as follows: 
• If only day is missing (year and month are available): impute as the first day of the month 
(01/MON/YYYY) 
• If both day and month are missing (only year is available): impute as mid date of the year 
(01/JUL/YYYY) 
In case HD diagnosis occurred in the same year as screening, the difference will be set to 0 
(instead of rounding down). 
On/off treatment 
On treatment flag will be created for efficacy and safety endpoints including sNFL, volMRI, 
clinical endpoints, Nerve Conduction Studies (NCS), neuro exam, neuropathy symptoms 
 
at visit level. An assessment is defined as on treatment if the collection date ≤ { last 
dosing date + 13}. An assessment is defined as off treatment if the collection date ≥ { last dosing 
date + 14}. 
Visit windows 
Visit-windows will be used for by visit summary tables. For any assessment, there are the 
protocol defined scheduled visits around which visit windows were created to cover the 
complete range of days within the study. When visit windows are used, all visits will be re-
aligned, i.e., they will be mapped into one of the visit windows.  
However, for figures that involves individual trajectory (NFL, volMRI, mHTT) and for reports 
related (regarding worsening and recovery) to Neuro exam or Neuropathy questionaire, an 
additional analysis visit based on actual analysis time (in weeks) instead of mapped windows 
will be used. This will be derived as ceiling of{ADY/7 }. ADY is study day defined in Section 
2.1.1. 
Details on calculation of visit windows based on the protocol will be provided in Section 5.4. 
2.2 
Analysis sets  
The Screened set will consist of all screened participants. 
The Randomized Analysis Set (RAS) will consist of all participants who received a 
randomization number, regardless of whether participants received study medication. 
The Full Analysis Set (FAS) will consist of all randomized participants who received at least 
one dose of study drug.  
The Safety Set (SAF) will consist of all participants who received at least one dose of study 
drug. All analysis will be conducted on SAF except PK related analysis. 
The PK analysis set will consist of all participants with at least one evaluable concentration 
data sample. All PK analysis will be conducted on PK analysis set. 
2.2.1 
Subgroup of interest 
Below participants will be flagged at participants level for various analyses: 


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• Participants with subdural hematoma. This will be used for volMRI analysis. 
• AEs indicative of neuro toxicity/peripheral neuropathy. This will be used for recovery 
analysis. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Analyses for subject disposition, demographic characteristics, other baseline characteristics, 
will be summarized based on SAF by treatment group. Descriptive statistics of mean, standard 
deviation, minimum, median and maximum will be used for continuous variables. Frequency 
distributions will be used for categorical variables.  
2.3.1 
Patient disposition 
Summary tables 
• The number and proportion of participants, who completed the study will be presented by 
treatment group.  
• The number and proportion of participants who discontinued the study prematurely along 
with the primary reason for discontinuation will be presented by treatment group.  
• The number and proportion of participants who discontinued the study drug prematurely 
along with the reason for the study drug discontinuation will be summarized and presented 
by treatment group. 
• The number and percentage of participants in each analysis set described above will also be 
presented. Reason for screen failure will be summarized for all screen-failed participants. 
• The number and percentage of participants with protocol deviations will be summarized by 
treatment group and following category: 
o Selection criteria not met 
o Participants not withdrawn as per protocol 
o Treatment deviation  
o Prohibited concomitant medication 
o Other deviations (important deviations that do not fall in the above four categories) 
Listings 
Listing will be provided for primary reason for early discontinuation. 
2.3.2 
Demographics and other baseline characteristics 
Summary tables 
Patient demographics will be summarized with descriptive statistics for the SAF by treatment 
and overall. Parameters include: 
• Age (at screening) 


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• Sex 
• Race 
• Ethnicity 
• Height 
• Weight 
• BMI 
• Educational level, years of education 
• Smoking and alcohol history 
• Country/region 
Summary of HD history will include: 
• CAG repeat length (larger allele from central lab) 
• CAG age product (CAP) score defined as  
o Definition 1: CAP score = (length of CAG repeat – 35.0) × age at screening 
o Definition 2: CAP score = (length of CAG repeat – 30.0)/6.49 × age at screening 
• Family history: 
o a Parent affected: (only) mother affected, (only) father affected, both parents 
affected, no parent affected, and unknown 
• Age at clinical HD diagnosis (defined in Section 2.1.1) 
Other baseline characteristics: 
• Unified Huntington's Disease Rating Scales (UHDRS)  
o Total Function Capacity (TFC) 
o Total motor score (TMS) 
o Independence scale (IS) 
 
 
 
 
 
 
• mHTT protein in CSF  
• volMRI by region 
2.3.3 
Medical history  
Medical history entered on the Medical History (MH) eCRF will be coded with the Medical 
Dictionary for Regulatory Activities terminology (MedDRA) using the most recent version at 
the time of reporting.  


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Summary tables 
Relevant medical history and current medical condition will be summarized by primary system 
organ class (SOC), preferred term (PT) and treatment group using the SAF.  
 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The SAF will be used for the below analyses. 
Summary tables 
• Duration of total follow-up time (including both on and off treatment period) will be 
summarized descriptively by number of weeks. 
• Duration of exposure to study drug (only on treatment period) will be summarized 
descriptively by number of doses and in days. 
The investigational drug is applied as a weekly dose. Exposure in days will be calculated by the 
number of doses taken × 7 days using category (≥ 1mos, ≥ 2 mos., ≥ 3 mos., ≥ 4 mos., ≥ 5 mos.. 
etc.). 
Figures 
• Follow-up time (in weeks) will be displayed graphically for each individual, color coded by 
treatment group and using different shades for on and off treatment. 
Listings 
2.4.2 
A listing showing exposure in doses and days. Prior, concomitant and 
post therapies 
Please refer to Section 2.1.1 for the definition of prior and concomitant medication. 
Summary tables 
• The number and percentage of participants receiving concomitant medications and 
significant non-drug therapy will be summarized using the SAF by ATC class and preferred 
term (according to the World Health Organization drug dictionary (WHO-DD), including 
Anatomical Therapeutic Chemical (ATC) classification code, using the most recent version 
at the time of reporting), by treatment group and overall. 
• Prior medication and non-drug therapies will also be summarized in a similar way. 
2.5 
Analysis supporting primary objective(s) 
Due to the early termination, the primary estimand and statistical modelling for dose-response 
relationship is no longer applicable. Primary endpoint of mHTT in CSF will be summarized 
descriptively. No sensitivity analysis or supplementary analysis will be performed. 
The other primary endpoint safety and tolerability will be detailed the safety Section 2.7. 


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2.5.1 
Primary endpoint(s) 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The efficacy primary endpoint is the % change from baseline of mHTT protein concentration 
in CSF at week 17, which is expressed as: 
(mHTTwk17 - mHTTbaseline)/ mHTTbaseline * 100% 
Summary tables 
• Summary statistics of raw, change, % change and annualized % change by visit  
• Difference between active and placebo for % change by visit 
• Mean time (in days) from last dose to lumbar puncture (LP)  for week 9 and 17 (protocol 
scheduled visit window will be used to derive week 9 and week 17) 
Days from last dose to LP = date of {LP} - date of {previous dosing date} 
Note, if a dose is taken on the same day of LP performed, the previous dosing date should be 
used instead of the same day.  
Figures 
• Spaghetti plot of % change over time (using actual weeks)  
• Mean % change over time (using scheduled weeks) and error bar (standard error) by 
treatment group (group average and N will be added on x-axis) 
2.5.3 
Handling of intercurrent events  
Not applicable. 
2.5.4 
Handling of missing values not related to intercurrent event 
The missing values will be treated as missing. Unless otherwise stated, missing data will not be 
inputed for the analysis. 
2.6 
Analysis supporting secondary objectives  
2.6.1 
Secondary endpoint(s) 
The secondary objective is to assess  
• The pharmacodynamics (PD) of branaplam in participants with HD on clinical, imaging and 
biomarker endpoints relevant to HD. 
• The pharmacokinetics (PK) of branaplam and its metabolite UFB112 in plasma and CSF 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Secondary endpoints include: 
• Clinical endpoints: Unified Huntington's Disease Rating Scale (UHDRS) Total Functional 
Capacity (TFC), UHDRS Total Motor Score (TMS), UHDRS Independence Scale (IS) 


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• Vol MRI: Ventricular, Caudate and Total Brain Volume 
• PK: branaplam and its metabolite UFB112 in plasma and CSF.  
• The biomarker secondary endpoints (total HTT in CSF, 
 plasma, and mHTT in 
 plasma) will NOT be reported due to assay issues with the vendor. 
2.6.2.1 
Clinical endpoints 
Summary tables 
• The clinical endpoints will be summarized with appropriate descriptive tables by visit, and 
treatment group.  
Figures 
• Average change from baseline with error bars (standard error) will be provided by group 
(group average and N will be added on x-axis)  
2.6.2.2 
Volumetric MRI 
In order to assess atrophy rate, volMRI images from follow-up timepoints are compared to those 
from earlier timepoints using the boundary shift integral (BSI) technique in selected brain 
regions. The technique determines the total volume through which the boundaries of a given 
cerebral structure have moved, and hence, it aims at quantifying the amount of change in these 
selected brain regions. Absolute volume is provided using Medical Image Display and Analysis 
Software (MIDAS). BSI change is provided by vendor directly in the database, % change and 
annualized % change will be derived using BSI change and baseline from MIDAS. The output 
of the method is a change from BL in volume (atrophy). The direction of change (BSI) varies 
by region as illustrated in Table 2-1. 
Table 2-1 
 BSI measuring atrophy by region 
Region 
Sign 
direction of change 
Whole brain 
+ 
mean atrophy, ie volume reduction 
Ventricles 
+ 
ventricular expansion, ie volume increase 
Caudate 
+ 
mean atrophy, ie volume reduction 
For all the volMRI analyses, the QC failures (QCGRADE= “Failed”) should always be 
excluded. For ADaM data, the sign will be unified for BSI such that “-“ always indicates atrophy 
(ie a volume reduction), and “+” always indicates an expansion (ie a volume increase) across 
regions. 
Flags: 
• on/off treatment flag will be derived at visit level 
• Participants with subdural hematoma (from AE panel). 
Summary tables 
• Summary statistics of raw, change, % change and annualized % change by visit and by 
on/off trt and by brain region 


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• Repeat after excluding Participants with subdural hematoma 
Figures 
• Spaghetti plot of change, and % change over time (at actual weeks) and by treatment group 
and by brain region 
• Mean % change from baseline with error bars (standard error) will be provided by group at 
scheduled timepoint (group average and N will be added on x-axis) 
• Repeat after excluding Participants with subdural hematoma 
2.6.2.3 
Pharmacokinetic (PK) endpoints 
Sample analysis have been executed using all PK samples available and reconciled by SGS. PK 
samples are only analyzed for participants on active treatment. Therefore, the population of this 
PK report is the active treatment participants whose PK samples were analyzed. 
PK parameters will be estimated using actual times. All unscheduled samples will be reviewed 
and used for PK parameter analysis if they could be assigned to nominal collection times and 
are within the treatment period. Unscheduled samples collected outside of the treatment period 
will not be used for PK parameter assessment if the use cannot be not justified. 
Only few samples have been collected at 12 h at week 1 and week 17. The concentrations at 12 
h will be listed in the concentration listings and presented in the individual spaghetti plots. The 
consideration of the samples for PK parameter analysis will be tested in the PK parameter 
analysis and its use for PK parameter assessment will be decided after data review by the PK 
expert. Due to the limited number of samples for the 12 h time point compared to the other time 
points, both time points will not be used for descriptive statistics per timepoint, and not 
presented in the summary plots. 
Outlier in terms of unexpected high or low concentrations will be identified and reviewed during 
PK parameter estimation. In case an outlier will be identified, the concentration will not be 
included into the descriptive summary statistics of the concentrations at the respective timepoint 
and will also not be used for PK parameter derivation. The justification of the exclusion will be 
added to the concentration data file. The identification of outliers and decision about exclusion 
of extreme concentration values will be handled by the pharmacokineticist of the study. 
Descriptive statistics of branaplam and UFB112 concentrations 
Summary tables 
The following descriptive summary statistics of branaplam and UFB112 concentrations will be 
calculated in plasma and CSF for all available visits and timepoints: mean, geometric mean, 
SD, median, min, max, CV% mean, CV% geometric mean. Geometric mean and CV% will not 
be calculated in case any value is equal to 0. 
Figures 
For branaplam and UFB112 in plasma, spaghetti plots showing longitudinal data of all 
participants across the complete observation period (from first dosing 0 h, showing 
concentrations from all available time points and visits, up to the last available time point) will 


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be presented. In addition, for branaplam and UFB112 in plasma, similar spaghetti plots 
including only the data over the first week will be presented. 
PK parameters in plasma 
Summary tables 
Ctrough will be presented for every visit (from week 2 to week 17). Accumulation ratios 
between  Ctrough later than week 2 and  Ctrough  at week 2 will be calculated. 
For branaplam in plasma, PK parameters including Tmax (h), Cmax (ng/mL), AUC0-168h 
(h*ng/mL), AUCinf (h*ng/mL) will be presented for week 1 and week 17. In addition, the 
accumulation ratio (the week 17/week 1 ratio of the parameter) will be calculated for Cmax and 
AUC0-168h. 
Note that, at the week 17 visit, the PK sample is not collected at 168 h as per design. As 
illustrated in Table 2-2, the time 0 h (pre-dose) concentration value will be used as the 
concentration at 168h, which enables the estimation of the AUC0-168h. 
Table 2-2 
Plasma PK samples schedule for week 1 and week 17 
Week 1 
Day  
Time point 
PK sample # 
1 
0 h pre-dose 
101 
1 
4 h postdose 
102 
1 
7 h postdose 
103 
1 
12 h post-dose  
104 
2 
22 h post-dose 
105 
4 
72 h  
post-dose 
106 
8 
0 h pre-dose as well as 168 h 
post dose 
107 
Week 17 
Day  
Time point 
PK sample # 
113 
0 h pre-dose 
115 
113 
4 h postdose 
116 
113 
7 h postdose 
117 
113 
12 h post-dose  
118 
114 
22 h post-dose 
119 


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116 
72 h  
post-dose 
120 
NA 
168 h post dose will be imputed 
using 0 h pre-dose on day 113 
NA 
 
Figures 
Spaghetti plots for Ctrough will be presented over time (from week 2 to week 17). 
All above analysis will be repeated for UFB112 plasma. In addition, ratio of 
UFB112/branaplam will be calculated for the PK parameters (Cmax and AUClast at week 1 
and 17) and summarized in tables. The UFB112/branaplam ratio will be calculated as follows: 
metabolite ratio = 
 
(PK_parameter_UFB112/PK_parameter_LMI070) * (molecular weight_LMI070/molecular 
weight_UFB112) 
The molecular weights are 393.4 g/mol and 409.4 g/mol for branaplam and UFB112, 
respectively. 
PK parameters in CSF 
Summary tables 
Branaplam concentrations (Ctrough) in CSF (ng/ml) and plasma (ng/ml) will be summarized at 
Week 9 and Week 17, as well as the mean concentration ratios: CSF/plasma and CSF/free 
plasma. The free plasma concentration will be calculated by multiplying the plasma 
concentration by the fraction unbound (fu: branaplam 0.349, fu UFB112: 0.0220, DMPK 
R1900562). 
Figures 
Scatter plots of Ctrough in CSF vs. plasma will be presented to explore the correlation (color 
coded by visit 9 and 17). 
All above analysis will be repeated for UFB112. 
Listings 
Listings will be provided for all concentrations and PK plasma in both serum and CSF. 
2.6.3 
Handling of intercurrent events  
Not applicable. 
2.6.4 
Handling of missing values not related to intercurrent event 
The missing values will be treated as missing. Unless otherwise stated, missing data will not be 
inputted for the analysis. 


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2.7 
Safety analyses 
All safety analyses will be carried out based on the SAF. For some ECG, vital signs and lab 
assessments, if time is expected but missing at the end of study visit, will be imputed as 0 hour 
pre-dose as applicable. 
2.7.1 
Adverse events (AEs) 
AEs will be considered as treatment-emergent (TEAE) if the event is starting after the start of 
double-blind treatment or the event is present prior to start of double-blind treatment but 
increased in severity after the start of treatment based on preferred term. 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. 
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). The MedDRA version used for reporting the study will 
be described in a footnote on AE related outputs. 
Additionally, Participant with AEs indicative of neurotoxicity / peripheral neuropathy (listed in 
Table 2-3) will be flagged at participants level for recovery.  
Table 2-3 
AEs indicative of neuro toxicity / peripheral neuropathy 
SOC 
Preferred Term 
Reported term  
Nervous system disorders 
Axonal and demyelinating 
polyneuropathy 
SENSOMOTORIC AXONAL 
POLYNEUROPATHY 
Nervous system disorders 
Axonal neuropathy 
AXONAL NERVE 
CONDUCTION CHANGE 
Nervous system disorders 
Coordination abnormal 
HAND COORDINATION 
PROBLEM 
Nervous system disorders 
Electric shock sensation 
PAIN LIKE ELECTRIC SHOCK 
RIGHT THIGH 
Nervous system disorders 
Hypogeusia 
HYPOGEUSIA 
Nervous system disorders 
Hyporeflexia 
DECREASE IN REFLEXES 
Nervous system disorders 
Loss of proprioception 
PROPRIOCEPTIVE 
DIFFICULTY IN THE HANDS 
BILATERALLY 
Nervous system disorders 
Neuralgia 
NEUROPATHIC PAIN 
Nervous system disorders 
Neuropathy peripheral 
NEUROPATHIE 
Nervous system disorders 
Paraesthesia 
TINGLING IN THE UPPER 
EXTREMITIES 
Nervous system disorders 
Paraesthesia 
TINGLING IN THE LOWER 
EXTREMITIES 
Nervous system disorders 
Paraesthesia 
PARESTHESIA 
Nervous system disorders 
Paraesthesia 
PARESTHESIA (BILATERAL) 


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SOC 
Preferred Term 
Reported term  
Nervous system disorders 
Paraesthesia 
TINGLING IN THE HANDS 
AND FEET 
Nervous system disorders 
Peripheral sensory neuropathy 
SENSORY NEUROPATHY 
Nervous system disorders 
Polyneuropathy 
POLYNEUROPATHY 
Gastrointestinal disorders 
Oral discomfort 
BURNING MOUTH 
 
 
*THICK FIBER SENSORY 
POLYNEUROPATHY 
PREDOMINANTLY LOWER 
EXTREMITIES ENGLISH 
* Reported term/SOC has not been coded and is subject to change 
Summary tables 
The number (and percentage) of participants with TEAE will be summarized by treatment group 
and presented by the SOCs in alphabetical order and the PTs in descending incidence in the 
total column. A patient with multiple AEs within a given category is only counted once for 
summary purposes. TEAEs, regardless of study drug relationship, will be summarized in the 
following ways: 
• By treatment and PT 
• By treatment and SOC 
• By treatment, SOC and PT 
• By treatment, SOC, PT and maximum severity 
Separate summaries by SOC and PT will be provided for: 
• TEAEs suspected to be study medication related 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to dose interruptions and/or adjustments 
• Serious treatment emergent AEs 
Listings 
Listing will be provided  for all AEs and SAEs. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of special interest. The most recent list of adverse events 
of special interest at the time of database lock will be used. 
Summary tables 
• The number (and percentage) of participants who reported treatment emergent adverse 
events of special interest will be summarized by risk name, PT, maximum severity and 
treatment group.  


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In the summary table, risk names will be sorted alphabetically and, within each risk name, the 
PTs will be sorted in descending order of frequency in the total column. If a patient reported 
more than one adverse event with the same PT, the AE will be counted only once. If a patient 
reported more than one AE within the same risk, the patient will be counted only once at that 
risk.  
• SAEs of special interest will also be summarized by risk name, PT, maximum severity and 
treatment group. 
2.7.2 
Deaths 
Summary tables 
Deaths regardless of relationship to study drug by SOC and PT will be summarized on the SAF. 
Listings 
Deaths will be listed by treatment including the start date of the study treatment, the last date 
on study treatment, the death date and the primary cause (and contributing cause if any) for 
death. 
2.7.3 
Laboratory data 
Only central lab parameters will be included in reporting. The summary of laboratory 
evaluations will be presented for six groups of laboratory tests: Chemistry, Hematology, 
Urinalysis, Coagulation, Pregnancy Test and additional tests. On presenting abnormalities 
laboratory data will be grouped and displayed in an alphabetical order within each of the six 
groups.  
Summary tables 
• Absolute values and change from baseline will be summarized for continuous laboratory 
parameters by visit.  
• For selected laboratory tests, the number and percentage of participants with newly 
occurring or worsening laboratory/liver enzyme abnormalities meeting the clinically 
notable criteria at any time post baseline will be summarized. Clinically notable criteria are 
defined in Appendix 5.5.  
For a participant to meet the criterion of a newly occurring clinically notable value, the 
participant needs to have a baseline value that is not clinically notable for that parameter. For a 
participant to meet the criterion of a worsening clinically notable value, the participant needs to 
have a baseline value that is clinically notable and also have a worse post-baseline value. For 
participants with missing baseline value, any post-baseline notable value will be considered as 
newly occurring.  
For each participant, all applicable post-baseline values (including unscheduled or unplanned 
visits) will be checked against the respective criteria. If at least one of the results, for a particular 
parameter, exceeds the criteria, the participant will be considered as clinically notable abnormal 
for that parameter. A participant can be counted in both low and high categories. If multiple 


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abnormality occurrences exist for the same lab parameter, the worst case within a lab parameter 
will be used to categorize the abnormality. 
Figures 
• Box-plots for lab parameters will be provided over time by treatment group. 
Listings 
• Laboratory data of participants with at least one clinically notable value will be listed.  
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
ECG 
Triplicate ECGs (3 ECGs are collected) are performed at week 1 and week 9. Regular ECGs 
are performed for the rest of scheduled visits. ECG clinically significant abnormalities will be 
recorded on the eCRF as either medical history/current medical conditions or AEs as 
appropriate. For the analysis of continuous ECG parameter, for triplicate ECG, the mean value 
of the 3 ECG measurements will be used, for ECG interpretation, all findings of the 3 ECGs 
will be considered. ECG parameters include heart rate, PR duration, QT duration, QRS duration, 
QTcF (QT corrected using Fridericia’s correction formula). 
Summary tables 
• Absolute values and change from baseline will be summarized for ECG parameters by visit 
and time point. 
• The number and percentage of participants with newly occurring or worsening ECG 
abnormalities at any post-baseline visits will be summarized.  
For derivation of notable values of triplicate ECG, the mean of the triplicate ECGs will be used. 
Notable criteria are defined in Appendix 5.5.  
Listings 
ECG data of participants with at least one abnormal value will be listed. 
Echocardiogram with Global Longitudinal Strain (GLS) 
Two dimensional echocardiography measurements will be assessed during the study. Central 
assessment results will be used for reporting.  
Summary tables 
Descriptive statistics will be summarized for the following parameters by visit: 
• Left ventricular ejection fraction (LVEF) 
• Left Ventricular Global Longitudinal Strain (LVGLS) 
The number and percentage of participants with clinically notable values at any post baseline 
visits will be summarized by period, parameters. The clinically notable are defined in 
Appendix 5.5. 
Listings 


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Echocardiogram data will be listed for the participants with clinically notable values.  
2.7.4.2 
Vital signs 
Vital signs includes temperature, blood pressure (sitting systolic and diastolic) and pulse. 
Summary tables 
• Absolute values and change from baseline will be summarized for vital signs parameters by 
visit.  
• The number and percentage of participants with newly occurring or worsening clinically 
notable vital sign values at any time post baseline will be summarized. Clinically notable 
changes are defined in Appendix 5.5. All applicable post-baseline values (including 
unscheduled or unplanned visits) will be checked against the respective criteria. 
Figures 
• Box-plots for vital signs parameters will be provided over time by treatment group. 
Listings 
• Vital signs data of participants with at least one clinically notable value will be listed.  
2.7.4.3 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses suicidal ideation and suicidal behavior. The C-SSRS must be administered at each visit, 
including unplanned visits. At the first study visit, the “baseline/screening” version of the C-
SSRS will be administered. This version assesses suicidal ideation and suicidal behavior during 
the participant's lifetime and during a predefined period. At subsequent visits, the “since last 
visit” version will be administered. AE and SAE will be reported respectively for events of 
“Non-Suicidal Self-Injurious Behavior” and life-threatening events.  
Summary tables 
• Summary showing numbers and percentages of participants who have an answer “yes” to a 
suicidal behavior or ideation category at any post-baseline visit. 
• The number and percentage of participants who have an answer “yes” to a suicidal behavior 
or ideation category for the lifetime assessment at screening will be included. 
Listings 
• All data of participants with any “Yes” on item 4 or item 5 of the Suicidal Ideation section 
of the CSSRS or any “Yes” on any item on the suicidal behavior section will be listed. 
2.7.4.4 
Neurological Exam 
Neurological examinations are conducted at each visit to monitor for any clinically significant 
abnormalities. The exam has three subcategories: Motor function, Deep tendon reflexes and 
Sensory system. Each subcategory includes multiple exams on various body locations. AE and 
SAE will be reported respectively in case of clinically significant findings.  


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A worsening at post BL is defined as: a decrease from baseline and the score is NOT normal. 
In order to systematically summarize the worsening from baseline, the following flags will be 
created to capture different degrees of worsening and recovery: 
Flags by visit and by parameter level: 
 By visit flag 1 (worsening): reduced grade (decrease) in at least 2 consecutive visits post 
BL (same worsening at the same parameter/location/laterality). Flag the last visits with 
worsening. 
 By visit flag 2 (recovery): For participants who met the criterion for 2 consecutive visits, 
flag visits after last visit with worsening (this worsening stands for any worsening and 
don’t have to be consecutive) that the grade is back to baseline  
Flags by participant level and by three subcategories based on the above visit-based:  
 participant level flag 1: Participant without any worsening at 2 consecutive visits by 
Motor function, DTR, and Sensory 
 participant level flag 1.5: Participant without any worsening at 2 consecutive visits in 
any subcategory 
 participant level flag 2 (worsening): Participant with any worsening at 2 consecutive 
visits by Motor function, DTR and Sensory 
 participant level flag 3 (recovery): Participant with any worsening at 2 consecutive visits 
followed by recovery (worsening no longer present in all parameters within the category) 
by Motor function, DTR and Sensory 
 participant level flag 4 (partial recovery): Participant with any worsening at 2 
consecutive visits followed by partial recovery (worsening no longer present in at least 
one of the parameters within the category) by Motor function, DTR and Sensory 
 participant level flag 5 (overall worsening): Participant with worsening at 2 consecutive 
visits in any subcategory 
 participant level flag 6 (overall recovery): Participant with worsening at 2 consecutive 
visits in any subcategory followed by recovery (recovered in all parameters)  
 participant level flag 7 (overall partial recovery): Participant with worsening at 2 
consecutive visits in any subcategory followed by partial recovery (worsening no longer 
present in at least one of the parameters)  
Note that flags will be created based on weekly basis window instead of protocol scheduled 
visit window. 
Tables 
• Summary tables showing number and frequencies of participants for the following 
categories: no consecutive worsening; consecutive worsening; partial recovery; full 
recovery by category Motor function, DTR and Sensory and overall  




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 Participant level flag 3 (recovery): participants with any finding at 2 consecutive visits 
and followed by recovery (finding no longer present in all worsened questionnaire) 
 Participant level flag 4 (partial recovery): participants with any finding at 2 consecutive 
visits and followed by partial recovery (finding no longer present in at least one of the 
worsened questionnaire) 
 Participant level flag 4: Participant without any finding at any visit 
 Participant level flag 5: participants with any finding at any visit 
 Participant level flag 6 (recovery): participants with any finding and followed by 
recovery (finding no longer present in all worsened questionnaire) 
Participant level flag 6.5 (partial recovery): participants with any finding and followed by partial 
recovery (finding no longer present in at least one of the worsened questionnaire)Note that, 
flags will be created based on weekly basis window instead of protocol scheduled visit window. 
 
Tables 
• Summary tables showing number and frequencies of participants with at least 2 
consecutive worsening change, recovery and partial recovery  
• Summary tables showing number and frequencies of participants with any worsening 
change recovery and partial recovery  
Listings 
• Listing will be provided for participants with consecutive findings. 
2.7.4.6 
Nerve conduction study (NCS) 
NCS are conducted at baseline and repeated in every patient as per USM. 
Table 2-5 
Nerve Conduction Safety Parameters 
Maximum of 3 measures performed per nerve 
1a Sural SNAP Measurement #1 #2 #3 
1b Sural Sensory NCV measurement #1 #2 #3 
2a Tibial CMAP measurement #1 #2 #3 
3b Tibial Motor NCV measurement #1 #2 #3 
Numbers with a/b refer to the fact that these measurements are yielded from one and the same 
stimulation. 
There are four parameters included in NCS indicated in Table 2-5, each will be measured three 
times on either laterality or both. For each parameter, per visit, the max value will be derived 
to calculate change from baseline: 
Change = max (post-BL measurement #1,  #2,  #3) - max (BL measurement #1,  #2,  #3)  
Note that, if a measurement is not repeated three times, max will be derived using available 
measurements (maybe less than three times).  
The following flags and analyses will be created to capture worsening and recovery for each 
parameter by laterality: SNAP, sural NVC, tibial NCV and CMAP: 


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Flags by visit level: 
 By visit flag 1: ≥50% reduction  
 By visit flag 2 (recovery): For participants who met the criterion flag1 reduction ≥ 50%: 
Flag the visits after last visit with reduction ≥50% that the criteria (reduction ≥50%) is no 
longer met  
Flags by participant level for each parameter SNAP, sural NVC, tibial NCV and CMAP based 
on the above visit-based:  
 Participant level flag 1: participants without any reduction ≥50% at any visit on any side 
 Participant level flag 2: participants with a reduction of ≥ 50% at any visit on any side 
 Participant level flag 3: participants with reduction of ≥ 50% at any visit and followed by 
recovery for all the side(s) that had worsening 
Tables 
• For each parameter, summary tables showing number and frequencies of participants 
with reduction of  ≥ 50% at any visit, and followed by recovery and partial recovery 
Listings 
Listing will be provided for participants and parameters with findings. 
2.7.4.7 
Overall safety findings and recovery 
Results from Neuro findings including: NCS, neuro exam, symptoms (AEs and neuro 
questionnaire) will be summarized in one table for participants on active to show number (%) 
of participants with finding together with the information about recovery (yes/no) at the end of 
observation. 
2.7.4.8 
Ophthalmologic Examination 
New findings/changes in ophthalmologic examination, compared to baseline or previous 
assessment considered clinically significant will be documented and reported as AE.  
Summary tables 
Frequency table will be provided for any retinal atrophy by visit.  
Listings 
Listing will be provided for participants with retinal atrophy.  
 
2.8 
Pharmacokinetic endpoints  
PK as secondary endpoint analysis is described in Section 2.6. 
2.9 
PD and PK/PD analyses 
Not applicable 


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2.11 
Biomarkers 
2.11.1 
NFL in serum and CSF 
Serum and CSF NFL levels are used to monitor neurotoxicity.  
Visit level Flags: 
• on/off treatment (serum only) 
• sNFL > 100 pg/mL  
• sNFL > 2 x BL sNFL 
• sNFL: > 100 pg/mL or > 2 x BL 
• sNFL recovery: for participants who met the criterion for any increase of sNfL (sNFL > 100 
pg/mL or sNFL > 2 x BL sNFL) at any visit: Flag the visits after last visit with increase that 
criteria are no longer met (sNFL ≤ 100 pg/mL and sNFL ≤ 2 x BL sNFL) 
• CSF NfL > 10000 pg/ml 
• CSF NfL > 2 x BL CSF NfL 
• CSF NfL > 2 x CSF NfL of the previous assessment 
• CSF NfL > 2 x BL CSF NfL or CSF NfL > 2 x CSF NfL of the previous assessment 
• CSF NfL > 10000 pg/ml or CSF NfL > 2 x BL CSF NfL or CSF NfL > 2 x CSF NfL of the 
previous assessment 
• CSF NfL recovery: for participants who met the criterion for any increase of CSF NfL at 
any visit: Flag the visits after last visit with increase that criteria are no longer met (CSF 
NfL ≤ 10000 pg/ml and CSF NfL ≤ 2 x BL CSF NfL and CSF NfL ≤ 2 x CSF NfL of the 
previous assessment) 
Participant level flag: 
• Participant without any increase in sNfL 
• participants with any increase in sNfL 
• participants with any increase in sNfL followed by recovery (sNFL ≤ 100 pg/mL and sNFL 
≤ 2 x BL sNFL) 
• Participant without any increase in CSF NfL; 
• participants with any increase in CSF NfL;  
• participants with any increase in CSF NfL followed by recovery (CSF NfL ≤ 10000 pg/ml 
and CSF NfL ≤ 2 x BL CSF NfL and CSF NfL ≤ 2 x CSF NfL of the previous assessment) 






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The Multiple Comparison Procedure – Modelling (MCP-Mod) methodology (Bretz et al 2005 
and Pinheiro et al 2014) will be employed to test for an overall dose response (DR) signal and 
to estimate the DR curve. Five candidate sigmoidal Emax models will be used for the testing 
step with parameter (ED50, h) being (5, 1), (20, 2), (50, 1), (50, 3), and (90, 6). 
For the primary endpoint of mHTT reduction in CSF, the planned minimum sample size of N 
= 75 for 3 dose arms (3 active treatment groups with n = 20 each and a placebo group with n = 
15) will be sufficient to reach > 80% power on average for detecting DR signal using MCP-
Mod methodology (under the MCP step) with one-sided significance level of 5%. Power will 
be higher if Cohort 3 and/or Cohort 4 are initiated (N=80 and 100 respectively). The calculations 
are based on assumption of 40% mHTT lowering in CSF (for the highest dose) and 0% mHTT 
lowering for placebo. The assumptions on SD were based on Tabrizi et al 2019. An inflation 
factor of 50% has been applied to the SD of both the active groups (SD = 0.195) and placebo 
group (SD = 0.471) in order to be conservative leading to an overall treatment effect size of 1. 
The sample size calculation is performed in RStudio 3.6.1 using package "DoseFinding". 
For the safety endpoint, no formal sample size calculation is performed. In general, AEs/SAEs 
with higher incidence rate will be identified more likely. Low incidence AEs/SAEs are less 
likely to be observed until later in the study when there are more participants recruited. 
Table 3-1 presents the likelihood to identify AEs/SAEs at different timing of the cohort gating 
assessments and interim analysis. 
Table 3-1 
Likelihood of Identifying AEs/SAEs with Hypothetical Incidence Rate 
Time of Assessment 
# in active group  
Incidence rate 
Likelihood to observe 
at least one AE/SAE 
Cohort Gating 
Assessment 1 
16 
1% 
15% 
5% 
56% 
10% 
81% 
Cohort Gating 
Assessment 2 
24 
1% 
21% 
5% 
71% 
10% 
92% 
Cohort Gating 
Assessment 3 
32 
1% 
28% 
5% 
81% 
10% 
97% 
Interim analysis 
Minimum 60 
1% 
45% 
5% 
95% 
10% 
99% 
3.2 
Secondary endpoint(s) 
The study is not powered for secondary endpoint. 
4 
Change to protocol specified analyses 
See above. 


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5 
Appendix 
5.1 
Imputation rules 
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 date imputation 
To decide whether the event 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. 
• If both start date and time are missing, the event will be defined as being post-dosing. 
 
Table 5-1 
Imputation of start dates 
 
Missing elements 
Rule 
Day, month, and year 
The date uncertainty is too high to impute a rational date. 
Therefore, if the year value is missing, the imputed start date is set 
to NULL. 
Day and month 
• If available year = year of study treatment start date then 
− If end date contains a full date and end date is earlier than 
study treatment start date then set start date = 01JanYYYY 
− 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 
− If end date contains a full date and end date is earlier than 
study treatment start date then set start date= 
01MONYYYY. 
− Else set start date = study treatment start date. 
• If available month and year > month and year of study 
treatment start date then 01MONYYYY 


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• If available month and year < month year of study treatment 
start date then 15MONYYYY 
 
5.1.3 
Concomitant medication date imputation 
The same rule as AE imputation will be applied. 
5.1.4 
Values below LLOQ 
For biomarker parameters, values below the lower limit of quantification (LLOQ) will be set to 
LLOQ/2 for statistical analysis. LLOQ value may differ across samples. For statistical analysis, 
the sample specific LLOQ and ULOQ value should be used. 
5.2 
AEs coding/grading 
AEs are coded using the MedDRA terminology. The latest version of MedDRA will be used 
and will be specified in the footnote of relevant output.  
AEs grade are assessed by investigators and captured on the AE CRF based on three levels: 
mild, moderate, and severe. 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Visit windows 
In general, if two consecutive visits Vt and Vs are x days apart, the upper limit of the visit 
window for Vt will be Vt+x/2 and the lower limit for the visit Vs will be Vs-x/2 +1 (if x is 
even). The algorithm needs to ensure that visit windows are not overlapping and that there are 
no gaps, such that each assessment can be uniquely allocated to one visit window. 
Both scheduled and unscheduled assessments will be considered. 
In case of competing assessments within a visit window: 
- 
For efficacy parameters: the assessment value closest to the scheduled visit day will be 
used. In case of equal distances, the earliest assessment value will be used.  
- 
For safety parameters: the worst assessment value within the visit window will be used 
(see Section 5.4). If more than one assessments are equally worst, the one closer to visit 
window will be used. 
Note that NFL (both serum and CSF) will be considered as safety parameters (the higher 
the worse). 
For tables displaying the worst-case scenario for safety assessment, all assessments within a 
visit window will be used to identify the worst.  
Listings will include all assessments, sorted by date of assessment, flagging unscheduled visits. 
The listings will flag to indicate the assessment’s inclusion in the analysis. 


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In the below tables, the end of Core period is defined as the day of last assessment for Core 
period and the end of OLE is defined as the day of last assessment for OLE. 
Table 5-2 
Visit windows for Neurological Exams, nerve conduction studies, 
weight, urinalysis, C-SSRS
 
Label 
Start day 
Target day 
End day 
Baseline 
See baseline assessment of the Study (Section 2.1.1, 
baseline definition) 
Wk 1 
 
 
 
Wk 2 
2 
8 
11 
Wk 3 
12 
15 
22 
Wk 5 
23 
29 
43 
Wk 9 
44 
57 
71 
Wk 13 
72 
85 
99 
Wk 17 
100 
113 
127 
Wk 21 
128 
141 
155 
Wk 25 
156 
169 
183 
Wk 29 
184 
197 
211 
Wk 33 
212 
225 
239 
Wk 37 
240 
253 
267 
Wk 41 
268 
281 
295 
Wk 45 
296 
309 
323 
Wk 49 
324 
337 
351 
Wk 53 
352 
365 
421 
 
 
 
 
 
 
 
 
 
 
 
 
Wk 69 
422 
477 
until end of study 
Table 5-3 
Visit window for vital Signs, ECG, Hematology, chemistry, NTproBNP, 
Troponin  
Same as Table 5-2 except the beginning phase: 
Label 
Start day 
Target day 
End day 
Baseline 
See baseline assessment of the Study (Section 2.1.1, 
baseline definition) 
Wk 1 
1 (planned post-
dose) 
1 
4 
Wk 2 
5 
8 
11 
Wk 3 
12 
15 
22 
.... 
 
 
 
Table 5-4 
Visit windows for echocardiogram 
 


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Label 
Start day 
Target day 
End day 
Baseline 
See baseline assessment of the Study (Section 2.1.1, 
baseline definition) 
Wk 2 
 
 
 
Wk 3 
 
 
 
Wk 5 
2 
29 
57 
Wk 9 
 
 
 
Wk 13 
58 
85 
113 
Wk 17 
 
 
 
Wk 21 
114 
141 
169 
Wk 25 
 
 
 
Wk 29 
170 
197 
225 
Wk 33 
 
 
 
Wk 37 
 
 
 
Wk 41 
 
 
 
Wk 45 
 
 
 
Wk 49 
 
 
 
Wk 53 
338 
365 
393 
Wk 57 
 
 
 
Wk 61 
 
 
 
Wk 65 
 
 
 
Wk 69 
 
 
 
Table 5-5 
Visit windows for ophthalmologic examination 
 
Label 
Start day 
Target day 
End day 
Baseline 
See baseline assessment of the Study (Section 2.1.1, 
baseline definition) 
Wk 2 
 
 
 
Wk 3 
 
 
 
Wk 5 
 
 
 
Wk 9 
 
 
 
Wk 13 
2 
85 
169 
Wk 17 
 
 
 
Wk 21 
 
 
 
Wk 25 
 
 
 
Wk 29 
 
 
 
Wk 33 
 
 
 
Wk 37 
170 
253 
309 
Wk 41 
 
 
 
Wk 45 
 
 
 
Wk 49 
 
 
 
Wk 53 
310 
365 
449 


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Label 
Start day 
Target day 
End day 
Wk 57 
 
 
 
Wk 61 
 
 
 
Wk 65 
 
 
 
Wk 69 
 
 
 
Table 5-6 
Visit windows for UHDRS scores (TFC, TMS, IS, 
), 
 
 and brain MRI 
 
Label 
Start day 
Target day 
End day 
Baseline 
See baseline assessment of the Study (Section 2.1.1, 
baseline definition) 
Wk 2 
 
 
 
Wk 3 
 
 
 
Wk 5 
 
 
 
Wk 9 
 
 
 
Wk 13 
 
 
 
Wk 17 
2 
113 
169 
Wk 21 
 
 
 
Wk 25 
 
 
 
Wk 29 
 
 
 
Wk 33 
170 
225 
295 
Wk 37 
 
 
 
Wk 41 
 
 
 
Wk 45 
 
 
 
Wk 49 
 
 
 
Wk 53 
296 
365 
421 
Wk 57 
 
 
 
Wk 61 
 
 
 
Wk 65 
 
 
 
Wk 69 
422 
477 
until end of study 
 


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Table 5-8 
Visit windows for biomarker collected via lumbar puncture 
(
 Nfl
) 
 
Label 
Start day 
Target day 
End day 
Baseline 
See baseline assessment of the Study (Section 2.1.1, 
baseline definition) 
Wk 1 
 
 
 
Wk 2 
 
 
 
Wk 3 
 
 
 
Wk 5 
 
 
 
Wk 9 
2 
57 
85 
Wk 13 
 
 
 
Wk 17 
86 
113 
169 
Wk 21 
 
 
 
Wk 25 
 
 
 
Wk 29 
 
 
 
Wk 33 
170 
225 
295 
Wk 37 
 
 
 
Wk 41 
 
 
 
Wk 45 
 
 
 
Wk 49 
 
 
 
Wk 53 
296 
365 
421 
Wk 57 
 
 
 
Wk 61 
 
 
 
Wk 65 
 
 
 


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Label 
Start day 
Target day 
End day 
Wk 69 
422 
477 
until end of study 
 
5.5 
Notable and abnormality criteria 
Please notice that in the below tables, we always used ‘baseline’ for clarity. For the OLE 
summaries, please replace by Baseline-Ext, as appropriate. 
Table 5-9 
Clinically notable criteria for vital signs 
Vital Sign Variable 
Notable Criteria 
Pulse Rate (beats/min) 
> 120bpm or Increase of ≥15 bpm from baseline 
or 
< 50bpm or Decrease of ≥15 bpm from baseline 
Systolic BP (mmHg) 
>180 mm Hg  or Increase of ≥20 mm Hg from baseline 
Or 
< 90 mm Hg  or Decrease of ≥ 20 mm Hg from baseline 
Diastolic BP (mmHg) 
> 105 mmHg or Increase of ≥ 15 mm Hg from baseline 
Or 
< 50 mmHg or Decrease of ≥ 15 mm Hg from baseline 
Body weight (kg) 
Decrease ≥ 7% from baseline weight 
Increase ≥ 7% from baseline weight 
Body Temperature (oC) 
High: >=38 oC 
 
 
Table 5-10 
Abnormal ranges for ECG 
ECG Parameter 
Abnormality Flags 
Lower bound 
Upper bound 
Notable value  
HR 
<50 bpm or <= -15 bpm 
change from baseline 
>120 bpm or >= 15 bpm 
change from baseline 
RR Interval 
< 600 msec   
> 1200 msec 
PR interval 
< 120 msec  
> 200 msec 
QRS Interval 
< 60 msec  
> 109 msec 
QT Interval 
< 320 msec 
> 450 msec 
QTcF Interval 
(Fridericia's correction) 
< 320 msec 
> 450 msec 
Notable relative change from previous visit 
QTcF Interval 
(Fridericia's correction) 
≤ -20%; 
≥ 20% 
 


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Table 5-11 
Clinically notable criteria for selected hematology tests 
 
US or Other unit 
SI unit 
Laboratory 
parameter 
Lower bound 
Upper bound 
Lower bound 
Upper bound 
Notable value   
 
 
Hemoglobin 
8(g/dL) 
20 (g/dL) 
80 (g/L) 
200 (g/L) 
Hematocrit 
 
24% 
60% 
0.24 (v/v) 
0.6 (v/v) 
White blood cells 
2 (x103/uL) 
35 (x103/uL) 
2 (x10E9/L) 
35 (x10E9/L) 
Platelets 
50 (x103/uL) 
1000 (x103/uL) 
50 (x10E9/L) 
1000 (x10E9/L) 
Neutrophils 
10 (x103/uL) 
 
10 (x10E9/L) 
 
 
 
Table 5-12 
Clinically notable criteria for selected chemistry tests 
 
US or Other unit 
SI unit 
Laboratory parameter 
Lower bound 
Upper bound 
Lower bound 
Upper bound 
Notable value  
 
 
Sodium 
120 (mmol/L) 
160 (mmol/L) 
120 (mmol/L) 
160 (mmol/L) 
Potassium 
3 (mmol/L) 
6 (mmol/L) 
3 (mmol/L) 
6 (mmol/L) 
Magnesium 
1 (mg/dL) 
6.1(mg/dL) 
 0.4 (mmol/L) 
2.5 (mmol/L) 
Albumin  
 25 (g/L) 
 
25 (g/L) 
 
Gamma-glutamyl-
transferase (GGT)  
 
 3 X ULN 
 
3 X ULN 
estimated Glomerular 
filtration rate (eGFR) 
<=30 (mL/min) 
 
<=30 (mL/min) 
 
Lipase 
 
1.5 x ULN 
 
1.5 x ULN 
Amylase 
 
1.5 x ULN  
 
1.5 x ULN  
Notable relative change from baseline 
 
 
Creatinine* 
>50%  
 
>50% 
* Baseline Creatinine is calculated as the average of 
screening and baseline (if either one is missing, the non-
missing one will be used as baseline, if multiple screening 
assessments is available, average screening assessments 
first and then average with baseline) 
 
 
 
 
Table 5-13 
Clinically notable criteria for selected Other Lab parameters 
 
US or Other unit 
SI unit 
Laboratory parameter 
Lower 
bound 
Upper bound 
Lower bound 
Upper bound 


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Study No LMI070C12203 
 
 
Notable value  
 
 
Dipstick proteinuria 
 
≥ 3+  
 
≥ 3+  
FSH (male only) 
 
> 5 (mIU/mL) 
 
> 5 (U/L) 
Troponin T 
 
>= 14.0 (ng/L) 
 
>= 0.014 (ug/L) 
NTproBNP 
 
>125 pg/mL   
 
> 14.75 pmol/L 
Dipstick Hematuria 
 
≥ 3+ on  
 
≥ 3+  
Combined rules 
 
 
Urine protein-
creatinine ratio 
 
Dipstick proteinuria ≥ 3+ 
OR 
PCR  ≥ 1g/g (or ≥ 113 
mg/mmol equivalent as 
converted by the 
measuring laboratory) 
 
Dipstick 
proteinuria ≥ 3+ 
OR 
PCR  ≥ 1g/g (or 
≥ 113 mg/mmol 
equivalent as 
converted by the 
measuring 
laboratory) 
Notable relative change from baseline 
 
 
FSH (male only) 
 
double from baseline 
and value> 5 mIU/mL  
 
double from 
baseline and 
value> 5 (U/L) 
Table 5-14 
Clinically notable criteria for Echocardiogram with GLS 
Parameter 
Lower bound 
Upper bound 
Notable value 
Left Ventricular Ejection 
Fraction (LVEF)  
< -50% 
 
 
 
Table 5-15 
Clinically notable liver function test values 
Criterion 


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Study No LMI070C12203 
 
 
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin (BILI) > 1 x ULN 
Total bilirubin (BILI) > 1.5 x ULN 
Total bilirubin (BILI) > 2 x ULN 
ALP > 1.5 x ULN 
ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law) 
 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur within a 3-day window. A case where all criteria 
are met at a post-baseline time point will be considered as newly occurring if the criteria are not 
met at baseline and will be considered as worsening if the criteria are met at baseline and at 
least one component is worsening from baseline irrespective of whether the other(s) are better. 
Rule of exclusion criteria of analysis sets.  
 
5.6 
Rule of exclusion criteria of analysis sets  
Table 5-16 
Subject Classification 
Analysis Set 
PD ID that cause 
participants to be 
excluded 
Non-PD criteria that cause  
participants to be excluded 
All analysis sets 
NA 
Not having informed consent 
RAS/FAS/SAF/ 
NA 
Not randomized 


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Study No LMI070C12203 
 
 
Analysis Set 
PD ID that cause 
participants to be 
excluded 
Non-PD criteria that cause  
participants to be excluded 
FAS/SAF/ 
NA 
No double-blind study drug taken 
 
6 
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Bretz, F., Pinheiro, J. C., & Branson, M. (2005). Combining multiple comparisons and 
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Pinheiro, J., Bornkamp, B., Glimm, E., & Bretz, F. (2014). Model‐based dose finding under 
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