Clinical trial NCT05475483
Conditions: Huntington Chorea
Keywords: Huntington Chorea SOM3355
Sponsor: SOM Innovation Biotech SA
Start date: 2022-08-02; Completion date: 2024-07-15
Enrollment: 139 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase IIb, randomized, double-blind, placebo-controlled study in parallel groups assessing the efficacy and safety of two doses of SOM3355 in patients suffering from Huntington's Disease with choreic movements.

Detailed description:

Arms: arm 1: Placebo capsules were administered twice daily (BID) for at least 9 weeks at maintenance dose. arm 2: SOM3355 200 mg capsules were administered twice daily (BID) for at least 9 weeks at maintenance dose. arm 3: SOM3355 300 mg capsules were administered twice daily (BID) for at least 8 weeks at maintenance dose.
Interventions: intervention 1: Placebo capsules intervention 2: SOM3355 200 mg capsules intervention 3: SOM3355 300 mg capsules
Intervention descriptions: intervention 1: Treatment was blind for the whole duration of the study. intervention 2: Treatment was blind for the whole duration of the study. intervention 3: Treatment was blind for the whole duration of the study.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
Sponsor Study Reference: 
SOMCT03 
NCT number: NCT05475483    
Version and date:  
V1.1 – IT  
May 17, 2022 
EudraCT number:  
  2021-003453-28 
Study title: 
Phase IIb, randomized, double-blind, placebo-controlled study in 
parallel groups assessing the efficacy and safety of two doses of 
SOM3355 in patients suffering from Huntington’s Disease with 
choreic movements. 
Drug name: 
SOM3355 (bevantolol hydrochloride) 
Indication: 
Huntington’s disease 
Drug development phase: 
Phase IIb 
Sponsor:  
 
SOM Innovation Biotech SA (SOM Biotech) 
Baldiri Reixac, 4. 08028 Barcelona, Spain 
Tel +34 934 020 150 
CRO: 
 
ERGOMED PLC 
1 Occam Court, Surrey Research Park, Guildford GU2 7HJ, Surrey, 
United Kingdom. 
Tel: +44 (0)1483 503 205 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the 
Sponsor representative, the Investigator Team, Regulatory Authorities, and members of the Research Ethics 
Committee and Institutional Research Board.  
Regulatory statement 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), with 
the Declaration of Helsinki, and with other applicable regulatory requirements. 
 


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TABLE OF CONTENTS 
  
Table of Contents ................................................................................................................................ 2 
List of Abreviations ............................................................................................................................. 8 
1. 
PROTOCOL SUMMARY ....................................................................................................... 10 
1.1. 
Synopsis ............................................................................................................................ 10 
1.2. 
Study schema .................................................................................................................... 20 
1.3. 
Schedule of activities ........................................................................................................ 21 
2. 
INTRODUCTION .................................................................................................................... 22 
2.1. 
Background ....................................................................................................................... 22 
2.1.1. 
Huntington’s Disease and chorea symptoms ............................................................. 22 
2.1.2. 
Current treatments of chorea ..................................................................................... 23 
2.1.3. 
SOM3355 selection as VMAT2 inhibitor ................................................................. 24 
2.1.4. 
Summary of Relevant Non-Clinical Studies with SOM3355 .................................... 24 
2.1.5. 
Summary of Previous Relevant Non-Clinical Studies with Bevantolol (SOM3355) 25 
2.1.6. 
Summary of Relevant Clinical Studies ..................................................................... 25 
2.2. 
Risk / Benefit Assessment ................................................................................................. 28 
2.2.1. 
Known Potential Risks .............................................................................................. 28 
2.2.2. 
Known Potential Benefits .......................................................................................... 29 
2.2.3. 
Assessment of Potential Risks and Benefits .............................................................. 29 
2.3. 
Study Rationale ................................................................................................................. 30 
3. 
OBJECTIVES AND ENDPOINTS .......................................................................................... 31 
3.1. 
Objectives of the study ...................................................................................................... 31 
3.2. 
Primary Efficacy Endpoint ................................................................................................ 31 
3.3. 
Secondary Efficacy Endpoints .......................................................................................... 31 
3.4. 
Safety Endpoints ............................................................................................................... 32 
3.5. 
PK-PD Assessments .......................................................................................................... 32 
4. 
STUDY DESIGN ..................................................................................................................... 33 
4.1. 
Overall Design .................................................................................................................. 33 
4.2. 
PK sub-study ..................................................................................................................... 34 
4.3. 
Rationale for study design ................................................................................................. 34 


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4.4. 
Justification for dose ......................................................................................................... 35 
4.5. 
End of Study Definition .................................................................................................... 35 
5. 
STUDY POPULATION ........................................................................................................... 36 
5.1. 
Inclusion Criteria ............................................................................................................... 36 
5.2. 
Exclusion Criteria .............................................................................................................. 36 
5.3. 
Concomitant medications .................................................................................................. 37 
5.3.1. 
Prohibited treatments ................................................................................................. 37 
5.3.2. 
Authorized treatments ............................................................................................... 38 
5.4. 
Contraception .................................................................................................................... 38 
5.5. 
Screen failures ................................................................................................................... 39 
5.6. 
Patient identification and Randomization ......................................................................... 39 
5.7. 
Patient Withdrawal Criteria ............................................................................................... 40 
5.8. 
Study Discontinuation ....................................................................................................... 41 
5.8.1. 
Criteria for terminating the trial ................................................................................ 41 
5.8.2. 
Criteria for terminating the study at site .................................................................... 41 
6. 
INVESTIGATIONAL TREATMENT ..................................................................................... 42 
6.1. 
Investigational Medicinal Product (IMP) .......................................................................... 42 
6.2. 
Packaging and Labelling ................................................................................................... 43 
6.3. 
Management and Storage .................................................................................................. 43 
6.4. 
Study Drug Dispensing ..................................................................................................... 44 
6.5. 
Treatment Compliance and Accountability ....................................................................... 44 
6.6. 
Procedure for emergency individual unblinding ............................................................... 44 
7. 
STUDY ASSESSEMENTS ...................................................................................................... 45 
7.1. 
Unified Huntington’s Disease Rating Scale (UHDRS®) ................................................... 45 
7.2. 
EFFICACY ASSESSMENTS ........................................................................................... 45 
7.2.1. 
Total Maximal Chorea score (TMC) of the UHDRS® .............................................. 45 
7.2.2. 
Total Motor Score (TMS) of the UHDRS® ............................................................... 46 
7.2.3. 
Clinical Global Impression (CGI) Scale ................................................................... 46 
7.2.4. 
Patient Global Impression (PGI) Scale ..................................................................... 46 
7.2.5. 
EQ-5D-5L.................................................................................................................. 46 
7.3. 
SAFETY ASSESSMENTS ............................................................................................... 47 


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7.3.1. 
Laboratory Assessments ............................................................................................ 47 
7.3.2. 
Physical Examination ................................................................................................ 48 
7.3.3. 
Vital signs (Heart rate and Blood Pressure) .............................................................. 48 
7.3.4. 
Electrocardiograms (ECGs) ...................................................................................... 48 
7.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS) .................................................. 49 
7.3.6. 
Beck Depression Inventory (BDI) ............................................................................. 49 
7.3.7. 
Epworth Sleepiness Scale (ESS) ............................................................................... 50 
7.3.8. 
Total Functional Capacity (TFC) of the UHDRS® .................................................... 50 
7.3.9. 
Functional Assessment (FA) of the UHDRS®........................................................... 50 
7.3.10. 
Barnes Akathisia Rating Scale (BARS) ................................................................ 50 
7.3.11. 
Montreal Cognitive Assessment (MoCA) scale .................................................... 50 
7.3.12. 
Problem Behavior Assessment short form (PBA-s) .............................................. 51 
7.4. 
SAFETY REPORTING .................................................................................................... 51 
7.4.1. 
Definitions ................................................................................................................. 51 
7.4.2. 
Procedures for recording, analyzing and reporting AEs ........................................... 53 
7.4.3. 
Reporting Serious Adverse Events (SAEs) ............................................................... 55 
7.4.4. 
Procedures for Reporting Pregnancy Exposure and Birth Events ............................. 55 
7.4.5. 
Data Safety Monitoring Board (DSMB) ................................................................... 56 
7.5. 
PK-PD ASSESSMENTS................................................................................................... 56 
7.5.1. 
SOM3355 plasma concentration ............................................................................... 56 
7.5.2. 
Prolactin plasma level ............................................................................................... 56 
7.5.3. 
PK sub-study ............................................................................................................. 57 
8. 
CONDUCT OF THE STUDY .................................................................................................. 58 
8.1. 
Study procedures at each visit ........................................................................................... 58 
8.1.1. 
Visit 0 - Screening visit – within 14 days before inclusion ....................................... 58 
8.1.2. 
Visit 1 - Day 0 - Inclusion visit - Randomization ..................................................... 59 
8.1.3. 
Visit 2 - Week 3 - Day 21 - End of up-titration......................................................... 60 
8.1.4. 
Visit 3 - Week 6 - Day 42 - Interim visit at maintenance dose ................................. 61 
8.1.5. 
Visit 4 - Week 9 - Day 63 - 1st assessment at end of maintenance dose ................... 61 
8.1.6. 
Visit 5 - Week 10 - Day 70 - 2nd assessment at end of maintenance dose ................. 62 
8.1.7. 
Visit 6 - Week 12 - Day 84 - End of study ................................................................ 62 


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8.2. 
Study Conduct During a COVID-19 Outbreak ................................................................. 63 
9. 
STATISTICAL CONSIDERATIONS ..................................................................................... 64 
9.1. 
Analysis Populations ......................................................................................................... 64 
9.2. 
Statistical Assumptions ..................................................................................................... 64 
9.3. 
Sample Size Determination ............................................................................................... 64 
9.4. 
Statistical Analyses ........................................................................................................... 65 
9.4.1. 
Primary Efficacy Endpoint ........................................................................................ 65 
9.4.2. 
Secondary Efficacy Endpoints .................................................................................. 66 
9.4.3. 
Safety Analysis .......................................................................................................... 67 
9.4.4. 
PK-PD Analysis ........................................................................................................ 67 
9.5. 
Futility Analysis ................................................................................................................ 68 
10. ETHICS AND LEGAL CONSIDERATIONS ......................................................................... 69 
10.1. Regulation ......................................................................................................................... 69 
10.2. Ethics Committee / Institutional Review Board Approval ................................................ 69 
10.3. Patient Informed Consent Procedure ................................................................................. 69 
10.4. Protocol Amendment......................................................................................................... 70 
11. QUALITY CONTROL AND QUALITY ASSURANCE ....................................................... 71 
11.1. Good Clinical Practice (GCP) ........................................................................................... 71 
11.2. Monitoring ......................................................................................................................... 71 
11.3. Investigator Qualifications and Responsibilities ............................................................... 71 
11.4. Quality Control and Audit ................................................................................................. 72 
11.5. Protocol Deviation............................................................................................................. 72 
12. DATA HANDLING AND RECORD KEEPING .................................................................... 73 
12.1. Data Entry in the eCRF ..................................................................................................... 73 
12.2. Data Management ............................................................................................................. 74 
12.3. Record Retention ............................................................................................................... 74 
12.4. Data Protection .................................................................................................................. 74 
12.5. Confidentiality and Property Rights .................................................................................. 75 
13. FINANCES AND INSURANCE ............................................................................................. 76 
13.1. Financing ........................................................................................................................... 76 
13.2. Insurance ........................................................................................................................... 76 


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14. PUBLICATION POLICY ........................................................................................................ 76 
15. REFERENCES ......................................................................................................................... 77 
16. APPENDICES .......................................................................................................................... 80 
16.1. UHDRS® - Motor Part including Total Motor Score (TMS) and Total Maximal Chorea 
(TMC), Dystonia and Gait sub-scores .......................................................................................... 80 
16.2. UHDRS® - Total Functional Capacity (TFC) ................................................................... 80 
16.3. UHDRS® - Functional Assessment (FA) .......................................................................... 80 
16.4. Clinical Global Impression (CGI-S and CGI-C) ............................................................... 80 
16.5. Patient Global Impression (PGI-S and PGI-C) ................................................................. 80 
16.6. EQ-5D-5L ......................................................................................................................... 80 
16.7. Columbia Suicide Severity Rating Scale (C-SSRS) .......................................................... 80 
16.8. Beck’s Depression Inventory (BDI) .................................................................................. 80 
16.9. Epworth Sleepiness Scale (ESS) ....................................................................................... 80 
16.10. Barnes Akathisia Rating Scale (BARS) ............................................................................ 80 
16.11. Montreal Cognitive Assessment (MoCA) ......................................................................... 80 
16.12. Problem Behavior Assessment short form (PBA-s) .......................................................... 80 
16.13. Guidance of the European Society of Hypertension for Blood Pressure and Orthostatic BP 
measurement ................................................................................................................................. 80 
 
 
 
 


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Tables and figures 
 
Figure 1: Study Schema.................................................................................................................................... 20 
Figure 2: Appearance and Details of Calvan® 100 mg Tablets ........................................................................ 43 
 
Table 1: Schedule of Activities by Visit ........................................................................................................... 21 
Table 2: Overview of the Doses of Bevantolol Used in the Main Published Clinical Trials in Hypertension and 
Angina Pectoris ................................................................................................................................................ 26 
Table 3: Laboratory Parameters ....................................................................................................................... 47 
Table 4: Estimand of the Primary Analysis ...................................................................................................... 65 
 
 


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LIST OF ABREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AUC 
Area under the plasma concentration curve 
BARS 
Barnes Akathisia Rating Scale 
BDI 
Beck Depression Inventory 
BID 
Twice daily 
BP 
Blood Pressure 
bpm 
Beats per minute 
CAG 
Cytosine-Adenine-Guanine 
CGI 
Clinical Global Impression 
Cmax 
Maximum observed plasma concentration 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Clinical Trial 
DBP 
Diastolic Blood Pressure 
deuTBZ 
Deutetrabenazine 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
ESS 
Epworth Sleepiness Scale 
FA 
Functional Assessment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HD 
Huntington's Disease 
HPLC 
High Performance Liquid Chromatography 
HR 
Heart Rate 
HTT 
Huntingtin gene 
Htt 
Huntingtin protein 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 


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Abbreviation 
Definition 
IMP 
Investigational Medicinal Product 
IWRS 
Interactive Web Response System 
MAO 
Monoamine Oxidase 
MoCA 
Montreal Cognitive Assessment 
PBA-s 
Problem Behavior Assessment-short form 
PD 
Pharmacodynamics 
PGI 
Patient Global Impression 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PoC 
Proof of Concept 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SmPC 
Summary of Product Characteristics 
SOM3355 
Bevantolol hydrochloride (racemate) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBZ 
Tetrabenazine 
TEAE 
Treatment Emergent Adverse Event 
TFC 
Total Functional Capacity 
Tmax 
Time corresponding to occurrence of Cmax 
TMC 
Total Maximal Chorea 
TMS 
Total Motor Score 
UHDRS® 
Unified Huntington's Disease Rating Scale 
US 
United States 
VMAT2 
Vesicular monoamine transporter type 2 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
SYNOPSIS 
Title 
Phase IIb, randomized, double-blind, placebo-controlled study in parallel 
groups assessing the efficacy and safety of two doses of SOM3355 in 
patients suffering from Huntington’s Disease with choreic movements. 
Phase 
Phase IIb. 
Indication 
Treatment of Huntington’s Disease (HD) patients with choreic movements. 
Rationale 
Huntington’s disease (HD) is an inherited progressive neurodegenerative 
disease. Chorea, an involuntary jerky movement that is purposeless and 
abrupt, is one of the most prominent symptoms in HD. No effective disease-
modifying therapies exist for HD, and treatment is symptomatic relief. 
Chorea is treated by tetrabenazine (TBZ), approved in Europe and the United 
States (US), and the long-acting derivative deutetrabenazine (deuTBZ), 
approved in the US only. Both drugs are vesicular monoamine transporter 
type 2 (VMAT2) inhibitors depleting monoamines in presynaptic neurons. It 
is thought that the consequent modulation of dopamine signaling across 
neural synapses reduces the dyskinetic movements, such as chorea. The 
labels of both compounds carry a black-box warning by the Food and Drug 
Administration (FDA) and special warnings by the European Medicines 
Agency (EMA) since they can increase the risk of depression and suicidality 
in HD patients. 
SOM Biotech, using a computational virtual screening approach 
(SOMAIPRO) combined with in vitro screening methods, aimed to discover 
new potential treatments for HD that might offer clinical benefits over the 
current marketed HD treatments. Potential candidates were identified to be 
repositioned as VMAT2 inhibitors. One candidate named SOM3355 was 
bevantolol 
hydrochloride, 
developed 
and 
commercialized 
as 
an 
antihypertensive drug in Japan, China, and South Korea.  
In vitro, SOM3355 provided functional inhibition of the VMAT2 with 
similar potency to that of TBZ but different binding properties that may 
provide less risk of severe side effects. Relying on its VMAT2 inhibition 
activity, and the good tolerability shown in previous trials at doses from 100 
to 600 mg/day administered once or twice daily (OD or BID), SOM Biotech 
is now developing SOM3355 for the treatment of the dyskinetic movement 
disorders related to HD. 


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A first proof-of-concept (PoC) Phase IIa trial was conducted in 32 HD 
patients to test the efficacy and safety of SOM3355 100 and 200 mg BID 
doses compared to placebo. This provided confirmation of the expected 
effects of SOM3355 on the chorea symptoms measured by the Total 
Maximal Chorea (TMC) score, which significantly improved while patients 
were receiving 200 mg BID SOM3355 in comparison to placebo. SOM3355 
was well-tolerated, with no concern about depression or suicidality risk, and 
the most frequent treatment emergent adverse events, all mild or moderate, 
being bradycardia, hypotension, insomnia, and falls, which were expected 
and explained by the known effects of the drug.   
Following the results of the first PoC and the PK-PD assessment indicating 
that higher doses may be more efficacious, this Phase IIb study will be 
conducted. 
Objectives 
The primary objective of the study is to assess the efficacy of two doses of 
SOM3355 (400 mg/day and 600 mg/day taken twice daily [BID] over at least 
8 weeks at maintenance dose) compared to placebo to reduce chorea in HD 
patients measured by the change in TMC score (primary efficacy endpoint).  
Secondary objectives of the study are:  
To evaluate the safety and tolerability of two doses of SOM3355 (400 
mg/day and 600 mg/day taken) compared with placebo in HD patients, with 
particular attention to depression and suicidality and to the cardiovascular 
hemodynamic parameters.  
And to evaluate the efficacy of the two doses of SOM3355 (400 mg/day and 
600 mg/day taken BID) compared with placebo on: 
the change of Clinical Global Impression (CGI-C),  
the change of Patient Global Impression (PGI-C),  
the percentage of responders based on the improvement ≥2 in TMC score,  
the percentage of change of TMC score.  
A pharmacokinetic (PK) sub-study in a subset of 24 patients will allow to 
determine the PK profile of the two doses of SOM3355 (200 mg and 300 mg 
given twice per day) at steady state and to model PK-PD assessments of 
hemodynamic and cardiac parameters. 
Study design 
This is an international, multicenter, double-blind, randomized, placebo-
controlled, parallel-group Phase IIb study assessing two doses of SOM3355 
(400 or 600 mg/day), taken as 200 mg BID or 300 mg BID, in patients 
presenting choreic symptoms related to HD. 


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Patients who meet all of the eligibility criteria will be randomized at the 
inclusion visit (Visit 1) to one of 3 treatment arms to receive either SOM3355 
400 mg/day, SOM3355 600 mg/day, or placebo, all given BID. Dosing will 
start with an up titration in the first 3 weeks and will be maintained at a fixed 
dose for 7 weeks. After 10 weeks, patients will down titrate to 1 capsule a 
day of study drug for 1 week, followed by 1 capsule a day of placebo to 
assess the effect of drug interruption.  
Ambulatory patients will be recruited by reference centers for HD in 
collaboration with patient advocacy groups and the European HD network. 
A sub-study will characterize the PK profile of the 2 doses (400 mg/day or 
600 mg/day) given twice daily for at least one week in a subset of patients  
(n = 24) who consent to be hospitalized for 24 hours for blood sampling and 
cardiac and hemodynamic assessments. 
Sample size 
A total of 129 patients (43 in each arm, accounting for a drop-out rate of 
10%) will be randomized (1:1:1). 
Inclusion criteria Eligibility criteria to participate in this study are: 
1. Males or females ≥21 years old.  
2. Patients with a diagnosis of Huntington’s Disease determined by a 
movement disorders expert and confirmed by a number of HTT gene 
cytosine-adenosine-guanine (CAG) repeats ≥36. 
3. UHDRS® Total maximal chorea (TMC) score ≥10. 
4. UHDRS® Total Functional Capacity (TFC) ≥7 (corresponding to mildly 
to moderately impaired patients). 
5. Able to walk independently or with minimal assistance. 
6. Females of child-bearing potential must use a medically accepted 
effective method of birth control, agree to continue this method for the 
duration of the study and for at least 1 month following the last dose of 
study drug, and be negative to serum pregnancy test performed at the 
screening visit (Refer to section 5.4 for complete advice on contraception 
requirements of this study). Female patients should not be breast-
feeding. 
7. In the opinion of the Investigator, the patient must have adequate support 
to comply with the entire study requirements as described in this protocol 
(e.g. transportation to and from the trial site, self-rating scales, drug 
compliance, scheduled visits, etc.).  


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8. Able and willing to provide written informed consent prior to any study-
related procedure being performed at the screening visit. 
Exclusion 
criteria 
Patients are excluded from the study if any of the following criteria apply: 
1. Onset of HD symptoms prior to age of 21 years, corresponding to 
juvenile forms of HD. 
2. HD patients presenting rigid akinesia. 
3. Use of other vesicular monoamine transporter type 2 (VMAT2) 
inhibitors such as tetrabenazine, deutetrabenazine, or valbenazine within 
3 months before enrollment, and at any time during the study period; and 
use of other antichoreic treatment such as any neuroleptic within 2 
months or amantadine, memantine, riluzole within 1 month before 
enrollment and along the study.  
4. Patients who experienced severe depression or suicide attempt in the last 
5 years. 
5. Severe untreated or under-treated psychiatric illness such as active 
suicidal ideation or behavior (BDI-21 item #9 >0 and active suicidal 
ideation in C-SSRS) or depression at screening and/or initiation visit 
(BDI-21 items total score >30); although patients taking authorized 
antidepressant therapy at a stable dose for at least 2 months and stabilized 
can be enrolled. 
6. Patients with a history of, or current, hypotension (SBP <110 mmHg), 
bradycardia (HR <50 bpm), or orthostatic hypotension as defined by the 
European Society of Hypertension (reduction in SBP ≥20 mmHg or in 
DBP ≥10 mmHg). 
7. Patients with hypertension already treated with more than 2 
antihypertensive drugs.  
8. Other active clinically significant illness, including unstable 
cardiovascular disease, angina pectoris, congestive heart failure, 
pulmonary hypertension, peripheral arterial disease, history of 
pheochromocytoma, asthma, COPD, diabetic ketoacidosis or metabolic 
acidosis, or neoplastic pathology, which could interfere with the study 
conduct, or counter-indicate the study treatment, or to place the patient 
at risk during the trial, or compromise their study participation. 
9. Any significant serious abnormality in the electrocardiogram (ECG), e.g. 
recent myocardial infarction, significant sinus bradycardia (<50 bpm), 
atrioventricular block (grades I to III with PR >240msec), sinoatrial 
block, atrial sinus disease or prolonged QTc interval at screening (ECG 


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Bazett’s corrected QT interval (QT / [HR/60] >450 msec for males or 
>470 msec for females), or a known history of long QTc syndrome. 
10. Patients with severe hepatic impairment, or with severe renal 
impairment, or with any other significant abnormality in the physical 
examination or clinical laboratory results that, in the Investigator’s 
opinion, would not be compatible with study participation or represent a 
risk for the patient while in the study. 
11. Females who are pregnant or lactating, or who intend to become pregnant 
during the study period. 
12. Patients with allergy under desensitization, with known psoriasis, or a 
known allergy / hypersensitivity to any ingredients of the trial medication 
or placebo. 
13. History of alcohol or substance abuse in the previous 12 months.  
14. Patients participating in any other study, and the use of any 
investigational therapy, within 1 month prior to entry in this study. 
Previous and 
concomitant 
medications 
Prohibited treatments: 
VMAT2 inhibitors such as tetrabenazine, deutetrabenazine, or valbenazine 
are forbidden within 3 months prior to randomization and at any time 
during the whole study.  
Neuroleptics indicated to treat chorea such as haloperidol, pimozide, or 
tiapride, and all other neuroleptics used off label as dopamine D2 receptor 
blockers to treat chorea are forbidden within 2 months prior to 
randomization and at any time during the whole study.  
The following treatments are forbidden within 1 month prior to 
randomization and during the whole study: 
• All monoamine oxidase (MAO) inhibitors.  
• Levodopa 
and 
dopa-agonist 
drugs: 
apomorphin, 
ropinirole, 
pramipexole, rotigotine. 
• Reserpine. 
• Glutamate antagonists: amantadine, memantine, riluzole. 
• Anti-arrhythmic drugs inducing bradycardia: diltiazem, verapamil, 
amiodarone, digitalis, quinidine, sotalol, disopyramide. 
• Any other beta blocker antihypertensive medication.  
• Central 
antihypertensive 
treatments: 
clonidine, 
methyldopa, 
rilmenidine. 
 


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Authorized treatments:  
Patients treated with antihypertensive drugs such as diuretics, angiotensin 
converting enzyme (ACE) inhibitors, angiotensin receptor blockers 
(ARBs), or calcium blockers (dihydropyridines only) can continue their 
treatment at a stable dose during the whole study, with maximum of a dual 
combination of 2 antihypertensive drugs, and if the patient has stable blood 
pressure. 
Patients treated for depression and stabilized with non IMAO (inhibitors of 
MAO) antidepressants can continue their treatment at stable dose during 
the whole study. Allowed antidepressants are:  
• 
SSRIs (selective serotonin reuptake inhibitors): fluoxetine, paroxetine 
(see precautions below), citalopram, sertraline. 
• 
SNRIs (serotonin-noradrenaline reuptake inhibitors): duloxetine, 
venlafaxine. 
• 
TCAs (tricyclic antidepressants): amitriptyline, clomipramine, 
imipramine, nortriptyline, lofepramine. 
Neuroleptics treatment (excluding haloperidol, pimozide, and tiapride), if 
needed to treat a behavior disorder and prescribed for at least 3 months at 
a stable dose, can be maintained at a stable dose during the whole study, 
provided that it is approved on a case-by-case basis by the Steering 
Committee before enrolment of the patient.  
Treatments to be used with precautions (because of risk of interactions): 
• 
Alpha-blockers. 
• 
Local beta-blockers (eye drop) or pilocarpine (eye drop). 
• 
Anticholinesterase drugs: donepezil, rivastigmine. 
• 
Strong CYP2D6 inhibitors may increase the blood levels of SOM3355 
(such as paroxetine fluoxetine, quinidine, bupropion, dacomitinib, 
tipranavir). 
Investigational 
treatments 
The study medication will be provided in capsules of SOM3355 dosed at 200 
mg or 300 mg, or matching placebo. SOM3355 capsules will contain 2 or 3 
tablets of 100 mg of the commercial form of bevantolol (Calvan® 100 mg 
tablets). The capsules will be identical in appearance to ensure that neither 
the patient nor the Investigator or the clinical staff know the exact nature of 
the study medication. 
Patients should take 1 capsule in the morning during the first week and then 
1 capsule twice per day, one in the morning and one in the evening (every 12 
hours) during the following 9 weeks, and then only 1 capsule in the morning 
during the last 2 weeks. Capsules can be taken with food.  


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At the inclusion visit (Day 0), patients will be allocated according to the 
randomization list to one of the 3 treatment arms, starting with 3 weeks of 
up-titration, to receive either SOM3355 400 mg/day, SOM3355 600 mg/day, 
or placebo for up to 10 weeks. This will be followed by 1 week of down 
titration and 1 week of placebo wash-out period to assess the effect of drug 
interruption.  
The total treatment duration of this double-blind study, from the inclusion 
visit, will be 12 weeks (+ 1 or 2 weeks for screening before inclusion): 11 
weeks under the active drug treatment (or placebo), and 1 week under 
placebo for all patients at the end of the study. 
Primary efficacy 
endpoint 
The primary measure of efficacy will be the change in Total Maximal Chorea 
(TMC) sub-score of the Unified Huntington's Disease Rating Scale 
(UHDRS®) between baseline and end of maintenance dose (the mean of Visit 
4 and Visit 5 minus the mean of Visit 0 and Visit 1). 
The TMC score is a standardized, reliable chorea assessment based on 
frequency and severity in 7 body regions. 
Secondary 
efficacy 
endpoints 
Key secondary efficacy endpoint:   
• Change from baseline in the Clinical Global Impression (CGI-C). 
Other secondary efficacy endpoints: 
• Change from baseline in the Patient Global Impression (PGI-C). 
• TMC-response defined as improvement ≥2 in TMC score between 
baseline and end of maintenance dose. 
• Percentage of change in TMC score between baseline and the end of 
maintenance dose. 
• Change from baseline in Total Motor Score (TMS) of the UHDRS®.  
• Change from baseline in Gait sub-score of the UHDRS®. 
• Change from baseline in Dystonia sub-score of the UHDRS®. 
• Change from baseline in EQ5D-5L measuring quality of life. 
Safety endpoints 
Safety assessments will include the following: 
• Incidence, frequency, and severity of adverse events (AEs) in each 
treatment group. 
• Change from baseline in: 
• Vital signs: blood pressure (BP), including orthostatic BP, and heart 
rate (HR). 


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• ECGs.   
• Clinical laboratory test results (chemistry, hematology). 
• Physical examination findings, weight. 
• Columbia-Suicide Severity Rating Scale (C-SSRS) assessing 
suicidality.  
• Beck Depression Inventory (BDI) scale assessing depression.  
• Epworth Sleepiness Scale (ESS) assessing sleepiness. 
• Total Functional Capacity (TFC) of the UHDRS® assessing 
functioning.  
• Functional Assessment of the UHDRS®.  
• Barnes Akathisia Rating Scale (BARS) assessing akathisia. 
• Montreal Cognitive Assessment (MoCA) scale to assess cognitive 
disturbances. 
• Problem Behaviors Assessment short form (PBA-s) to assess 
behavioral symptoms in HD. 
PK-PD 
assessments 
SOM3355 plasma concentration will be measured at each visit under 
treatment with SOM3355 (i.e. from Visit 2 to Visit 5) in all patients. Plasma 
samples will be collected pre-dose (before the dug intake) and 2 hours after 
the drug intake (corresponding to the expected Tmax) at Visit 2 and Visit 4, 
and only pre-dose at Visit 3 and Visit 5. 
Prolactin plasma level will be measured at each visit from Visit 1 to Visit 6 
in all patients. Plasma samples will be collected pre-dose (before the dug 
intake) and 2 hours after the drug intake (at Tmax) at Visit 2 and Visit 4, and 
only pre-dose at Visit 1, Visit 3, Visit 5, and Visit 6. 
PK sub-study 
A PK sub-study will be conducted to characterize the PK profile of repeated 
doses of SOM3355 at 400 and 600 mg/day. This analysis will be performed 
by collecting 12-hour PK samples (H0, H0.5, H1, H1.5, H2, H3, H5, H8, and 
H12) in 8 patients per arm (24 patients in total) that will be hospitalized for 
24 hours at Visit 2. In addition, cardiac and hemodynamic parameters will 
be collected in parallel, with 12-hour cardiac Holter and blood pressure 
measurements before each PK sample, to allow PK-PD modeling 
assessments. These patients will be recruited by 3 or 4 sites able to manage 
the logistics of PK sampling.   


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Sample size and 
statistical 
methodology 
Sample size calculation 
The sample size requires enrollment of a total of 129 patients in the 
randomized treatment period, allowing for a drop-out rate of 10%. Eligible 
patients will be randomized in blinded fashion in a 1:1:1 ratio i.e. 43 patients 
in each arm (SOM3355 400 mg/day, SOM3355 600 mg/day, or placebo). 
Assuming a treatment difference of -2.5 points in the change from baseline 
of TMC score compared to placebo and a standard deviation of 3.5, 39 
patients per arm are needed to provide at least 80% power that at least 1 dose 
of SOM3355 will be significantly superior to placebo at the 2-sided 0.025 
significance level. This is based on the use of a two-sided t-test for the mean 
TMC score change. With a dropout rate of approximately 10%, 43 patients 
per arm have to be enrolled i.e. a total of 129 patients. If the dropout rate is 
higher than 10%, then an upward adjustment of sample size might be 
considered. 
Statistical methods 
The primary efficacy analyses will be based on the modified intent-to-treat 
(mITT) Population, which is defined as all randomized patients with at least 
one dose of the study treatment and one post-baseline assessment of the TMC 
score.   
A mixed-effect linear model for repeated measures (MMRM) will be used to 
compare each active treatment group to placebo for change in TMC score 
from baseline (defined as the average values from Visit 0 and Visit 1) to the 
end of maintenance therapy (defined as the average values from Visit 4 and 
Visit 5), 9-10 weeks after the start of study treatment. The least square mean 
(LSM) estimate for each treatment group and difference in LSM estimates at 
end of maintenance dose between active treatments and placebo group with 
their confidence intervals will be provided. 
To control the overall type I error at 0.05 for the statistical comparisons of 
the 2 dose levels vs placebo, a Holm procedure will be used for the primary 
endpoint. For the secondary endpoints, the significance level is set at two-
sided 0.05.    
An interim analysis for futility is planned when 65 patients enrolled (around 
50% of the total patients) have either completed Visit 5 or have discontinued 
the study early.  
Safety analyses will be based on the safety population, which is defined as 
all randomized patients having received at least one dose of study treatment. 


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Study duration 
and sites 
The total duration of this double-blind study will be 12 weeks + 1 or 2 weeks 
for screening.   
The study will be conducted in 16 to 20 investigating sites located in Europe. 
Each site should be able to recruit at least 6 eligible patients. Proposed 
countries are Spain, France, Italy, Germany, Poland, UK, and Switzerland.  
Study Timelines 
The study is planned to start by the end of 2021 (Q4) and last one year. 


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1.2. 
STUDY SCHEMA  
Figure 1: Study Schema 


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1.3. 
SCHEDULE OF ACTIVITIES 
Table 1: Schedule of Activities by Visit 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
 
Screening 
(baseline 1) 
Randomization 
(baseline 2) 
End of 
Up-titration 
Maintenance 
Dose (interim) 
Maintenance 
Dose (end 1) 
Maintenance 
Dose (end 2) 
End of study 
Day 
D-7 to -14 
D0 
D21 ± 2 days 
D42 ± 2 days 
D63 ± 2 days 
D70± 2 days 
D84 ± 2 days 
Week 
W-1 to -2 
W0 
W3 
W6 
W9 
W10 
W12 
Informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
Physical and neurological examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs (HR, BP, …) 
X 
X 
X 
X 
X 
X 
X 
UHDRS® motor part  
X 
X 
X 
X 
X 
X 
X 
CGI, PGI 
 
X 
X 
X 
X 
X 
X 
C-SSRS, BDI, ESS 
X 
X 
X 
X 
X 
X 
X 
UHDRS® (TFC, FA) 
X 
X* 
 
 
 
X 
 
EQ-5D, BARS, MoCA and PBA-s 
 
X 
 
X*** 
 
X 
 
ECG 
X 
X** 
X 
 
X 
 
X 
Blood sample for safety 
X 
 
 
X 
 
X 
 
Blood sample for prolactin level 
 
  X1 
X2 
X1 
X2 
X1 
  X1 
Blood sample for PK  
 
 
X2 
X1 
X2 
X1 
 
Hospitalization for 12-h PK sampling 
 
 
X**** 
 
 
 
 
Pregnancy test in female 
X 
 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Co-medications 
X 
X 
X 
X 
X 
X 
X 
Dispensation of study drug 
 
X 
X 
X 
X 
X 
 
Drug accountability & compliance 
 
 
X 
X 
X 
X 
X 
* Only TFC at V1 (inclusion visit)   
** ECG triplicated at V1 (inclusion visit)   
*** PBA-s only 
**** At V2, hospitalization of only 8 patients per arm (24 patients in total) for 12-h PK sampling by 3-4 selected sites + ECG Holter and BP measurement at each sampling time point  
 
1 Blood sample only at pre-dose   
2 Blood sample at pre-dose and at Tmax (2 hours after drug intake) 


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2. 
INTRODUCTION 
2.1. 
BACKGROUND 
2.1.1. 
Huntington’s Disease and chorea symptoms 
HD is an inherited progressive neurodegenerative disease for which the precise pathological process 
is far from understood. HD is caused by an expanded repeat sequence of three nucleotides, cytosine-
adenine-guanine (CAG) in the Huntingtin gene (HTT) on chromosome 4. This results in the 
production of a mutant huntingtin (mHtt) protein with an abnormally long polyglutamine repeat 
sequence. As long as the number of CAG repeats in the HTT gene is lower than 27, the section is 
stable (normal range). If the number of repeats is between 27 and 35 (intermediate repeat length), that 
individual will not develop HD. However, a CAG repeat number of 27 or more is unstable and liable 
to increase when passed on to the next generation, meaning that those children carry a risk of 
developing HD. Individuals with a CAG repeat number between 36 and 39 may develop HD, but 
only late in life, with a less severe phenotype. This is known as the reduced-penetrance repeat length 
range. When the number of CAG repeats is higher than 39, a person will develop HD within a normal 
lifespan – most often in mid-adult life. In rare cases, the CAG expansion can be exceptionally long, 
leading to disease onset in adolescence or childhood (juvenile HD). Patients who develop the disease 
before the age of 10 often have more than 80 CAG repeats (McColgan et al, 2018; Ross et al, 2009). 
The mutant Huntingtin (mHtt) protein has a propensity to form abnormal aggregates that impact 
multiple cellular processes. Furthermore, the multiple functions of the protein are disturbed. 
The age of clinical onset in HD is highly variable, with a mean of ~45 years (Ross et al, 2014). Most 
people with the CAG repeat expansion seem healthy until adulthood; however subtle motor, cognitive 
and psychiatric deficits can be identified up to 10-15 years before the onset of manifest disease and 
this is referred to as the premanifest stage of the disease (McColgan et al, 2018). The course of typical 
adult-onset HD can be divided into premanifest and manifest periods. The premanifest period is 
subdivided into the pre-symptomatic phase, in which individuals are clinically unaffected, and the 
prodromal phase, characterized by subtle multimodal features, in which chorea is prominent. The 
manifest period follows, in which motor and cognitive symptoms become more pronounced. In later 
stages of manifest HD, incoordination, dystonia, bradykinesia, rigidity, and cognitive impairment are 
commonly more prominent than chorea (Ross et al, 2014). 
Chorea is one of the most prominent symptoms in HD and occurs early in the disease. It is an 
involuntary jerky movement that is purposeless and abrupt. Chorea predominantly affects the distal 
extremities and facial muscles in early stages of the disease (Ross et al, 2010). The severity of chorea 
in patients with HD varies, but abnormal movements usually become gradually more serious and 
many patients develop very severe chorea that compromises daily living (Vuong et al, 2018). Chorea 
then spreads to involve more proximal regions of the body, increasing in amplitude and amount until 
some patients may be affected for the entire time they are awake. Activation of facial and neck 
muscles can cause head turning, eye closure, and tongue protrusion, whereas involvement of axial 
muscles can lead to extension and arching of the back. It can cause problems with writing and can 
also contribute to falling Pharmacological intervention is aimed at symptomatic relief by restoring 


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the balance of neurotransmitters thought to be involved in the pathogenesis of HD, particularly 
dopamine.  
The central dopaminergic pathways in HD patients are affected with dysfunction of both dopamine 
release and dopamine receptors. Dopamine is released from pre-synaptic terminals, which activates 
dopamine receptors. The dopamine is then transported back into the pre-synaptic terminal, where 
vesicular monoamine transporter type 2 (VMAT2) repackages the dopamine into the vesicles.  
Although motor onset is usually the point at which a diagnosis is made, most HD patients experience 
personality changes, depression, and anxiety before chorea (the hallmark of HD). Psychiatric 
symptoms are another common manifestation of HD, along with cognitive decline and behavioral 
difficulties. Data from the European Huntington’s Disease Network’s Registry suggested that 
approximately 39.3% of their participants had severe psychiatric problems such as suicidal ideation 
and attempts, depression, irritability, aggressive behaviors and psychosis (Orth et al, 2010). 
Moreover, cognitive changes, manifested by loss of recent memory, poor judgment, and impaired 
concentration and acquisition, occur in nearly all HD patients (Fahn et al, 2011). Chorea, a hallmark 
characteristic of HD, contributes to balance impairment and falls, which greatly impact quality of life. 
Falls are one of the strongest predictors of nursing home placement (Wheelock et al, 2003). As further 
evidence of the central role chorea plays in HD, one study demonstrated a direct connection between 
chorea and worsened condition. This study used the United Huntington’s Disease Rating Scale 
(UHDRS®), which measures motor function, cognitive function, behavioral abnormalities, and 
functional capacity, to see which aspects of HD impacted patients the most (Huntington Study Group, 
1996). They found that only shifts in the UHDRS® chorea score correlated with changes in complex 
task performance after 3 years, such as peg insertion, which particularly reflects motor impairment, 
as well as higher cognitive and executive dysfunction (Andrich et al, 2007). 
A drug to improve chorea in HD patients would have great benefit. Based on the widespread effects 
of chorea in this patient population, such a drug might have the potential to reduce the negative effects 
of the disease, possibly improving quality of life, patient independence, and survival (Coppen et al, 
2017).  
2.1.2. 
Current treatments of chorea 
Currently, chorea is treated by tetrabenazine (TBZ) the first approved drug for the treatment of chorea 
in HD both in Europe and in the United States. The long-acting derivative deutetrabenazine (deuTBZ) 
is approved in the US only. Both existing drugs are vesicular monoamine transporter type 2 (VMAT2) 
inhibitors. They deplete monoamines in presynaptic neurons by inhibiting the VMAT2 uptake from 
the cytoplasm into the synaptic vesicles for storage, resulting in rapid degradation of cytoplasmic 
dopamine by MAOs. It is thought that the consequent modulation of dopamine signaling across neural 
synapses reduces the dyskinetic movements, such as chorea. The labels of both compounds carry a 
black-box warning by the Food and Drug Administration (FDA) and special warnings by the 
European Medicines Agency (EMA) since they can increase the risk of depression and suicidality in 
HD patients. Thus, they are contraindicated in patients who are actively suicidal and in patients with 
inadequately treated depression or severe depression, and patients must be closely monitored for the 
development of depressive symptoms or suicidal ideation. In addition, their co-administration with 


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other neuroleptic drugs may increase the possibility of parkinsonism, neuroleptic malignant syndrome 
and akathisia (Caroff et al, 2020). 
A variety of other available agents are used off-label (e.g. amantadine, neuroleptics, etc.) to treat 
chorea symptoms with lack of high quality evidence (Mestre et al, 2009). The use of neuroleptics for 
HD chorea is primarily based on years of clinical experience, especially when psychiatric symptoms 
such as psychosis, depression, or aggressive behavior are present, but the evidence for their use to 
treat chorea is limited to mostly small open-label studies, case reports, or retrospective chart reviews. 
In Europe, since a recent revision of its labelling in 2017, haloperidol is the only neuroleptic that has 
the indication of the “treatment of mild to moderate chorea in HD, when other medicines do not work 
or have unacceptable side effects”. Pimozide and tiapride are also authorized in some European 
member states for the treatment of abnormal involuntary movements that occur in HD, such as chorea. 
Atypical neuroleptics (olanzapine, clozapine, risperidone) are more frequently used off label to treat 
chorea in patients presenting associated psychiatric disorders or aggressive behavior, but again these 
treatments have not shown strong evidence of their efficacy on chorea and have a less favorable safety 
profile (agranulocytosis with clozapine, weight increase with risperidone). 
2.1.3. 
SOM3355 selection as VMAT2 inhibitor 
SOM Biotech, using a computational virtual screening approach (SOMAIPRO) combined with in vitro 
screening methods, aimed to discover new potential treatments for HD from a database of compounds 
that already have regulatory approval and that might offer clinical benefits over the current marketed 
HD treatments. Potential candidates were identified, which could be repositioned as VMAT2 
inhibitors. One candidate named SOM3355 was bevantolol hydrochloride, which was originally 
developed by Warner-Lambert in the ‘80s and commercialized as an antihypertensive drug by Nippon 
Chemiphar Co. Ltd in Japan, China, and South Korea. In addition to its known activity as a selective 
β1-blocker, SOM Biotech has discovered a new activity of bevantolol as a VMAT2 inhibitor. 
SOM Biotech is developing SOM3355 (bevantolol hydrochloride) as an inhibitor of VMAT2 for the 
treatment of dyskinetic movement disorders related to HD. 
2.1.4. 
Summary of Relevant Non-Clinical Studies with SOM3355 
Consequent to the virtual screening, in vitro validation of the VMAT2 inhibitory properties of 
SOM3355 was undertaken. 
2.1.4.1. 
In vitro assays and mechanism of action 
The pharmacology of SOM3355 (bevantolol hydrochloride) in relation to its desired therapeutic 
effect of inhibiting VMAT2 was characterized in in vitro studies. 
In vitro, SOM3355 provided functional inhibition of the VMAT2 with similar potency to that of TBZ, 
but binding to the TBZ site of the VMAT2 was found approximately 50-fold lower, suggesting that 
SOM3355 binds to another site on the VMAT2 or in a different mode to TBZ at the TBZ site. 
Furthermore, unlike TBZ, it was found that SOM3355 also inhibits the VMAT1. The role of VMAT1 
in the brain is only now beginning to be unraveled. These differences in the modulation of the VMATs 
between SOM335 and TBZ may play an important role in the context of the complex involvement of 


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dopaminergic neural pathways in mediating HD dyskinesia and the prominent psychiatric effects of 
TBZ. 
2.1.4.2. 
In vivo assays  
In male Sprague Dawley rats, SOM3355 does not show the same in vivo catalepsy syndrome typical 
of TBZ even at very high doses. These differences may translate into a better efficacy/safety profile 
in patients. 
2.1.5. 
Summary of Previous Relevant Non-Clinical Studies with Bevantolol (SOM3355) 
Bevantolol was first developed as a selective beta-adrenergic blocking agent in the ’80s by Warner-
Lambert and a battery of non-clinical studies were conducted, including pharmacology (primary PD, 
secondary PD, safety pharmacology), PK (absorption, distribution, metabolism and excretion), and 
toxicity studies including acute and repeat-dose toxicity, genotoxicity, carcinogenicity, and 
reproductive and developmental toxicity. Extensive non-clinical characterization of bevantolol 
hydrochloride is available from the legacy file (see Investigator’s Brochure §5.1.2).  
The in vitro and in vivo profile of the compound, and how this translates to the clinical situation, have 
been extensively reviewed (Kaplan et al, 1985; Kaplan et al, 1986; Frishman et al, 1988). 
Information on non-clinical PK, and Absorption, Distribution, Metabolism, and Excretion (ADME) 
is summarized in the Investigator’s Brochure §5.2. 
2.1.6. 
Summary of Relevant Clinical Studies 
2.1.6.1. 
First Proof of Concept study in Huntington ‘s Disease patients (SOM-CT02) 
A proof-of-concept (PoC) Phase IIa trial was conducted, with the existing formulation of bevantolol 
hydrochloride (Calvan®). It was a double-blind, randomized, placebo-controlled crossover study in 
32 HD patients, to test the efficacy and safety of SOM3355 100 mg BID and 200 mg BID doses 
compared to placebo. Patients were randomly assigned to 2 arms of 4 sequential 6-week dose periods, 
in which they received placebo and SOM3355 at 100 and 200 mg twice daily in a crossover design. 
The primary endpoint was defined as improvement of at least 2 points in the TMC sub-score of the 
motor part of the UHDRS® in any active drug period compared with the placebo period. A responder 
analysis and a mixed model analysis were performed for the primary endpoint. Secondary endpoints 
were CGI-C and PGI-C, as well as the total functional capacity, functional assessment, total motor 
score, and gait sub-score of the UHDRS®. Safety was assessed by evaluating adverse events (AEs), 
with special attention to blood pressure and cardiac function, and the Columbia Suicide Severity 
Rating Scale, assessing suicidal ideation and behavior. Plasma prolactin levels were also measured 
during the study.  
The responder analysis revealed that more than half of the patients (57.1%) had improvements in the 
TMC score of at least 2 points in any period with SOM3355 compared with placebo, thus reaching 
the primary endpoint. Even greater improvements in the TMC score of at least 3, 4, 5, and 6 points 
compared with placebo were seen with SOM3355 in 28.6%, 25.0%, 17.9%, and 10.7% of the patients, 
respectively. The mixed-model analysis comparing the different periods showed significant 
improvement in the TMC score with 200 mg twice daily of SOM3355 compared with placebo 


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(P=0.0224), which was confirmed in ratings of CGI-C and PGI-C. In the other outcome measures of 
the UHDRS®, no statistical differences were found between SOM3355 and placebo. SOM3355 was 
well tolerated with only mild or moderate AEs, and with no implications for depression or suicidality 
risk. The most frequent AEs during SOM3355 administration, all mild or moderate, could be 
explained by the known effects of the drug such as insomnia, and bradycardia or hypotension that are 
both related to the β1-blocking effects of bevantolol. Mild elevations in plasma prolactin levels were 
recorded with SOM3355 (P<0.005), probably reflecting the inhibitory effect on the dopamine 
pathway, consistent with the profile of VMAT2 inhibition. This study confirmed that SOM3355 
reduces chorea in patients with HD and has a good safety profile. 
2.1.6.2. 
Previous clinical trials in hypertensive patients (bevantolol) 
• 
Studies conducted in Caucasian population (by Warner Lambert) 
Initially, bevantolol was developed in Western and Northern Europe by Warner-Lambert in the 1980s 
as a β1-adrenoreceptor antagonist for the treatment of hypertension and angina pectoris. A high 
number of clinical studies assessing bevantolol were conducted including more than 1400 subjects. 
Amongst the Phase I studies, there were 8 key Phase I studies that determined the PK profile of 
bevantolol in healthy volunteers (single and repeated doses, administered intravenously [IV] or orally 
as solution or tablet), and special PK-PD studies in patients with hypertension (N=32) or angina 
pectoris (N=12), or in patients with renal or pulmonary impairment (N=50) (Latts et al, 1986). 
The oral formulation was then tested in 4 controlled trials in patients with angina pectoris (N=165) 
at doses of 150 to 300 mg/day given twice daily for 2 to 12 weeks, and in 4 controlled trials in patients 
with hypertension (N=772) at doses of 100 to 600 mg/day given either once or twice daily for 6 weeks 
to 6 months. The majority of the patients (N=715) in these controlled trials were treated for 4 to 8 
weeks, 56 received bevantolol for 12 weeks and 132 for 6 months. 
In one trial in patients with hypertension, the dosage was up-titrated to 600 mg/day in 47 patients 
until the end of the 6-week double-blind period, and then continued for further 6 months of double-
blind treatment. At the end, the non-responders on hypertension (n=17) were given a further 4/8 
weeks of treatment (under review every 2 weeks) with a combination of bevantolol 400 mg/day given 
in 2 intakes plus hydrochlorothiazide (25 mg twice daily, increased if necessary to 50 mg twice daily 
after 2 weeks) (Maclean 1988; WL-775-101). 
Additionally, under 600 patients were treated for 12 weeks or longer (up to 4 years) at doses up to 
600 mg/day in long-term open label extension studies. 
Table 2: Overview of the Doses of Bevantolol Used in the Main Published Clinical Trials in 
Hypertension and Angina Pectoris 
Study 
Study design 
Highest 
dose/day  
Number of 
patients 
Study duration 
Angina pectoris 
(Gimeno et al., 1986) 
Randomized, Placebo-Controlled, 
Double-Blind Study on Acute, 
Short- and Long-Term  
300 mg 
12 
14 months 


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Study 
Study design 
Highest 
dose/day  
Number of 
patients 
Study duration 
(Salonen al., 1986) 
Randomized Double-blind study 
comparing bevantolol to atenolol 
300 mg 
40 
12 weeks 
(Farnham et al., 1986) 
Randomized Placebo-Controlled 
Study 
300 mg 
107 
6 weeks 
(Rodrigues et al., 1988) 
Randomized Double-blind study 
comparing bevantolol and atenolol 
400 mg 
39 
8 weeks 
Hypertension 
(Okawa,1986) 
Randomized Placebo-Controlled 
double-blind study 
400 mg 
139 
8 weeks 
(Jain, 1986) 
Randomized Placebo-Controlled 
double-blind study OD vs BID 
400 mg 
133 
7 weeks 
Open label extension 
400 mg 
133 
Up to 2 years 
(Al-Khawaja and 
Jankovic, 2008) 
Single center open-label study OD 
vs BID +24-hour ambulatory intra-
arterial blood pressure (BP) 
recording 
600 mg 
17 
10 weeks 
(MacLean, 1988) 
Randomized double-blind 
controlled trial comparing 
bevantolol to propranolol 
600 mg 
266 
8 months 
Open-label extension in non-
responders Combination bevantolol 
200 mg BID + hydrochlorothiazide 
25-50 mg BID 
400 mg 
17 
8 weeks 
Clinical therapeutics & 
medicine 
8(9): 
2147-
2191, 1992 
Bevantolol vs metoprolol 
200 mg 
236 
12 weeks 
(Noshiro, 1995)  
bevantolol vs propranolol 
200 mg 
 
12 weeks 
 
NC -Study Cl-06 
Open-label bevantolol in 
combination with other types of 
antihypertensive agent 
100 mg 
28 
8 weeks 
Hypertension or angina pectoris 
(Bray, 1986) 
Safety review of 8 double-blind 
randomized clinical trials in 
hypertension or angina pectoris 
400 mg 
579 
Up to 4 years 
(Takeda)  
(linked to NC-Study Cl-
09) 
Effect of bevantolol on renal 
function in hypertensive patients 
with or without renal impairment 
200 mg 
13 
14 days 
Dilated cardiomyopathy 
(Hara et al., 2002) 
Open-label study comparing 
Bevantolol vs metoprolol 
80 mg 
41 
6 months 


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The integrated summary of safety in all Caucasian trials conducted by Warner-Lambert relate a total 
of 937 patients having received bevantolol in controlled trials and 706 patients in uncontrolled trials. 
The most frequently reported AEs (>5%) were fatigue and headache (see Investigator’s Brochure § 
6.2.1). Previous clinical experience indicates that bevantolol used in multiple studies at doses up to 
600 mg/day was safe and effective in the treatment of Caucasian patients with hypertension or chronic 
angina. 
• 
Studies conducted in Asian population (by Nippon Chemiphar)  
Additional studies were performed in the Asian population, in a total of 951 subjects/patients enrolled 
in trials conducted in Japan by Nippon Chemiphar at doses up to 400 mg/day. 
2.1.6.3. 
Marketing experience in hypertension 
Moreover, the drug is marketed since 1997 by Nippon Chemiphar in Japan and South Korea 
(Calvan®) to treat hypertension. The cumulative number of patients exposed from July 1997 to 
February 2021 is estimated to be more than 2,5 million patients, without any change to the safety 
profile as reported in the successive PSURs and PBRER.  
 
2.2. 
RISK / BENEFIT ASSESSMENT 
2.2.1. 
Known Potential Risks  
Bevantolol is a cardio selective β1-blocker that is shown to selectively block the positive chronotropic 
and inotropic action of isoproterenol and is essentially devoid of intrinsic sympathomimetic activity 
(ISA). It has a mild chronotropic effect at rest and reduces exercise-induced tachycardia and pressor 
responses. The β1-blocking effects are almost at the same level as that of metoprolol (β1-selective 
blocker), while being slightly weaker than the effect of propranolol (β1-nonselective blocker).  
The safety profile of SOM3355 (bevantolol) in healthy subjects and patients with cardiovascular 
diseases is well characterized and demonstrated to be safe and tolerable up to 600 mg/day. Therefore, 
there is no specific reason to suspect that the administration of this compound in non-hypertensive 
patients can induce clinically relevant complications and in the first trial conducted in HD patients it 
was well tolerated at doses up to 400 mg/day (see Investigator’s Brochure § 7.2). The most frequent 
AEs during SOM3355 administration in the first Phase 2a study in HD patients were all mild or 
moderate, did not induce treatment withdrawal, and could be explained by the known effects of the 
drug such as insomnia, and also bradycardia and hypotension (which are both related to the β1-
blocking effects of bevantolol).  
Safety assessments will include monitoring of HR and BP at each visit (measured according to 
standardized conditions, first in the sitting position and then in the supine and standing positions to 
detect orthostatic hypotension), and ECG performed at key visits will be assessed with central 
reading.  
Moreover, a wide variety of neuropsychiatric symptoms occur in HD, including, depression, anxiety, 
irritability, obsessive compulsive behavior and psychosis. Depression is the most common condition 


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with life time prevalence between 40% and 50% (Du et al, 2013) and suicide rates over five times 
that found among the general population (Paulsen et al, 2005; Orth et al, 2010, Fahn et al, 2011). 
Some drugs acting on the dopamine pathway like TBZ have warnings about the risk of aggravation 
of depression and suicidality. But the differentiation of SOM3355 (bevantolol) in pre-clinical assays 
with differences in the modulation of the VMATs compared to TBZ may play an important role in 
the context of the complex involvement of dopaminergic neural pathways in mediating HD prominent 
psychiatric effects. Therefore, we consider that bevantolol would not induce the same psychiatric 
effects as they were not reported during the clinical experience of its use in hypertension. However, 
the risk of depression and suicidality will be carefully assessed along the study with the Beck 
Depression Inventory scale and the Columbia–Suicide Severity Rating Scale.  
The Sponsor is aware that in the current environment, hospitals should preferentially treat subjects 
with COVID-19 and give priority to trials for the prevention or treatment of COVID-19 infection. 
This trial will therefore only be initiated at a time when it is ethically and operationally feasible for 
each of the selected study sites to do so (see Section 8.2). There is currently no known increased risk 
of contracting COVID-19 as a result of taking the IMP. In addition, study visits will be conducted in 
such a manner as to ensure patient safety is paramount and to eliminate potential risks of COVID-19 
transmission. 
2.2.2. 
Known Potential Benefits  
SOM3355 might bring advantages to treat dyskinetic movements related to HD with a better safety 
profile than similar existing drugs. Currently, the treatment modality for such patients is based on 
tetrabenazine, a VMAT2 inhibitor which is associated with severe secondary effects, including risk 
of worsening depression, and suicidal thoughts and behavior in patients with HD. Thus, secondary 
complications of tetrabenazine treatment nowadays are limiting its clinical benefit in patients 
suffering from this pathological condition. Such effects were not reported with bevantolol neither 
during its use to treat hypertension nor in the previous trial in HD.  SOM3355 presents a similar 
VMAT2 inhibitory capacity than the reference compound tetrabenazine but with different binding 
properties leading to its differentiation in monoamines signaling and also a specific binding to 
VMAT1 receptors that may explain its different safety profile. The previous Phase IIa study 
conducted with SOM3355 in HD patients showed that more than half of the patients had an 
improvement of their chorea symptoms measured by a reduction of at least 2 points in the TMC score 
with SOM3355 compared to placebo, and some patients had even greater improvements, while no 
neuropsychiatric symptoms were reported.  
2.2.3. 
Assessment of Potential Risks and Benefits  
Patients could benefit from treatment with SOM3355, which is known to reduce chorea symptoms as 
shown in the previous Phase 2a study, and it will be assessed as the primary endpoint.  
SOM3355 is a well-known drug which has proven its good safety profile since more than 25 years of 
use as hypertensive drug. It has no warning regarding neuropsychiatric side effects and it was also 
well tolerated in the previous trial in HD patients, with no worsening of depression or suicidality 
although the sample was very limited.  


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Safety will be carefully monitored along the trial, particularly the risk of depression and suicidality 
will be assessed at each visit by the physician through specific scales (Beck Depression Inventory 
and Columbia-SSRS). Patients with known depression should be treated and stabilized with 
antidepressant therapy. Patients with severe untreated or under-treated depression at screening, or 
presenting a risk of suicide (item on suicidality >0 in BDI scale) are excluded from this study, and if 
the risk of suicide arises during the trial the patient should be immediately withdrawn from the study.  
The known effect of bevantolol as beta blocker may induce potential side effects such bradycardia or 
orthostatic hypotension. Patients with a history of, or current, hypotension or bradycardia (HR <50 
bpm) at the screening will be excluded from the study. Hemodynamic parameters (HR and BP) will 
be carefully monitored during the study as well as the recording of ECG to assess any abnormality. 
Severe permanent bradycardia will be excluded.   
 
2.3. 
STUDY RATIONALE 
In vitro, SOM3355 provided functional inhibition of the VMAT2 with similar potency to that of TBZ 
but different binding properties that may provide a change in monoamine signaling improving the 
chorea symptoms of HD with less risk of severe side effects. Relying on its VMAT2 inhibition 
activity, and good tolerability at doses from 100 to 600 mg/day administered once or twice daily (OD 
or BID), SOM Biotech is now developing SOM3355 for the treatment of the dyskinetic movement 
disorders related to HD.  
The first Proof of Concept Phase 2 study (SOMCT02) assessing SOM3355 in HD patients is 
suggestive of its clinical effect on chorea. PK-PD analysis assessed the relationship between plasma 
levels of SOM3355 and the absolute reduction of TMC score with a linear model. Dose 
proportionality was shown and modelling allowed us to predict that plasma concentration values 
around 3000 ng/ml will induce a mean reduction of TMC score of at least 3.0 points compared to 
placebo. Assuming the dose proportionality, an increase of the dose to 300 mg BID (600 mg/day) 
would be required in the next trial to obtain such improvement in TMC score and therefore substantial 
decrease of chorea symptoms that could be comparable to the TBZ effect. 
 
 


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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
OBJECTIVES OF THE STUDY 
 
3.2. 
PRIMARY EFFICACY ENDPOINT 
The TMC score is a standardized, reliable chorea assessment based on frequency and severity in 7 
body regions. 
 
3.3. 
SECONDARY EFFICACY ENDPOINTS 
Key secondary efficacy endpoint:   
• 
Change from baseline in Clinical Global Impression (CGI-C),  
Other secondary efficacy endpoints: 
• 
Change from baseline in Patient Global Impression (PGI-C). 
• 
TMC-response defined as improvement ≥2 in TMC score between baseline and end of 
The primary objective of the study is to assess the efficacy of two doses of SOM3355 (400 mg/day 
and 600 mg/day taken twice daily [BID] over at least 8 weeks at maintenance dose) compared to 
placebo to reduce chorea in HD patients, measured by the change in TMC score (primary efficacy 
endpoint). 
Secondary objectives of the study are:  
To evaluate the safety and tolerability of two doses of SOM3355 (400 mg/day and 600 mg/day taken 
BID) compared with placebo in HD patients, with particular attention to depression and suicidality 
and to the cardiovascular hemodynamic parameters.  
And to evaluate the efficacy of the two doses of SOM3355 (400 mg/day and 600 mg/day taken BID) 
compared with placebo on: 
o the change of Clinical Global Impression (CGI-C),  
o the change of Patient Global Impression (PGI-C),  
o the percentage of responders based on the improvement ≥2 in TMC score,  
o 
the percentage of change of TMC score.  
A PK sub-study in a subset of 24 patients will allow to determine the PK profile of the two doses of 
SOM3355 (200 mg and 300 mg given twice per day) at steady state and to model PK-PD assessments 
of hemodynamic and cardiac parameters. 
The primary measure of efficacy will be the change in TMC sub-score of the UHDRS® between 
baseline and end of maintenance dose (the mean of Visit 4 and Visit 5 minus the mean of Visit 0 and 
Visit 1). 


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maintenance dose. 
• 
Percentage of change in TMC score between baseline and the end of maintenance dose.      
• 
Change from baseline in Total Motor Score (TMS) of the UHDRS®.  
• 
Change from baseline in Gait sub-score of the UHDRS®. 
• 
Change from baseline in Dystonia sub-score of the UHDRS®.     
• 
Change from baseline in EQ5D-5L measuring quality of life. 
 
3.4. 
SAFETY ENDPOINTS 
Safety assessments will include the following: 
• Incidence, frequency, and severity of AEs in each treatment group. 
• Change from baseline in:  
- 
Vital signs: BP, including orthostatic BP, and HR. 
- 
ECGs.   
- 
Clinical laboratory test results (chemistry, hematology). 
- 
Physical examination findings, weight. 
- 
C-SSRS assessing suicidality.  
- 
BDI scale assessing depression.  
- 
ESS assessing sleepiness. 
- 
TFC of the UHDRS® assessing functioning.  
- 
Functional Assessment of the UHDRS®. 
- 
BARS assessing akathisia. 
- 
MoCA scale to assess cognitive disturbances.   
- 
PBA-s to assess behavioral symptoms in HD. 
 
3.5. PK-PD ASSESSMENTS   
SOM3355 plasma concentration will be measured at each visit under treatment with SOM3355 (i.e. 
Visit 2 to Visit 5) in all patients. Plasma samples will be collected pre-dose (before the dug intake) 
and 2 hours after the drug intake (corresponding to the expected Tmax) at Visit 2 and Visit 4, and only 
pre-dose at all other visits (Visit 3 and Visit 5). 
Prolactin plasma level will be measured at each visit from Visit 1 to Visit 6 in all patients. Plasma 
samples will be collected pre-dose (before the dug intake) and 2 hours after the drug intake (at Tmax) 
at Visit 2 and Visit 4, and only pre-dose at all other visits (Visit 1, Visit 3, Visit 5 and Visit 6). 
 
 
 


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4. 
STUDY DESIGN 
4.1. 
OVERALL DESIGN 
This is an international, multicenter, double-blind, randomized, placebo-controlled, parallel-group 
Phase IIb study assessing two doses of SOM3355 (400 or 600 mg/day), taken as 200 mg BID or 300 
mg BID, in patients presenting choreic symptoms related to HD. 
The study will enroll 129 patients with a genetically-proven diagnosis of Huntington’s Disease 
(confirmed by HTT gene CAG repeats ≥36), of mild to moderate severity (TFC score ≥7) with choreic 
symptoms (TMC score ≥10). The patients will be recruited in investigating sites in various European 
countries. Ambulatory patients will be recruited by reference centers for HD in collaboration with 
patient advocacy groups and the EHDN. 
Patients who meet all of the eligibility criteria will be randomized at Visit 1 in a 1:1:1 ratio to one of 
the 3 treatment arms to receive either SOM3355 400 mg/day, SOM3355 600 mg/day, or placebo, all 
given BID. Dosing will start with an up titration in the first 3 weeks and will then be maintained at a 
fixed dose for 7 weeks. After 10 weeks, patients will down titrate to 1 capsule a day of study drug for 
1 week, followed by 1 capsule a day of placebo to assess the effect of drug interruption.  
The overall study duration is 12 weeks plus 1 or 2 weeks for screening.  
Screening period (1 or 2 weeks before inclusion, from Visit 0 to Visit 1): patients will undergo an 
independent evaluation by a qualified healthcare provider to determine their capacity to provide 
informed consent and their eligibility according to the study selection criteria. After informed consent 
is obtained, patients who are stable from a medical and psychiatric standpoint will undergo a 
screening evaluation to confirm their eligibility. The evaluations performed at Visit 0 and Visit 1 will 
be used as baseline to assess the treatment effect. 
Randomization (at Visit 1): patients who fulfil all selection criteria at the end of the screening period 
will be randomized and will initiate therapy with either SOM3355 or placebo.  
Up-Titration period (between Visit 1 and Visit 2): patients will start the active treatment with an 
up-titration period of 3 weeks. They will be instructed to take one capsule every day in the morning 
during the first week, and then two capsules, one in the morning and one in the evening every day 
from the second week.  
▪ Patients allocated to 400 mg/day treatment arm will receive 200 mg once daily (OD) the first 
week, and then 200 mg BID the second and third week.  
▪ Patients allocated to 600 mg/day treatment arm will receive 200 mg OD the first week, 200 mg 
BID the second week, and then 300 mg BID the third week.  
▪ Patients allocated to the placebo arm will take matching placebo capsules according to the same 
pattern, once a day during the first week and twice per day from the second week.  
Maintenance dose (from Visit 2 to Visit 5): the dose reached in each arm (200 mg BID or 300 mg 
BID or placebo) will be maintained for 7 additional weeks. At the end of this maintenance dose 
period, two evaluations will be performed one week apart, at Visit 4 (end of Week 9) and at Visit 5 
(end of Week 10), to assess the treatment effect versus baseline.  


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End of study with 1-week down-titration and 1-week placebo washout (from Visit 5 to Visit 6): 
during the last 2 weeks (Week 11 and Week 12), the patients will be instructed to take only 1 capsule 
in the morning. The two arms receiving the active drug will be dispensed capsules dosed at 200 mg 
for one week to decrease the dosing to 200 mg/day. During the last week, all the patients will receive 
capsules of placebo.  
Patients will return for a last visit (Visit 6) to assess the withdrawal of the drug.  
 
4.2. 
PK SUB-STUDY 
A PK sub-study will be conducted to characterize the PK profile of repeated doses of SOM3355 at 
400 and 600 mg/day. This analysis will be performed by collecting 12-hour PK samples (H0, H0.5, 
H1, H1.5, H2, H3, H5, H8, and H12) in 8 patients per arm (24 patients in total) that will be 
hospitalized for 24 hours at Visit 2. These patients will be recruited by 3 or 4 sites able to manage the 
logistics of PK sampling.  
PK data from this sub-study will be collected in an independent database and analyzed by an 
independent un-blind central laboratory before the end of the clinical trial. The results will be given 
in a blinded manner until the final data lock.  
In addition, cardiac and hemodynamic parameters will be collected in parallel, with 12-hour cardiac 
Holter and blood pressure measurements before each PK sample, to allow PK-PD modeling 
assessments. 
 
4.3. 
RATIONALE FOR STUDY DESIGN  
This 12-week Phase 2b study is designed to evaluate in parallel groups the efficacy, safety and 
tolerability of two doses of SOM3355 (400 mg/day or 600 mg/day, taken either as 200 mg or 300 mg 
BID) compared with placebo in HD patients with chorea. A previous Phase 2a study (SOMCT02) has 
already tested the effect of 400 mg/day SOM3355 (given as 200 mg BID) compared with placebo in 
a crossover design on 6-week periods, and it has shown a reduction of choreic symptoms measured 
by a significant decrease of the TMC score, and a good tolerability at the tested dose. For this Phase 
2b trial, the regulatory authorities recommended a dose-finding study testing different fixed doses in 
parallel compared with placebo, to correctly assess the dose effect and determine the best dose to be 
tested in Phase 3. 
It is deemed prudent to initiate the treatment by escalating the dose with weekly increases (200 mg 
OD the first week and 200 mg BID the second week to reach 300 mg BID on the third week for the 
patients allocated to the 600 mg/day treatment arm) for better tolerability and to reduce the risk of 
hypotension or bradycardia at the start of treatment. Then, the reached dose (400 mg/day or 600 
mg/day) will be maintained for 7 additional weeks. 
At the end of the maintenance dose, the study drug is down-titrated for one week (at 200 mg/day) to 
avoid an abrupt interruption of the dose, followed by a 1-week placebo washout period to assess the 
effect of the interruption of the study drug.  


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4.4. 
JUSTIFICATION FOR DOSE 
The proposed clinical doses are within the dose range studied in the nonclinical program, and the 
lowest observed adverse effect level (LOAEL) in dogs corresponds to the calculated human 
equivalent dose (HED) of 1500 mg (see Investigator’s brochure § 5.3.2). 
The selected doses of 400 mg/day and 600 mg/day taken BID (i.e. 200 mg BID and 300 mg BID) 
have already been used in previous clinical trials.  
Bevantolol in doses up to 600 mg/day has been studied during the clinical development of the drug 
for the treatment of hypertension and angina pectoris (Maclean et al, 1988; Al.Khawaja et al, 1986). 
Notably in a randomized trial comparing bevantolol to propranolol in hypertension, 39 patients 
received the dose of 200 mg BID and 47 patients received the dose of 300 mg BID for a 6-month 
double-blind period after a 6-week double blind titration period. These doses were well tolerated 
during this long term therapy. 
The previous Phase 2a study in HD (SOMCT02) studied the effect of 400 mg/day SOM3355 (given 
as 200 mg BID) compared with placebo in a crossover design given for 6 weeks of dosing. The study 
showed good tolerability and safety of SOM3355 dosed at 200 mg BID in patients with HD. 
Moreover, in this study, PK-PD assessments have shown dose linearity of plasma concentrations, 
consistent with the previous published data (Latts et al, 1986), and the relationship between plasma 
levels of SOM3355 and the absolute reduction of TMC score analyzed with a linear model allowed 
us to predict that the dose of 300 mg BID would provide plasma concentration values that may induce 
a mean reduction of TMC score of at least 3 points compared to placebo and therefore substantial 
decrease of choreic symptoms that could be comparable to TBZ effect.  
 
4.5. 
END OF STUDY DEFINITION 
A patient is considered to have completed the study if he/she has completed all visits of the study. 
The end of the study is defined as the date of the last visit of the last patient in the study. 
 
 
 
 


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5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
 
5.2. 
EXCLUSION CRITERIA 
Patients are excluded from the study if any of the following criteria apply: 
1. Onset of HD symptoms prior to age of 21 years, corresponding to juvenile forms of HD. 
2. HD patients presenting rigid akinesia. 
3. Use of other vesicular monoamine transporter type 2 (VMAT2) inhibitors such as tetrabenazine, 
deutetrabenazine, or valbenazine within 3 months before enrollment, and at any time during the 
study period; and use of other antichoreic treatment such as any neuroleptic within 2 months or 
amantadine, memantine, riluzole within 1 month before enrollment and along the study.  
4. Patients who experienced severe depression or suicide attempt in the last 5 years. 
5. Severe untreated or under-treated psychiatric illness such as active suicidal ideation or behavior 
(BDI-21 item #9 >0 and active suicidal ideation in C-SSRS) or depression at screening or baseline 
(BDI-21 items total score >30); although patients taking authorized antidepressant therapy at a 
stable dose for at least 2 months and stabilized can be enrolled.  
Eligibility criteria to participate in this study are: 
1. Males or females ≥ 21 years old.  
2. Patients with a diagnosis of Huntington’s Disease determined by a movement disorders expert 
and confirmed by a number of HTT gene cytosine-adenosine-guanine (CAG) repeats ≥36. 
3. UHDRS® Total maximal chorea (TMC) score ≥10   
4. UHDRS® Total Functional Capacity (TFC) ≥7 (corresponding to mildly to moderately impaired 
patients). 
5. Able to walk independently or with minimal assistance. 
6. Females of child-bearing potential must use a medically accepted effective method of birth 
control, agree to continue this method for the duration of the study and for at least 1 month 
following the last dose of study drug, and be negative to serum pregnancy test performed at the 
screening visit (Refer to section 5.4 for complete advice on contraception requirements of this 
study). Female patients should not be breast-feeding. 
7. In the opinion of the Investigator, the patient must have adequate support to comply with the 
entire study requirements as described in this protocol (e.g. transportation to and from the trial 
site, self-rating scales, drug compliance, scheduled visits, etc.).  
8. Able and willing to provide written informed consent prior to any study-related procedure being 
performed at the screening visit. 


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6. Patients with a history of, or current, hypotension (SBP <110 mmHg) or bradycardia (HR <50 
bpm), and patients with known orthostatic hypotension as defined by the European Society of 
Hypertension (reduction in SBP ≥20 mmHg or in DBP ≥10 mmHg). 
7. Patients with hypertension already treated with more than 2 antihypertensive drugs.  
8. Other active clinically significant illness, including unstable cardiovascular disease, angina 
pectoris, congestive heart failure, pulmonary hypertension, peripheral arterial disease, history of 
pheochromocytoma, asthma, COPD, diabetic ketoacidosis or metabolic acidosis, or neoplastic 
pathology, which could interfere with the study conduct, or counter-indicate the study treatment, 
or to place the patient at risk during the trial, or compromise their study participation. 
9. Any significant serious abnormality in the electrocardiogram (ECG), e.g. recent myocardial 
infarction, severe sinus bradycardia (<50 bpm), atrioventricular block (grades I to III, with PR 
>240 msec), sinoatrial block, atrial sinus disease or prolonged QTc interval at screening (ECG 
Bazett’s corrected QT interval (QT / [HR/60] >450 msec for males or >470 msec for females), 
or a known history of long QTc syndrome. 
10. Patients with severe hepatic impairment, or with severe renal impairment, or with any other 
significant abnormality in the physical examination or clinical laboratory results that, in the 
Investigator’s opinion, would not be compatible with study participation or represent a risk for 
the patient while in the study. 
11. Females who are pregnant or lactating, or who intend to become pregnant during the study period. 
12. Patients with allergy under desensitization, with known psoriasis, or a known allergy / 
hypersensitivity to any ingredients of the trial medication or placebo. 
13. History of alcohol or substance abuse in the previous 12 months.  
14. Patients participating in any other study, and the use of any investigational therapy, within the 
1month prior to entry in this study.     
 
5.3. 
CONCOMITANT MEDICATIONS 
All concomitant treatment should be verified and reported in the electronic Case Report Form (eCRF) 
at each visit. 
5.3.1. 
Prohibited treatments 
VMAT2 inhibitors such as tetrabenazine, deutetrabenazine, or valbenazine are forbidden within 3 
months prior to randomization and at any time during the whole study. 
Neuroleptics indicated to treat chorea such as haloperidol, pimozide, or tiapride, and all other 
neuroleptics used off label as dopamine D2 receptor blockers to treat chorea are forbidden within 2 
months prior to randomization and at any time during the whole study. 
The following treatments are forbidden within 1 month prior to randomization and during the whole 
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• All monoamine oxidase (MAO) inhibitors.  
• Levodopa and dopa-agonist drugs: apomorphin, ropinirole, pramipexole, rotigotine. 
• Reserpine 
• Glutamate antagonists: amantadine, memantine, riluzole. 
• Anti-arrhythmic drugs inducing bradycardia: diltiazem, verapamil, amiodarone, digitalis, 
quinidine, sotalol, disopyramide. 
• Any other beta blocker antihypertensive medication.  
• Central antihypertensive treatments: clonidine, methyldopa, rilmenidine. 
5.3.2. 
Authorized treatments 
5.4. 
CONTRACEPTION 
According to the recommendations related to contraception and pregnancy testing in Clinical Trial 
Facilitation and Coordination Group (CTFG) guidance, based on Calvan® (bevantolol hydrochloride) 
Summary of Product Characteristics (SmPC) the risk of teratogenicity or fetotoxicity is considered 
Patients treated with antihypertensive drugs such as diuretics, angiotensin converting enzyme (ACE) 
inhibitors, angiotensin receptor blockers (ARBs), or calcium blockers (dihydropyridines only) can 
continue their treatment at a stable dose during the whole study, with maximum of a dual combination 
of 2 antihypertensive drugs, and if the patient has stable blood pressure. 
Patients treated for depression and stabilized with non IMAO (inhibitors of MAO) antidepressants 
can continue their treatment at a stable dose during the whole study. Allowed antidepressants drugs 
are:  
• SSRIs (selective serotonin reuptake inhibitors): fluoxetine, paroxetine (see precautions below), 
citalopram, sertraline. 
• SNRIs (serotonin-noradrenaline reuptake inhibitors): duloxetine, venlafaxine. 
• TCAs (tricyclic antidepressants): amitriptyline, clomipramine, imipramine, nortriptyline, 
lofepramine. 
Neuroleptics treatment (excluding haloperidol, pimozide, and tiapride, which all have the indication 
for the treatment of abnormal involuntary movements that occur in HD, such as chorea, in their 
labeling), if needed to treat a behavior disorder and prescribed for at least 3 months at a stable dose, 
can be maintained at a stable dose during the whole study, provided that it is approved on a case-by-
case basis by the Steering Committee before enrolment of the patient.  
Treatments to be used with precautions (because of risk of interactions): 
• Alpha-blockers. 
• Local beta-blockers (eye drop) or pilocarpine (eye drop). 
• Anticholinesterase drugs: donepezil, rivastigmine. 
• Strong CYP2D6 inhibitors may increase the blood levels of SOM3355 (such as paroxetine 
fluoxetine, quinidine, bupropion, dacomitinib, tipranavir).  


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as possible” in humans taking bevantolol. In consequence, recommendations related to contraception 
and pregnancy testing in this clinical trial are as following: 
Females of child-bearing potential (i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile) who test negative for pregnancy at screening (pregnancy test) 
must use a reliable method of birth control during the study and for at least 1 month following the 
last dose of study drug. A pregnancy test should be also performed at the end of the study (Visit 6). 
No contraception measures are needed for male subjects with female partner of childbearing potential. 
Highly effective methods of birth control for females include: 
• 
Intrauterine device or intrauterine hormone-releasing system. 
• 
Use of oral, implanted (under the skin), transdermal (patches placed on the skin), or other 
hormonal methods (shots/injection) of hormonal contraception that stop ovulation. These must 
have been used for at least 3 months before the Screening Visit. 
• 
Surgery to tie both fallopian tubes - female patients who have had both fallopian tubes tied.  
If the patient practices true abstinence because of a lifestyle choice (not just to participate in this 
study), the Investigator may consider an exemption for contraceptive requirements, however, for 
females a pregnancy test should be done at screening and at the end of the study.  
If a female becomes pregnant while receiving the study drug, she should immediately stop taking the 
medication and notify the Investigator. The patient should attend a final visit to assess her health 
status. Then, a follow-up with her family doctor / general practitioner should be performed to obtain 
information about her pregnancy and the birth of her child, including post-natal examination, which 
will be used to learn more about the effects of the study drug on pregnancy and an unborn baby. 
 
5.5. 
SCREEN FAILURES 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure patients, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
5.6. 
PATIENT IDENTIFICATION AND RANDOMIZATION 
Each country will be assigned a 1-digit country code (i.e., 1, 2, 3...). Each participating investigative 
study center within a country will be assigned a sequential 2-digit number (e.g., 01, 02, 03...), which 
will be added to the country code to generate the site code or site ID. Each patient will receive a 2-
digit number in sequential order at the screening visit after the consent form is signed (e.g., 01, 02, 


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03...), which will be added to the site code to obtain the patient code or patient ID. Therefore, the 
Patient IDs will be like 101-01, 101-02, ..., 102-01, 102-02, ..., 201-01, 201-02, ..., 202-01, 202-02....  
Enrolled patients who fail screening or discontinue study participation early, regardless of whether 
treatment was received or not, will retain their patient ID and a new ID will be assigned to the next 
enrolled patient. 
Patients who fulfil all entry criteria will be randomized to receive either SOM3355 at 400 mg/day or 
600 mg/day, or placebo, in a 1:1:1 ratio. Randomization will be site-specific and performed by a 
central Interactive Web Response System (IWRS). 
 
5.7. 
PATIENT WITHDRAWAL CRITERIA 
In accordance with the Declaration of Helsinki, patients will be free to withdraw from the study at 
any time if they wish to do so, for any reason specified or unspecified. Such withdrawal should not 
affect the required and provided medical care. 
In addition, the Investigator may interrupt the patient participation from the study at any time if he/she 
considers it necessary for any reason including:  
• 
Pregnancy. 
• 
Ineligibility (either arising during the study or retrospective having been overlooked at screening). 
• 
Significant protocol deviation. 
• 
Significant non-compliance with treatment regimen or study requirements. 
• 
An AE which requires discontinuation of the study medication or results in inability to continue 
to comply with study procedures, particularly if the patient presents a severe depression (BDI-
21 item total score ≥30), or suicidal ideation or behavior (BDI-21 Item #9 >0 and active suicidal 
ideation in C-SSRS), or severe hypotension (SPB/DBP <90/60 mmHg), or orthostatic 
hypotension as defined by the ESH, or sustained un-tolerated bradycardia (HR <50 bpm). 
• 
Consent withdrawn. 
• 
Lost to follow-up.  
• 
The Investigator or Sponsor determines it is in the best interest of the subject to discontinue the 
patient’s participation in the study. 
Patients who discontinue study treatment or active participation in the study will no longer receive 
study treatment but will be followed for safety. When a patient withdraws from the study, the 
reason(s) for withdrawal shall be recorded by the Investigator on the relevant page of the eCRF. 
Whenever possible, all patients who discontinue study treatment or withdraw from the study 
prematurely will undergo all end-of-treatment assessments. Patients who fail to return for final 
assessments will be contacted by the site staff. Following a minimum of 2 documented unsuccessful 
telephone calls, a registered letter will be sent to the patient in a final attempt to ensure protocol 
compliance. 


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It is vital to obtain follow-up data on any patient withdrawn because of an AE or SAE. In every case, 
efforts must be made to undertake protocol-specified, safety, follow-up procedures. 
 
5.8. 
STUDY DISCONTINUATION 
5.8.1. 
 Criteria for terminating the trial 
The Sponsor reserves the right to terminate the study but intends only to exercise this right for valid 
scientific or administrative reasons, and reasons related to protection of patients. In all cases the Ethic 
Committees (IRB/IEC) and Health Authorities should be informed. Possible reason for the study 
termination can include but are not limited to: 
• 
The discovery of an unexpected, significant or unacceptable risk to patients enrolled in the study. 
• 
A decision on the part of the Sponsor to suspend or discontinue the development of the 
investigational product. 
• 
Request of any relevant regulatory agency. 
5.8.2. 
Criteria for terminating the study at site 
The Sponsor reserves the right to terminate the study at any given investigational site at any time after 
the study initiation if: 
• 
ICH GCP regulations are not observed. 
• 
Serious and continuous protocol deviations. 
• 
The data generated are of poor quality. 
• 
Changes in personnel or facilities that may adversely affect performance of the study (e.g. low 
rate of inclusion). 
 
 


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6. 
INVESTIGATIONAL TREATMENT 
6.1. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
SOM3355 is bevantolol hydrochloride, a synthetic drug currently commercialized as a racemic 
mixture of S-bevantolol (-) and R-bevantolol (+) and used as antihypertensive drug. Bevantolol is 
approved and has been commercialized in Japan since 1995 as Calvan® by Nippon Chemiphar in the 
form of 100 mg film-coated tablets.   
Bevantolol is a synthetic propanolamine that is 3-aminopropane-1,2-diol in which the hydrogen of 
the primary hydroxy group is substituted by 3-methylphenyl and one of the hydrogens attached to the 
nitrogen is substituted by 2-(3,4-dimethoxyphenyl) ethyl. 
Chemical Name:  
Bevantolol HCl (racemate) 
Molecular formula:  
C20H27NO4·HCl 
Molecular Weight: 
381.897 g/mol 
IUPAC Name: 
(±)-1-[(3,4-Dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol 
hydrochloride 
CAS No:  
59170-23-9 
Chemical Structure: 
 
 
 
  
In this clinical trial, the investigational medicinal product (IMP) i.e. SOM3355 (bevantolol 
hydrochloride) will be administered as capsules of 200 mg and 300 mg containing 2 or 3 film-coated 
100 mg tablets of Calvan® (the commercial form of bevantolol) or matching capsules of placebo.  
The active study drug used in the capsules is the commercial formulation of Calvan® in 100 mg film-
coated tablets manufactured by Nippon Chemiphar, imported from Japan and released in Europe by 
the Contract Manufacturing Organization (CMO) Sharp Clinical Services Ltd, which is responsible 
for the encapsulation of the tablets and also manufactures the placebo matching capsules.  
Description of the 100 mg Calvan® tablets used: 
Composition: 
- 
100 mg of bevantolol hydrochloride per tablet 
- 
Additives: lactose hydrate, microcrystalline cellulose, carmellose, hydroxypropylcellulose, 
hydrogenated oil, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and 
carnauba wax. 


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Figure 2: Appearance and Details of Calvan® 100 mg Tablets 
According to the SmPC, stability of the tablets are 39 months in blister packs (polyvinylchloride 
film, aluminum foil) or in sealed brown glass bottles at room temperature and under accelerated 
test (40°C-75%RH).   
Expiration period: 3 years (according to stability test results).  
As it is a really stable drug, no special storage conditions are required. 
To ensure the blinding, the 100 mg Calvan® tablets will be over-encapsulated in hard gelatin capsules 
(Swedish orange DBcaps® AAel) in 2 different dosages: 200 mg and 300 mg.  
To obtain the different dosages, capsules containing 200 mg (i.e. 2 tablets) and 300 mg (i.e. 3 tablets) 
of SOM3355, and capsules containing placebo will be prepared by the CMO.  
Matching placebo capsules will have the same appearance as the active drug capsules (form, 
dimension, color, and taste) to ensure that neither the patient, nor the Investigator, nor members of 
the clinical staff know the identity of the study medication.  
 
6.2. 
PACKAGING AND LABELLING 
The IMP will be packed in HDPE Duma Twist-Off 100 mL bottles containing 14 capsules, which 
corresponds to 1 week of treatment. Bottles will be labelled in different languages according to 
country specific directives and regulations and then delivered to the sites’ pharmacies. 
 
6.3. 
MANAGEMENT AND STORAGE  
The IMP requested via IWRS will be provided by the CMO to the sites’ pharmacies, already packed 
in bottles and labelled, ready to be supplied to the patients. 
The medication product does not require any special storage conditions, so it can be stored at room 
temperature and no temperature control is needed for shipments and site storage.  
The medication will be stored in the sites’ pharmacies until the study staff pick them up according to 
IWRS allocation for dispensation to patients.  
All movements of study medication must be documented in an accountability log kept in the 
pharmacy service. Unused and returned study medication should be kept until the end of the study. 


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6.4. 
STUDY DRUG DISPENSING 
At each visit, the patient will be dispensed with the sufficient amount of IMP bottles: 1 bottle per 
week is needed, but additional bottles will be dispensed to secure any potential incident or any delay 
of the visits, i.e. 1 extra bottle will be added at some visits. 
Apart from the IMP bottles, the investigator will give the patient the corresponding page of the Patient 
Diary, where the patient will register the time and date of all the medication intakes and any incidents. 
During the following visit, the patient must return the Diary page completed and the bottles with any 
leftover medication or full or empty bottles to check treatment compliance and accountability. 
 
6.5. 
TREATMENT COMPLIANCE AND ACCOUNTABILITY 
The Investigator or designated study staff is responsible for monitoring the patient’s compliance with 
study medication during the trial. Compliance will be assessed by capsules count, i.e., evaluation of 
returned study medication (e.g., amount used/amount expected to be used in the interval between 
visits) and must be reviewed at every visit by interviewing the patient to determine if he/she is taking 
study medication as directed.  
Compliance will be evaluated by calculating the number of capsules used (capsules dispensed minus 
capsules returned) divided by the expected number of capsules to be used. A patient will be deemed 
compliant if the patient has taken ≥80% but ≤120% of the expected tablets of study drug. 
When the number of tablets used exceeds the number of expected tablets to be used, the Investigator 
must clarify the reason for this and in case of over dosage, this must be reported. 
 
6.6. 
PROCEDURE FOR EMERGENCY INDIVIDUAL UNBLINDING 
This study will be conducted in a double blind manner. Neither the patient nor the Investigator will 
know to which treatment a patient is randomized. The study blind should not be broken except in a 
medical emergency (where knowledge of the study drug received would affect the treatment of the 
emergency) or regulatory requirement (e.g., for SAEs or death [in Germany]). At that point, the 
Investigator may connect to the IWRS and have access to the treatment group for a specific patient.  
The unblinding of a patient’s treatment must be documented in the source documentation and in the 
patient's eCRF together with date and time, and the reason of unblinding and signed by investigator. 
If possible, such emergencies should be discussed with the trial Medical Manager prior to disclosure 
of the treatment allocation. Should the code be broken, the Sponsor must be notified immediately. 
 
 
 


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7. 
STUDY ASSESSEMENTS  
7.1. 
UNIFIED HUNTINGTON’S DISEASE RATING SCALE (UHDRS®) 
The standard clinical assessment tool in HD is the Unified Huntington's Disease Rating Scale 
(UHDRS®), developed by the Huntington Study Group to monitor disease progression in individual 
patients, and used in research and clinical practice to determine the efficacy of experimental therapies 
for the treatment of HD. It assesses 4 domains of clinical performance and capacity in HD: motor 
function, cognitive function, behavioral abnormalities, and functional capacity. The UHDRS® has 
undergone extensive reliability and validity testing and has demonstrated to be sensitive to detect 
longitudinal changes in manifest HD patients. It is used as a major outcome measure in controlled 
clinical trials (Huntington Study Group, 1996).   
The entire UHDRS® is composed of 6 sections (Motor, Cognitive, Behavioral, Functional 
Assessment, Independence Scale, and Total Functional Capacity). 
The motor section is made of 31 items including the assessment of chorea on 7 items (providing the 
TMC sub-score), dystonia, bradykinesia/rigidity, gait/balance and oculomotor function, and will be 
rated at each visit for efficacy assessment. 
The functional domain comprises 3 sections, namely the total functional capacity (TFC), the 
functional assessment scale (FA), and the independence scale (IS).  
In this study, UHDRS® motor part will be used to assess efficacy outcomes at each visit, and TFC 
and FA scales will be performed at baseline and at the end of the maintenance dose of study drug for 
safety assessment. The cognitive component and the behavioral assessment won’t be used, and are 
replaced by other recommended scales for HD (Mestre et al, 2018). 
At the inclusion, patients will be selected according to their functional status assessed by the TFC 
scoring the severity of HD and their functioning to exclude severe patients with TFC <7, and the 
severity of chorea symptoms assessed by the total chorea score that should be ≥10 at the inclusion.  
The main efficacy assessment is focused on the choreic movements measured with TMC score 
included in the motor part of the UHDRS® as primary endpoint.  Other sub-scores of the motor part 
of UHDRS® will also be considered such as TMS assessing overall motor function and the Gait sub-
score and Dystonia sub-score.   
 
7.2. 
EFFICACY ASSESSMENTS  
7.2.1. 
Total Maximal Chorea score (TMC) of the UHDRS® 
The TMC score is part of the motor assessment of the UHDRS® consist of the sum of the seven body 
regions used to assess chorea including the face, oral-buccal-lingual region, trunk and each limb 
independently. Each territory is scored from 0 (normal findings) to 4 indicating severe abnormalities 
(0=absent, 1=slight/intermittent, 2=mild, 3=moderate/ common, 4=marked prolonged). The 
minimum TMC score is 0 (absent) and the maximal score is 28. A decrease in score indicates 
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This scale, which specifically targets a single motor feature in HD (chorea) and has been validated 
for this purpose, is more adequate in assessing for a specific symptomatic treatment indication. 
TMC score will be assessed at each visit.   
7.2.2. 
Total Motor Score (TMS) of the UHDRS® 
The motor part of UHDRS® assessing the Total Motor Score is made of 31 items including chorea 
(TMC sub-score), dystonia, gait/balance, bradykinesia/rigidity, and oculomotor function. The items 
are rated from 0 to 4, with 0 indicating normal findings and 4 indicating severe abnormalities. The 
range of the Total Motor Score (TMS) is 0 to 124, with higher scores indicating more severe motor 
impairment.  
TMS score will be assessed at each visit.   
Sub-scores of gait and dystonia will also be analyzed as individual outcomes. 
7.2.3. 
Clinical Global Impression (CGI) Scale  
The CGI is a 7-point Likert Scale that asks the clinicians to rate, considering their total experience 
with this type of patients, the level of illness due to chorea at baseline on the illness severity ranging 
from normal (1) to extremely ill (7) (CGI-Severity), and after initiating therapy the overall global 
improvement (CGI-Change), since the initiation of study drug dosing, ranging from very much worse 
(7) to very much improved (1), to assess overall response to therapy by the clinician. 
CGI-S will be assessed at the inclusion (Visit 1 at Day 0), and CGI-C at each following visit. 
7.2.4. 
Patient Global Impression (PGI) Scale 
The PGI is a 7-point Likert Scale that asks the patients to assess their HD symptoms at specific visits: 
at baseline (PGI-Severity) on the illness severity ranging from normal (1) to extremely ill (7), and 
after initiating therapy (PGI-Change), ranging from very much worse (7) to very much improved (1), 
to assess overall response to therapy. In general, patient-rated global measures of change have face 
validity and have been shown to correlate with disability for a number of chronic conditions. 
PGI-S will be assessed at the inclusion (Visit 1 at Day 0), and PGI-C at each following visit.  
7.2.5. 
EQ-5D-5L  
EQ-5D-5L measuring quality of life is a validated self-report questionnaire developed by EuroQol 
Group. This scale is widely used in clinical trials, population studies and real-world clinical settings 
– and have proven to be valid, reliable and responsive in numerous conditions and populations. The 
EQ-5D-5L is used worldwide and has been translated into most major languages through a closely 
monitored translation process. 
Aspects of life quality are assessed by measuring 5-item dimension as following: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression, each dimension scored according to five 
response levels (no problems, slight problems, moderate problems, severe problems, and unable 


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to/extreme problems) coded from 1 to 5. The respondent is asked to indicate his/her health state by 
checking the box next to the most appropriate statement in each of the 5 dimensions.  
In addition, the patients will use a visual analogue scale (VAS) to assess their own health state on a 
vertical scale where the extreme endpoints are labelled ‘The best health you can imagine’ scoring 100 
and ‘The worst health you can imagine’ scoring 0. This information can be used as a quantitative 
measure of the patient’s perception of their overall health. 
EQ-5D-5L will be rated at the inclusion (Visit 1 at Day 0) and at the end of maintenance dose (Visit 
5 at end of Week 10). 
 
7.3. 
SAFETY ASSESSMENTS 
7.3.1. 
Laboratory Assessments 
Safety Laboratory tests (hematology, biochemistry) listed in Table 3 below will be performed at the 
screening visit (Visit 0), at the interim visit (Visit 3 at the end of Week 6), and at the end of 
maintenance dose (Visit 5 at end of Week 10). Blood samples for hematology and biochemistry should 
be obtained prior to study medication dosing. In total, approximately 10 mL blood should be drawn. 
Safety laboratory samples will be analyzed via local laboratories. Safety laboratory tests are to be 
reviewed by the Investigator.  
Abnormalities (e.g. AEs) will be defined as laboratory test results that are outside the reference range 
as defined by the normal range for laboratory test and clinically significant according to the 
Investigator’s assessment.   
Table 3: Laboratory Parameters 
Hematology 
 
 
Red blood cell count 
Mean corpuscular hemoglobin  
Reticulocytes 
Hematocrit 
Mean corpuscular volume 
White blood cell count with 
differential (neutrophils, 
lymphocytes, monocytes, 
eosinophils, basophils) 
Hemoglobin 
Platelet count 
Serum chemistry 
 
 
Alanine aminotransferase  
Aspartate aminotransferase 
Alkaline phosphatase 
Albumin 
C-reactive protein 
Calcium 
Total Protein 
Creatine kinase (CPK) 
Phosphate 
Bicarbonate 
Creatinine 
Chloride 
Bilirubin, direct and total 
Urea 
Potassium 
Gamma glutamyl transpeptidase 
Glucose 
Sodium  
Other 
 
 
Pregnancy test in women of childbearing potential 
 


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7.3.2. 
Physical Examination  
Physical examination will be performed at each visit. Any significant change in each system class 
should be recorded. 
7.3.3. 
Vital signs (Heart rate and Blood Pressure) 
Blood pressure and heart rate must be measured in clinic at the beginning of each visit (before ECGs 
and/or blood sample collection) according to the European Society of Hypertension guidelines 
(Stergiou et al. 2021 ESH guidelines). Standardization for blood pressure measurements is necessary 
to obtain consistency of the collected data. Vital signs should be measured at each visit in the same 
conditions, with a validated and calibrated electronic device and using an adequate cuff for the arm 
circumference of the patient. The electronic device to be used for blood pressure measurement must 
be listed among the validated devices in the: https://www.stridebp.org website. 
Four sequential measures should be performed as follows:  
First heart rate and blood pressure measurements should be taken after the patient has rested quietly 
in a comfortable sitting position for at least 5 minutes, his/her back and arm supported with the middle 
of the upper arm at heart level, legs uncrossed, and feet flat on the floor.  
Orthostatic blood pressure and pulse will be assessed in the supine and standing positions according 
to the ESH guidelines. The patient should be in supine position for at least 5 minutes before the supine 
blood pressure and pulse are measured.  
The patient will then move to the standing position. Standing blood pressure and pulse will be 
obtained after the patient has been in the standing position for 1 minute and 3 minutes. Register each 
measurement with the correct position/time. Ask the patient if he/she is experiencing any symptoms 
of light-headedness or dizziness. 
A drop in BP of ≥20 mm Hg, or in diastolic BP of ≥10 mm Hg, or experiencing light-headedness or 
dizziness is considered abnormal.  
All measurements will be recorded on the vital signs eCRF. Abnormal test results may be repeated at 
the discretion of the Investigator and must be reported on the corresponding eCRF.   
7.3.4. 
Electrocardiograms (ECGs) 
ECG will be performed according to the AHA/ACC recommendations for the standardization and 
interpretation of the ECG. All ECGs will be performed after at least 5 minutes’ rest in a supine or 
semi-supine position. 12-lead ECGs to assess safety will be recorded at Screening Visit, inclusion 
visit (Visit 1), Visit 2, Visit 4, and Visit 6.  
All ECG will be transferred by telemetry to the ECG central reading lab (Banook cardiabase) and 
ECG parameters (PR, QRS, QT, and QTcF) will be registered in the database and analyzed by a 
cardiologist. A report will be sent to the site within 48 hours after the visit. One paper version will be 
edited for the source document that can be examined by the Investigator during the visit. 


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At the inclusion, the ECG will be triplicated i.e. 3 successive records at 5 minutes of intervals and the 
average of all parameters will be calculated for baseline reference. This allows to have good quality 
for the reference ECG. Then the measurements of the 3 ECGs are averaged in a report. 
7.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS is a questionnaire developed by multiple institutions, including Columbia University 
with NIMH support, used to assess suicide risk in trials of central nervous system active compounds. 
It is a semi-structured clinical interview that assesses suicidal ideation severity, suicidal ideation 
intensity, and suicidal behavior (Posner et al, 2011).  
The C-SSRS is an interview performed by trained study personnel that should be done at baseline 
and at each visit during the study as outlined in the Schedule of activities to assess the status of the 
patient regarding suicide ideation and the risk of suicide attempt. The “Baseline/Screening” C-SSRS 
form provided at Screening collects the history of suicide attempts, while for subsequent visits the C-
SSRS form termed “Since the Last Visit” should be used.  
C-SSRS will be assessed at each visit.   
7.3.6. 
Beck Depression Inventory (BDI)  
The BDI scale is currently one of the most widely used instruments in both research and clinical 
practice for assessing depression, with good reliability and validity, which can be used to document 
changes brought by therapy. Created by Dr. Aaron T. Beck in 1961, and revised in 1996 (BDI-II) for 
more consistency with the revised DSMIV, it is a 21-question multiple-choice self-report inventory. 
The questionnaire is composed of items relating to symptoms of depression such as hopelessness and 
irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such 
as fatigue, weight loss, and lack of interest in sex (Wang , 2013).  
Each item has four possible degree of severity rated from 0 to 3, and the patient is asked to choose 
the one that is closest to how he/she feels. The 21 items are summed linearly to create a score which 
ranges from 0 to 63. It can be administered as an interview by the clinician or as a self-report 
instrument.  
The suicide item #9 includes the following: 
0. “I don't have any thoughts of killing myself.” 
1. “I have thoughts of killing myself, but I would not carry them out.” 
2. “I would like to kill myself.” 
3. “I would kill myself if I had the chance.” 
Total Score Levels of depression (Beck et al, 1988):  
  0  to 9:   No depression or minimal depression 
10  to 18: Mild to moderate depression   
19  to 29: Moderate to severe depression   
30  to 63: Severe depression  
BDI will be assessed at each visit.   


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A total score of BDI-21 items ≥30 or item 9 >0 results in an exclusion of the patient from further 
participation in the study. 
7.3.7. 
Epworth Sleepiness Scale (ESS)  
The ESS is a self-administered questionnaire comprised of eight questions that provides a measure of 
a patient’s general level of daytime sleepiness (Johns, 1991). The ESS asks respondents to rate, on a 
4-point Likert scale (0 – 3), their usual chances of dozing off or falling asleep in different situations 
or activities that most people engage in as part of their daily lives. The total ESS score is the sum of 
8 item scores and can range between 0 and 24 with a higher score indicating a higher level of daytime 
sleepiness. Most people can complete the ESS without assistance in 2 or 3 minutes.  
ESS will be assessed at each visit.   
7.3.8. 
Total Functional Capacity (TFC) of the UHDRS®  
The UHDRS®-TFC scale is a tool used by clinicians to assess the stage of HD and the level of 
functional capacity in patients on five items:  patients' ability to work, manage finances, run a house, 
take care of themselves, and live at home independently. The TFC score ranges from 0 (worse) to 13.  
TFC will be assessed at screening (Visit 0), at the inclusion (Visit 1), and at the end of maintenance 
dose (Visit 5 at end of Week 10). 
7.3.9. 
Functional Assessment (FA) of the UHDRS®  
The UHDRS®-FA scale includes 25 yes/no questions about common daily tasks (range 0 – 25).  
FA will be assessed at screening and at the end of the maintenance dose (Visit 5 at end of Week 10). 
7.3.10. 
Barnes Akathisia Rating Scale (BARS) 
The BARS (Barnes 1989) is administered by healthcare providers to assess the severity of drug-
induced akathisia and is scored as follows: Objective Akathisia, Subjective Awareness of 
Restlessness and Subjective Distress Related to Restlessness are rated on a 4-point scale from 0 – 
3 and are summed yielding a total score ranging from 0 to 9. Then Global Clinical Assessment of 
Akathisia uses a 5-point scale ranging from 0 – 4. 
BARS will be assessed at inclusion and at end of the maintenance dose (Visit 5 at end of Week 10). 
7.3.11. 
Montreal Cognitive Assessment (MoCA) scale 
The MoCA scale is a brief screening instrument recommended for the detection of mild cognitive 
impairment that is sensitive to executive dysfunction in a variety of neurological conditions (Mestre 
et al, 2018). When used in HD, it was more sensitive to detect mild to moderate cognitive impairment 
(Mickes et al, 2010; Videnovic et al 2010; Gluhm et al, 2013). 
The items of the MoCA examine attention and concentration, executive functions, memory, language, 
visuo-constructional skills, conceptual thinking, calculations, and orientation. 


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The attention/executive function items include Trail Making Test B, digit span, target detection, 
verbal fluency, abstraction, and serial seven subtraction. The visuospatial items include clock drawing 
and cube copying. The language items include object naming and sentence repetition. The memory 
items include recall of five previously presented words. The orientation items include six orientation-
based questions. 
MoCA will be assessed at inclusion and at end of the maintenance dose (Visit 5 at end of Week 10). 
7.3.12. 
Problem Behavior Assessment short form (PBA-s) 
The PBA short form is the recommended outcome measure for behavioral symptoms in HD (Carlozzi 
et al, 2014). It is a semi-structured interview containing 11 items, each designed to measure the 
severity and frequency of behavioral neuropsychiatric symptoms that are frequent in HD: depression, 
suicidal ideation, anxiety, irritability, aggressive behavior, apathy, obsessive-compulsive symptoms, 
perseverative thinking, paranoid thinking, hallucinations, and disorientation. 
Severity and frequency during the previous 4 weeks are rated separately for each symptom on a 5 
point (0–4) scale. 
PBA-s will be assessed at inclusion, at the interim visit (Visit 3 at the end of Week 6), and at the end 
of the maintenance dose (Visit 5 at the end of Week 10). 
 
7.4. 
SAFETY REPORTING 
7.4.1. 
Definitions 
7.4.1.1. 
Adverse Event (AE) 
The term Adverse Event covers any sign, symptom, syndrome, or illness which appears or worsens 
in a patient during the observation period in the clinical study, and which may impair the patient’s 
well-being.  
The term also covers laboratory findings or results of other diagnostic procedures which are 
considered to be clinically relevant (e.g. requiring unscheduled diagnostic procedures or treatment 
measures, or result in withdrawal from the study). 
An AE may be: 
• 
A new illness. 
• 
The worsening of a sign, or symptom of the condition under treatment, or of a concomitant illness. 
Associated symptoms of Huntington’s Disease (such as akathisia or dystonia) should not be 
considered as AEs except if they increase in terms of intensity and/or frequency. 
• 
A known effect of the study medication (as listed in the SmPC). 
• 
A combination of two or more of these factors. 
No causal relationship with the study medication or with the clinical study itself is implied by the use 
of the term “Adverse Event.” 


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7.4.1.2. 
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)  
A serious AE or drug reaction or any untoward medical occurrence that, at any dose, has one or more 
of the following attributes:  
• 
Results in death. 
• 
Is life-threatening, which means that the patient is at immediate risk of death at the time of the 
SAE; it does not refer to a SAE that hypothetically might have caused death if it was more severe. 
• 
Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization. 
Hospitalization is defined as inpatient care that covers more than one calendar day. 
• 
Results in persistent or significant disability/incapacity, which means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
• 
Is a congenital anomaly/birth defect.  
• 
Is medically important, defined as an event that may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above, or result in urgent 
investigation. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in patient hospitalization. 
7.4.1.3. 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the initiation 
of the study treatment, or any event already present which worsens either in intensity, or frequency 
following the exposure to the study treatment.  
7.4.1.4. 
Suspected Adverse Reaction  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug caused 
the AE. For the purposes of safety reporting, “reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the AE. A suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug. 
7.4.1.5. 
Adverse Reaction  
An adverse reaction means an AE that is caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions that conclude the drug caused the event. 
7.4.1.6. 
Unexpected Adverse Event or Suspected Adverse Reaction  
An adverse reaction or suspected adverse reaction is considered “unexpected” if the nature or severity 
of it is not consistent with the applicable product information (e.g. Investigator Brochure Reference 
Safety Information or Summary of Product Characteristics, as applicable). 


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7.4.2. 
Procedures for recording, analyzing and reporting AEs 
7.4.2.1. 
Monitoring and recording of AEs 
At each visit, occurrence of AEs will be assessed by verbally asking the patients if they have had any 
problems or symptoms since their last visit.  
For each AE, regardless of the suspected causal relationship to study drug, the Investigator has to 
report on the AE page(s) of the eCRF the relevant information of the AE including the nature, the 
anteriority (emergent or not), the timing of event occurrence and resolution, the frequency 
(intermittent or continuous), the severity (mild, moderate, severe), the relationship with the study 
drug, and actions taken to treat the adverse experience. The Investigator has also to pursue and obtain 
adequate information in order to determine the outcome of the AE and also to assess the seriousness, 
i.e. whether it meets the criteria for classification as a SAE requiring immediate notification to the 
Sponsor. 
Whenever possible, a unifying diagnosis should be recorded in the eCRF as the AE rather than 
individual signs or symptoms. Similarly, the unifying diagnosis should be recorded as the AE rather 
than the abnormal laboratory result (i.e. “anemia” instead of “low hemoglobin”). If the AE is a 
worsening of a past medical condition, the AE should clearly indicate that the past medical condition 
has worsened using words such as “worsening,” “aggravated,” or “exacerbation.” 
AEs will be coded according to the Medical Dictionary for Regulatory Activity (MedDRA current 
version). AEs will be individually listed per patient number, presenting System Organ Class (SOC), 
preferred term, emergence, description, date and time of onset, date and time of last study drug 
administration before AE, duration, time from onset since last study drug administration, frequency, 
severity and seriousness, relationship to study drug, the required action taken (corrective treatment, 
hospitalization), and outcome if any. 
All AEs (including SAEs) must be followed until satisfactory resolution or stabilization. 
Any AE and any measure taken and follow-up result must be recorded in the patient's eCRF, as well 
as in the patient’s source document. Follow-up laboratory results should be filed with the patient’s 
source documentation. 
7.4.2.2. 
Analysis and classification of AEs 
Assessment of Severity 
An assessment of the relative severity (or intensity) of an adverse experience is based on the 
Investigator’s clinical judgment by using the following scale. The maximum severity encountered 
during the evaluation period should be checked. The assessment of severity should be independent of 
the assessment of the seriousness of the AE. 
• 
Mild: No significant interference with the patient’s usual activities, easily tolerated.  
• 
Moderate: moderate interference with the patient’s usual activities. 
• 
Severe: major interference with the patient’s usual activities, considered as unacceptable by the 
physician, or required specific treatment or required discontinuation from the study. 


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Assessment of Causality 
The Investigator will make clinical judgement to determine whether or not, in their opinion, there is 
a reasonable possibility that the drug caused the adverse event 
• 
Related/likely: Clearly related to the investigational agent/procedure, i.e. an event that follows a 
reasonable temporal sequence from administration of the study intervention, follows a known or 
expected response pattern to the suspected intervention, that can be confirmed by improvement 
on stopping and reappearance of the event after rechallenge and that could not be reasonably 
explained by the known characteristics of the patient’s clinical state. 
• 
Possibly related/Possible: Follows a reasonable temporal sequence from administration of the 
study intervention, follows a known or expected response pattern to the suspected intervention, 
but that could readily have been produced by a number of other factors. 
• 
Not related/Unlikely: Clearly and incontrovertibly due only to extraneous causes, and does not 
meet criteria listed under possible (possibly related) or likely (related). 
Assessment of Outcome 
For all AEs the outcome should be documented at the latest at the last visit according to the following 
criteria: 
• 
Ongoing. 
• 
Recovered: the patient has fully recovered with no observable residual effects. 
• 
Recovered with sequelae: the AE has resulted in a permanent impairment. 
• 
Unknown: the outcome of the AE is not known because the patient did not return for follow-up 
(lost to follow-up). 
• 
Death if the patient died due to the AE. 
If an AE is still ongoing at the last visit the patient must be followed-up until the outcome can be 
documented without using the “ongoing” assessment.  
In case of sequelae a description of sequelae must be provided in the eCRF. When reporting a death, 
the Investigator should supply any additional requested information such as autopsy reports (if 
available) and final medical reports. 
In order to ensure the safety of the patients, the Investigator should take appropriate measures to 
follow all AEs until clinical recovery is complete and laboratory results have returned to normal, or 
until the patient has recovered, or until death. This may imply that observations will continue beyond 
the last planned visit per protocol, and that additional investigations may be requested by the 
monitoring team as it may be asked by the Sponsor. 
Assessment of Seriousness 
“Seriousness” is based on patient/event outcome or action criteria usually associated with events that 
pose a threat to a patient’s life or functioning. “Seriousness” (not severity) serves as a guide for 
defining regulatory reporting obligations for Serious Adverse Events (SAE). 


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7.4.3. 
Reporting Serious Adverse Events (SAEs)  
All SAEs occurring during study participation must be reported immediately (within 24 hours) to 
the Sponsor representative (or designee), and then to the governing IRB/IEC as required by the 
IRB/IEC, local regulations, and the governing health authorities. 
Prompt notification of SAEs by the Investigator to the appropriate Sponsor contact for SAE receipt 
is essential so that legal obligations and ethical responsibilities towards the safety of other patients 
are met. Any Unexpected SAE which is attributed to investigational product (SUSAR) requires 
immediate notification to the regulatory agencies. The full report will be sent to the regulatory 
agencies within the regulatory timelines. The Sponsor should also expedite the safety reporting to all 
concerned investigator/institutions, to IEC/IRB and regulatory agencies according to the local 
regulatory timelines. 
7.4.3.1. 
Notification of the SAE and Transmission of the SAE Report 
Once an investigator becomes aware that an SAE has occurred, he/she must report the information to 
the Sponsor (or designee) within 24 hours. The SAE form will always be completed as thoroughly 
as possible with all available details of the event, signed by the Investigator and forwarded to the 
Sponsor (or designee) within the designated time frames. If the Investigator does not have all 
information regarding an SAE, he should not wait to receive additional information before notifying 
the event and completing the form. The form will be updated when additional information is received. 
Whenever possible, the Investigator will provide an assessment of causality at the time of the initial 
report as described above. 
After the initial report, the SAE should be promptly followed by a detailed writing report including 
all data allowing to document the event and notably the anonymous copies (with patient study 
number) from hospitalization’s report and any additional examination(s) performed.  
For reported death, the Investigator should provide any additional requested information such as 
autopsy reports if available and terminal medical reports. 
7.4.3.2. 
SAE waived from expedited regulatory reporting to regulatory authorities 
For the purpose of the study the following events will not be designated as a SAE: 
• 
hospital admission as a part of the normal planned treatment or monitoring of the studied 
indication and not associated with any deterioration in condition, 
• 
hospitalization planned before inclusion in the study, 
• 
admission for diagnostic evaluation of an AE, 
• 
overnight hospitalization due to social or travel reasons. 
7.4.4. 
Procedures for Reporting Pregnancy Exposure and Birth Events  
The Investigator must promptly report all pregnancies to the Sponsor (or designee). While the 
pregnancy itself is not considered to be an AE or SAE, any pregnancy complications should be 
recorded as AEs or SAEs. Any pregnancy should be followed through its conclusion for observation 
of any congenital anomalies or birth defects which are a SAE.  


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7.4.5. 
Data Safety Monitoring Board (DSMB) 
According to ICH E6, an independent Data Safety Monitoring Board (DSMB) will be established to 
assess at intervals the progress of the clinical trial, safety data, and recommend to the Sponsor whether 
to continue, modify or terminate a trial. The DSMB will have written operating procedures and 
maintain records of all its meetings, including interim results; these should be available for review 
when the trial is complete. The independence of the DSMB is intended to control the sharing of 
important comparative information and to protect the integrity of the clinical trial from adverse impact 
resulting from access to trial information. The DSMB is a separate entity from an IRB or an IEC, and 
its composition should include clinicians and clinical trial scientists knowledgeable in the appropriate 
disciplines including statistics. 
A charter will define clearly the roles and responsibilities, the membership (with independent experts 
in the clinical aspects of the disease and one biostatistician), and organization of the meetings. The 
procedures should also address the way to keep confidential the data analyzed, the voting rules and 
the control of dissemination of interim trial results within the Sponsor organization. 
 
7.5. 
PK-PD ASSESSMENTS 
7.5.1. 
SOM3355 plasma concentration  
Blood samples for PK will be obtained in all patients at each visit under active treatment with 
SOM3355 (or placebo) from Visit 2 to Visit 5 for measurement of SOM3355 (bevantolol) plasma 
concentration at trough (pre-dose), and also 2 hours after dosing at Visit 2 and Visit 4.  
Complete information on blood sampling, conditions of plasma preparation and storage, as well as 
shipment details and central laboratory contact details will be supplied in a separate technical 
brochure provided by the central laboratory. 
Drug quantification will be performed using a validated bioanalytical method based on ultra HPLC 
coupled to tandem mass spectrometry (UHPLC-MS/MS). 
7.5.2. 
Prolactin plasma level 
An increase in prolactin plasma levels was observed with SOM3355 administration in the previous 
Phase 2a POC study, consistent with that seen with other VMAT2 inhibitors like tetrabenazine. 
However, the increase was found not to be dose-proportional with SOM3355 levels, showing a mean 
increase of 1.7- and 1.9-fold at the 100 mg and 200 mg BID doses, respectively (SOMCT02 – PK/PD 
Report). This may reflect changes in dopaminergic tone in the hypothalamus and/or pituitary gland 
(Orrillo et al, 2020). Therefore, prolactin plasma levels could be considered as a biomarker of the 
pharmacodynamic (PD) effect of SOM3355. 
Blood samples will be obtained at each visit from Visit 1 to Visit 6 in all patients to measure prolactin 
plasma concentration, before dosing at each visit and 2 hours after dosing at Visit 2 and Visit 4. 
Prolactin plasma quantification will be determined by chemiluminescence technique.  


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Samples will be collected and stored with the PK samples and analyzed by the central laboratory in 
order to keep the blind during the study. 
7.5.3. 
PK sub-study 
A PK sub-study will be conducted to characterize the PK profile of repeated doses of SOM3355 at 
400 and 600 mg/day. This analysis will be performed by collecting 12-hour PK samples (H0 before 
dosing, H0.5, H1, H1.5, H2, H3, H5, H8, H12) in 8 patients per arm (24 patients in total) that will be 
hospitalized for 24 hours at Visit 2.  
These patients will be recruited by 3-4 sites able to manage the logistic of PK sampling. PK sub-study 
data will be collected in an independent database and analyzed as soon as possible, before the end of 
the clinical trial. Complete information on blood sampling, conditions of plasma preparation and 
storage, as well as shipment details for PK sub-study and central laboratory contact details will be 
supplied in a separate technical brochure provided by the central laboratory. 
In addition, cardiac and hemodynamic parameters will be collected in parallel to allow PK-PD 
modeling assessments. For this, the patients will have cardiac Holter monitor placed on the chest to 
record ECG during the 12 hours of plasma sampling, allowing to analyze ECG parameters at the same 
time points than PK samples, and blood pressure will be measured 5 minutes before each PK sample 
(the patient resting quietly in a comfortable sitting position, his/her back and arm supported with the 
middle of the upper arm at heart level, legs uncrossed, and feet flat on the floor).  
 


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8. 
CONDUCT OF THE STUDY  
For each participant, the total treatment duration, from the inclusion visit, will be 12 weeks (+ 1 or 2 
weeks for screening before inclusion) with a total of 7 visits.  
The visit schedule and procedure assessments are listed in section 1.3. 
This is an outpatient study, except for 24 patients that will be enrolled in the PK sub-study who will 
be hospitalized for 24 hours at Visit 2. HD patients come to visit their specialist at the hospital on 
successive time-points. All visits must be performed by investigators and sub-investigators qualified 
for this study and who are experts in the management of HD patients. 
Visits are scheduled as follows: 
• 
V0 - 
Screening visit:    
 
 
at Day -7 to -14 max (Week -1 to -2 max) 
• 
V1 -   Inclusion visit (randomization):    
at Day 0 (Week 0) 
• 
V2 -  
End of up-titration: 
 
 
at Day 21 ± 2 Days (Week 3) 
• 
V3 -  
Interim visit at maintenance dose:   
at Day 42 ± 2 Days (Week 6) 
• 
V4 -  
End of maintenance dose #1 
 
at Day 63 ± 2 Days (Week 9) 
• 
V5 -  
End of maintenance dose #2 
 
at Day 70 ± 2 Days (Week 10) 
• 
V6 -  
End of study 
 
 
 
at Day 84 ± 2 Days (Week 12) 
If the date of one visit is changed (anticipated or delayed), the next visit should occur according to 
the original schedule. 
 
8.1. 
 STUDY PROCEDURES AT EACH VISIT 
8.1.1. 
Visit 0 - Screening visit – within 14 days before inclusion   
The eligibility of the patients will be assessed during the screening period that starts with the 
Screening Visit within 1 or 2 weeks before the inclusion. The duration of the screening period is up 
to 2 weeks and must be long enough to establish inclusion/exclusion criteria from Visit 0 to the 
inclusion visit (i.e. Visit 1 at Day 0). 
At Visit 0, the Investigator must first obtain the patient informed consent as described below, and 
then check that he/she meets all the inclusion criteria and none of the exclusion criteria. 
▪ Obtaining the Patient informed consent 
If a patient is eligible to be enrolled in the study, prior to conduct of any study-specific screening 
procedures, the Investigator, or designee, will explain to the patient the study procedures, including 
the risks involved and the fact that its participation is voluntary.  
The Investigator should give to the patient the study’s IRB/IEC-approved written informed consent 
form (ICF) and orally present all necessary information to the patient, in order to enable him/her to 
make an informed and unconstrained decision about participating in the study. An appropriately 


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signed ICF will be obtained prior to entry into the study for each patient who has made the decision 
to participate. Information regarding the collection of the patient informed consent should be 
registered in the source document (date, protocol number, and name of the Investigator or sub-
investigator who has informed the patient).  
In addition, the following assessments must be performed at Visit 0, and information must be 
collected and documented in the CRF within the screening period: 
- 
Patient medical history and history of HD diagnosis, with documented genetic diagnosis;   
- 
Patient history of all the treatments must be notified in the source documentation prior to 
randomization (with regimen, duration, and complications and their treatments); 
- 
Demographics characteristics (age, gender, and ethnic origin); 
- 
Physical and neurological examinations with the presence of chorea symptoms; 
- 
Vital signs (SBP, DBP, orthostatic BP, and heart rate measured according to the standardized 
method described in section 7.3.3), body height and weight; 
- 
List of current concomitant medications; 
- 
Clinical scores and functional tests: UHDRS®-Motor part (including TMS and TMC, gait and 
dystonia sub-scores), UHDRS®-Total Functional Capacity, UHDRS®-Functional assessment, and 
C-SSRS, BDI, and ESS;  
- 
12-lead ECG (sent for centralized reading by a cardiologist); 
- 
Safety laboratory tests (chemistry, hematology) analyzed by local laboratory (including a 
pregnancy test if female of childbearing potential). 
8.1.2. 
Visit 1 - Day 0 - Inclusion visit - Randomization 
At Visit 1, the Investigator must check that the patient still meets all the inclusion criteria and none 
of the exclusion criteria. In addition, the following assessments must be performed: 
- 
Physical and neurological examinations;  
- 
Vital signs (SBP and DBP, orthostatic BP, and HR); 
- 
Clinical scores and functional tests: UHDRS®-Motor part, UHDRS®-TFC, EQ-5D-5L, BARS, 
MoCA scale, PBA-s, C-SSRS, BDI, ESS, CGI-S, and PGI-S; 
- 
12-lead ECG triplicated as 3 successive records (sent for centralized reading by a cardiologist); 
- 
Blood sample at pre-dose for prolactin level (central lab);  
- 
List of current concomitant medications; 
- 
Recording of AEs; 
- 
Randomization and treatment allocation: if the patient meets the selection criteria, a treatment 
will be allocated according to the randomization number determined by IWRS; 
- 
Drug dispensation: the patient will receive 4 bottles of study medication and a Patient Diary 
and will be instructed to take one capsule per day in the morning during the first week, and 
then during the two following weeks two capsules per day (one in the morning and one in the 
evening) until the next visit and record the intakes in the Diary. An Extra bottle is dispensed to 


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be used only if next visit is delayed or Bottle 3 is empty to avoid an interruption of the study 
treatment. The drug can be taken with food. The first dose will be administered to the patient 
during the visit. The patient will be instructed to contact the Investigator by phone should an 
AE occur, and will be asked to bring back the used and unused study medication at the 
following visit. 
- 
The patient is asked to come at the next visit without taking the morning dose to enable the 
blood sampling for PK at trough.  
8.1.3. 
Visit 2 - Week 3 - Day 21 - End of up-titration  
At Visit 2, the Investigator must perform the following assessments: 
- 
Physical and neurological examinations; 
- 
Vital signs (SBP and DBP, orthostatic BP, and HR); 
- 
Clinical scores and functional tests: UHDRS®-Motor part only (including TMS and TMC, gait and 
dystonia sub-scores), C-SSRS, BDI, ESS, CGI-C and PGI-C;  
- 
12-lead ECG (sent for centralized reading by a cardiologist) 
- 
Blood sample at pre-dose and 2 hours after drug intake for PK and prolactin level (central lab); 
- 
List of current concomitant medications; 
- 
Recording of AEs; 
- 
Drug accountability of the returned study medication and review of compliance (the patient is 
asked whether the investigational treatment was taken as prescribed or any incidents occurred to 
double-check with the returned Patient Diary); 
- 
Drug dispensation: the patient will receive 4 bottles of study medication and a new Patient Diary 
and will be instructed to take two capsules per day, one in the morning and one in the evening 
until the next visit and record the intakes in the Diary. The drug can be taken with food. The first 
dose will be administered to the patient during the visit. The patient will be instructed to contact 
the Investigator by phone should an AE occur, and will be asked to bring back the used and unused 
bottles of study medication at the following visit. An Extra bottle is provided in case of delayed 
visit to avoid an interruption of the study treatment.  
- 
The patient is asked to come at the next visit without taking the morning dose to enable the blood 
sampling for PK at trough.  
A subset of 24 patients in 3-4 selected investigating sites will be hospitalized for 24 hours for PK 
sampling. Blood samples should be performed at pre-dose (H0), and 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 
and 12h post-dose. After the H12 blood sample, the evening intake of the study drug should be given 
to the patient.  
These patients will have cardiac Holter monitor placed on the chest during the 12 hours of plasma 
sampling to record ECG, and blood pressure should be measured 5 minutes before each PK sample 
(the patient resting quietly in a comfortable sitting position, his/her back and arm supported with the 
middle of the upper arm at heart level, legs uncrossed, and feet flat on the floor).  


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8.1.4. 
Visit 3 - Week 6 - Day 42 - Interim visit at maintenance dose 
At Visit 3, the Investigator must perform the following assessments: 
- 
Physical and neurological examinations; 
- 
Vital signs (SBP and DBP, orthostatic BP, and HR); 
- 
Clinical scores and functional tests: UHDRS®-Motor part only, PBA-s, C-SSRS, BDI, ESS, CGI-
C and PGI-C;  
- 
Safety laboratory tests (chemistry, hematology) analyzed by local laboratory 
- 
Blood sample for PK and prolactin level (central lab) at pre-dose only; 
- 
List of current concomitant medications; 
- 
Recording of AEs; 
- 
Drug accountability of the returned study medication and review of compliance (the patient is 
asked whether the investigational treatment was taken as prescribed or any incidents occurred to 
double-check with the returned Patient Diary); 
- 
Drug dispensation: the patient will receive 4 bottles of study medication and a new Patient Diary 
and will be instructed to take two capsules per day, one in the morning and one in the evening 
until the next visit and record the intakes in the Diary. The drug can be taken with food. The first 
dose will be administered to the patient during the visit. The patient will be instructed to contact 
the Investigator by phone should an AE occur, and will be asked to bring back the used and unused 
bottles of study medication at the following visit. An Extra bottle is provided in case of delayed 
visit to avoid an interruption of the study treatment;  
- 
The patient is asked to come at the next visit without taking the morning dose to enable the blood 
sampling for PK at trough.  
8.1.5. 
Visit 4 - Week 9 - Day 63 - 1st assessment at end of maintenance dose 
At Visit 4, the Investigator must perform the following assessments: 
- 
Physical and neurological examinations; 
- 
Vital signs (SBP and DBP, orthostatic BP, and HR); 
- 
Clinical scores and functional tests: UHDRS®-Motor part only, C-SSRS, BDI, ESS, CGI-C and 
PGI-C;  
- 
12-lead ECG (sent for centralized reading by a cardiologist) at Tmax (2 hours after dosing) just 
before the blood sample; 
- 
Blood sample for PK and prolactin level (central lab) at pre-dose and 2 hours after dosing; 
- 
List of current concomitant medications; 
- 
Recording of AEs; 
- 
Drug accountability of the returned study medication and review of compliance (the patient is 
asked whether the investigational treatment was taken as prescribed or any incidents occurred to 
double-check with the returned Patient Diary); 


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- 
Drug dispensation: the patient will receive 2 bottles of study medication and a new Patient Diary 
and will be instructed to take two capsules per day, one in the morning and one in the evening 
until the next visit and record the intakes in the Diary. The first dose will be administered to the 
patient during the visit. The patient will be instructed to contact the Investigator by phone should 
an AE occur, and will be asked to bring back the used and unused bottles of study medication at 
the following visit. An Extra bottle is provided in case of delayed visit to avoid an interruption of 
the study treatment;  
- 
The patient is asked to come at the next visit without taking the morning dose to enable the blood 
sampling for PK at trough.  
8.1.6. 
Visit 5 - Week 10 - Day 70 - 2nd assessment at end of maintenance dose 
At Visit 5, the Investigator must perform the following assessments: 
- 
Physical and neurological examinations; 
- 
Vital signs (SBP and DBP, orthostatic BP, and HR); 
- 
Clinical scores and functional tests: UHDRS®-Motor part, UHDRS®-Total Functional Capacity, 
UHDRS®-Functional Assessment, EQ-5D-5L, BARS, MoCA scale, PBA-s, C-SSRS, BDI, ESS, 
CGI-C, and PGI-C;  
- 
Safety laboratory tests (chemistry, hematology) analyzed by local laboratory; 
- 
Blood sample for PK and prolactin level (central lab) at pre-dose; 
- 
List of current concomitant medications; 
- 
Recording of AEs; 
- 
Drug accountability of the returned study medication and review of compliance (the patient is 
asked whether the investigational treatment was taken as prescribed or any incidents occurred to 
double-check with the returned Patient Diary); 
- 
Drug dispensation: the patient will receive 2 bottles of study medication - one bottle identified to 
be used the first week and the other for the second week - and a new Patient Diary and he/she 
will be instructed to take one capsule per day in the morning for 7 days from the first bottle, and 
then one capsule per day for 7 days from the second bottle and record the intakes in the Diary. 
The first dose will be administered to the patient during the visit. The patient will be instructed 
to contact the Investigator by phone should an AE occur, and will be asked to bring back the used 
and unused bottles of study medication at the following visit. No Extra bottle will be provided; 
- 
The patient is asked to come at the next visit without taking the morning dose.  
8.1.7. 
Visit 6 - Week 12 - Day 84 - End of study  
At Visit 6, the Investigator must perform the following assessments: 
- 
Physical and neurological examinations; 
- 
Vital signs (SBP and DBP, orthostatic BP, and HR); 
- 
Clinical scores and functional tests: UHDRS®-Motor part only, C-SSRS, BDI, ESS, CGI-C and 
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- 
12-lead ECG (sent for centralized reading by a cardiologist); 
- 
Blood sample at pre-dose for prolactin level (Central lab); 
- 
Pregnancy test for female of childbearing potential; 
- 
List of current concomitant medications; 
- 
Recording of AEs; 
- 
Drug accountability of the returned study medication and review of compliance (the patient is 
asked whether the investigational treatment was taken as prescribed or any incidents occurred to 
double-check with the returned Patient Diary). 
 
8.2. 
STUDY CONDUCT DURING A COVID-19 OUTBREAK  
The Sponsor acknowledges that hospitals should preferentially treat patients with COVID-19 and 
prioritize trials for the prevention or treatment of COVID-19 infection. Therefore, this trial will only 
be initiated when it is ethically and operationally feasible for the selected study sites to do so.   
In the event of a further COVID-19 outbreak or further restrictions, the Sponsor in conjunction with 
the Investigator will review the situation and initiate prepared plans based on the extent of the 
situation and local conditions. To mitigate for a future impact of the pandemic, the study will be 
conducted at multiple sites in Europe to increase the possibility of including patients in sites/countries 
not (or minimally) affected by COVID-19. The Sponsor will adhere to national and local regulations 
due to the pandemic, and the study or specific sites or countries will halt recruitment and stop 
treatment of enrolled patients as needed. In any event, the patients’ safety will be paramount, and all 
endeavors will be made to judge whether before a patient is enrolled into the study there is a 
possibility of all safety assessments being conducted during the patient’s entire study period. If the 
study were to continue, the Sponsor will consider initiating a range of options including, but not 
limited to: 
- 
Provision of private transport and protective equipment (at least a mask, gloves and hand 
sanitizer) to facilitate patient visits to the study site. 
- 
Feasibility of gaining remote (telephone or email) informed consent from patients in countries 
where this is permitted, following the current EMA guidance for management of clinical trials 
during COVID-19 pandemic.  
- 
Initiation and on-going central monitoring of data if study Monitors are not permitted access 
to study sites.   
Whilst general plans can be prepared in advance, the implementation of each activity will be 
dependent on local (country, site, patient) circumstances at the time, and the extent of the COVID-19 
situation. 
In the event that a patient is diagnosed with active COVID-19, the intention is for the patient to 
continue in the study, and to receive regular phone calls from study staff to monitor safety. The patient 
should not visit a study site until they have received medical clearance.   


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All Protocol Deviations as a result of COVID-19, COVID Infections, and any other COVID-19 
Impact will be noted as such for future analysis and reporting. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
ANALYSIS POPULATIONS  
Safety Population: The safety population will include all patients who were administered any study 
drug. Patients who are assigned a patient number but withdrew prior to dosing will not be included 
in the safety population. Patients will be included in the treatment group based on the treatment 
actually received. If relevant, details of their participation and reason for withdrawal will be listed 
separately in the study report. 
Intent-to-Treat (ITT) Population: The ITT Population will include all randomized patients. Patients 
will be included in the treatment group to which they were randomized, regardless of the treatment 
that was actually received.  
Modified Intent-to-Treat (mITT) Population: The mITT Population will include all patients from 
the ITT Population who were randomized to treatment, received at least one dose of study drug and 
had at least one post-baseline assessment of the TMC score. The primary efficacy analysis will be 
conducted on the mITT Population. Patients will be included in the treatment group to which they 
were randomized, regardless of the treatment that was actually received.  
Per Protocol (PP) Population: The PP Population will include all randomized patients who 
completed the study without important deviations from the protocol. The decision of the membership 
in the PP Population will be made during a blinded Data Review Meeting prior to database lock, 
reviewing all deviations occurred. 
 
9.2. 
STATISTICAL ASSUMPTIONS 
Power calculation is based on results from previous trials that tested VMAT2 inhibitors (TBZ and 
deuterbenazine) on chorea in HD patients with TMC score as primary endpoint, which showed a 
standard deviation of 3.5 and 3.9 respectively, and a treatment effect compared to placebo in TMC 
score of -3.5 and -2.5 respectively. 
So we assume a standard deviation of 3.5 and a target difference between active and placebo groups 
of -2.5 in TMC score in order to ensure a clinically relevant effect of at least -2 in the study.  
 
9.3. 
SAMPLE SIZE DETERMINATION 
The sample size will be a total of 129 patients. Eligible patients will be randomized in blinded fashion 
in a 1:1:1 ratio i.e. 43 patients in each arm (SOM3355 400 mg/day, SOM3355 600 mg/day, or 
placebo). Assuming a treatment difference of -2.5 points in the change from baseline of TMC score 
compared to placebo and a standard deviation of 3.5, 39 patients per arm will provide at least 80% 
power that at least 1 dose of SOM3355 will be significantly superior to placebo at the 2-sided 0.025 


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significance level. For the primary endpoint, the overall type I error will be controlled using a Holm 
procedure. To account for a 10% dropout rate, 43 patients per arm (i.e. a total of 129 patients) will be 
enrolled. 
9.4. 
STATISTICAL ANALYSES 
Details on the statistical analyses described below will be given in a Statistical Analysis Plan (SAP) 
to be prepared before any analysis or unblinding of data occur. 
9.4.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the change in Total Maximal Chorea (TMC) score 
from baseline (defined for each patient as the average of values at the screening visit (Visit 0) and the 
inclusion visit (Visit 1)) to the end of maintenance therapy (defined for each patient as the average of 
values from the end of Week 9 (Visit 4) and the end of Week 10 (Visit 5)). 
Primary efficacy analyses will be based on the modified intent-to-treat (mITT) Population. 
The estimand of the primary efficacy analysis is defined according to ICH-E9-R1. The estimand 
reflects a mixed strategy for the inter-current events as presented in the table below. 
Table 4: Estimand of the Primary Analysis 
Estimand 
attribute 
Primary definition 
Rationale (as needed) 
Population 
Patients with Huntington’s disease with choreic 
movements  
 
Endpoint 
Change from baseline (Visit 0 and Visit 1) to 
end of maintenance dose (Visit 4 and Visit 5) in 
TMC score   
 
Inter-current 
events 
Event 
Strategy 
Rationale (as needed) 
Receipt of assigned study 
treatment 
Treatment 
policy 
This strategy applied to align the 
estimand with the application of the 
ITT principle.  
Prohibited concomitant 
treatment during the treatment 
period 
While on 
treatment 
This strategy applied up to the time 
of the prohibited concomitant 
treatment. 
Discontinuation from study 
Hypothetical 
policy 
This strategy applied for randomized 
and treated patients using a MMRM 
approach under MAR assumptions.  
Summary 
measure 
Difference in adjusted LS means between active 
arms and placebo from baseline to end of 
maintenance visit. 
 


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The primary analysis of the primary efficacy endpoint will be based on a mixed-effect linear model 
for repeated measures (MMRM) to compare each active treatment group to placebo. The model will 
include the following factors: treatment group, visit, and treatment-by-visit interaction as fixed 
effects, and baseline TMC score as covariate. An unstructured (US) variance-covariance matrix will 
be used to model the within-patient errors. If no reliable results under the US assumption can be 
obtained, the Toeplitz (TP) covariance structure, followed by the autoregressive (AR1) and 
Compound Symmetry (CS) covariance structure will be used. The Kenward-Roger method will be 
used to estimate the denominator degree of freedom. 
The least square mean (LSM) estimate for each treatment group and difference in LSM estimates at 
end of maintenance dose between active treatments and placebo group with their confidence 
intervals will be provided. 
To preserve the family-wise error rate at the 0.05 level when comparing the two doses of SOM3355 
versus placebo, statistical testing will be carried out using the Holm procedure. The smallest p-value 
of the two comparisons will be first compared at the two-sided 0.025 level and if statistically 
significant, the other p-value will be compared at the two-sided 0.05 level. 
Sensitivity analyses on the primary efficacy endpoint will be conducted as follows:  
- 
Primary endpoint will be analyzed using the observed cases (no imputations) using an analysis 
of covariance (ANCOVA) model. 
- 
Primary endpoint will be analyzed for the ITT Population using a multiple imputation.  
- 
Primary efficacy analysis will be repeated for the PP Population. 
9.4.2. 
Secondary Efficacy Endpoints 
The secondary endpoints will be assessed hierarchically in the following order: 
- The CGI change between the baseline and the end of maintenance dose 
- TMC-response defined as improvement ≥ 2 in TMC score between the baseline and the end of 
maintenance dose in each group 
- The percentage of change in TMC score  
- The PGI change between the baseline and the end of maintenance dose 
- Total Motor Score (TMS) of the UHDRS® 
- Gait sub-score of the UHDRS® 
- Dystonia sub-score of the UHDRS® 
- EQ-5D-5L measuring quality of life 
Secondary efficacy endpoints will be analyzed using the mITT Population. 
For continuous efficacy endpoints with longitudinal data, the same MMRM model, as described for 
the primary endpoint will be performed. For other continuous efficacy endpoint measured at 
baseline and end of maintenance dose, an ANCOVA model will be used. 
Categorical efficacy endpoints will be analyzed using a logistic regression model. 


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The type I error will be set at 0.05 (two-sided) and the coverage level of confidence intervals to 95% 
for all secondary efficacy analyses. No multiplicity adjustment will be applied for the statistical 
inferences of the secondary efficacy endpoints. 
9.4.3. 
Safety Analysis 
Safety analyses will be based on the safety population, which is defined as all randomized patients 
having received at least one dose of study treatment. 
Adverse events: 
All AEs summaries will be restricted to Treatment Emergent Adverse Events (TEAEs), which are 
defined as any AEs that occurs or worsens at or after the initiation of IMP. The AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by system organ 
class (SOC) and preferred term. Each AE summary will be displayed by treatment group. 
Number of AEs, frequency and percentage of patients will be reported. For intensity level, the patient 
will be classified for the highest severity if the patients experienced several AEs.  
Onset time of AE from initiation of IMP and AE duration will also be summarized. 
Other safety endpoints that will be analyzed: 
- Vital signs: blood pressure (BP), including orthostatic BP measurement, and heart rate (HR). 
- 
Electrocardiograms (ECGs).    
- 
Clinical laboratory test results (chemistry, hematology). 
- 
Physical examination findings, weight. 
- 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
- 
Depression Inventory (BDI) scale assessing depression. 
- 
Epworth Sleepiness Scale (ESS) to assess sleepiness. 
- 
Total Functional Capacity (TFC) of the UHDRS®.  
- 
Functional Assessment (FA) of the UHDRS®. 
- 
Barnes Akathisia Rating Scale (BARS).  
- 
Montreal Cognitive assessment (MoCA). 
- 
Problem Behaviors assessment (PBA-s). 
9.4.4. 
PK-PD Analysis 
SOM3355 plasma concentration and prolactin level determination will be performed by a central 
laboratory and analysis of these parameters will be conducted separately and described in a specific 
Statistical Analysis Plan (SAP).  
Prolactin plasma levels and plasma concentrations of SOM3355 obtained from all patients will be 
listed and summarized using descriptive statistics in tables and graphs, as appropriate. 
PK sub-study: 12 hours PK sampling in 24 patients will allow to determine SOM3355 total plasma 
concentration at 9 time-points from at least 6 patients in each arm receiving active drug, while they 


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are taking the drug for at least 7 days at the full dose twice per day. PK analysis will be conducted 
separately and results will be provided in separate reports.  
Determination of SOM3355 plasma concentrations will be performed by a central laboratory. PK 
parameters (AUC, Cmax, t½, Clearance, etc.) from the individual concentration vs. time profiles will 
be derived using non-compartmental procedures. The PK analyses of this sub-group will also be 
described in the specific SAP. 
PK-PD analysis will be performed with ECG and BP measurements. 
 
9.5. 
FUTILITY ANALYSIS 
An unblinded interim analysis for futility (non-binding) will take place when at least half of the total 
number of planned patients (N = 65) have completed the study or discontinued early. The analysis will 
be prepared by a separate team that will communicate the results only to designated recipients, e.g. the 
Steering Committee and DSMB, to protect the study blind. The primary criterion to assess the futility 
of the study will be the probability of rejecting the null hypothesis conditional on the accumulated data 
and the planned sample size. In line with the chosen Holm-Bonferroni multiplicity adjustment, the 
decision will focus on that hypothesis that yielded the smallest p-value in the interim analysis of the 
TMC change. A non-binding stop for futility will be recommended if the conditional probability is less 
than 0.25. Otherwise the study shall be continued without modification unless otherwise recommended 
by the DSMB. 
If a decision is made to stop the trial, then a complete, final analysis will be performed including those 
patients that were enrolled into the study in the meantime. 
 


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10. 
ETHICS AND LEGAL CONSIDERATIONS 
10.1. 
REGULATION 
The trial will be conducted in accordance with the Declaration of Helsinki (and multiple revisions). 
and in compliance with the protocol, the ICH Guidelines for Good Clinical Practice (ICH E6), the 
European directives on Clinical Trial Regulation 536/2014 (applicable on 31 January 2022), repealing 
the Directive 2001/20/CE, and Data Protection General Requirements (2016/680), the General Data 
Protection Regulation (GDPR 2016/679), and the applicable local country laws/regulations.  
 
10.2. 
ETHICS COMMITTEE / INSTITUTIONAL REVIEW BOARD APPROVAL 
The final study protocol, including the Patient Information and Informed Consent (ICF), will be 
submitted for approval to the appropriate EC or IRB. Any amendment to these documents will be 
also submitted to the EC/IRB. In case the protocol amendment changes the scope of the study or 
increases the risks of the study patients, the Investigator should wait for approval of this amendment 
by the EC/IRB before implementing the protocol amendment. A copy of the written approval and the 
approved versions of the documents and a list of the EC/IRB members, their titles and occupations 
should be forwarded to the responsible study personnel. The written approval should identify the 
study and document the date of review. All correspondences with the EC/IRB and forward copies of 
such correspondence should be provided to the Sponsor via the responsible study personnel. 
 
10.3. 
PATIENT INFORMED CONSENT PROCEDURE 
It is the responsibility of the Investigator to give to each patient (or the patient’s legally authorized 
representative) prior to inclusion in the study, full and adequate verbal and written information about 
the objectives and the procedures of the study, potential risks involved and personal and societal 
benefits. The patients must be informed about their right to withdraw from the study at any time and 
for any reason, without sanction, penalty, or loss of benefits to which they are otherwise entitled, and 
that withdrawal from the study will not jeopardize their future medical care. Before deciding on 
whether or not to participate, the patient should have sufficient time to think about the study and to 
discuss the study with a third party if necessary. The Investigators and their staff will be available to 
answer questions from the patient at any time. Written information (Patient information and ICF) 
should be given to each patient before enrolment. Furthermore, it is the responsibility of the 
Investigator to obtain, in accordance with the pertinent local regulations, a signed ICF from each 
patient (or the patient’s legally authorized representative) prior to performing any study-related 
procedures.  
The Patient Information and ICF should be updated or amended whenever new important information 
that may be relevant to the patient becomes available. Modifications to these documents must be 
approved by the Sponsor and by the EC/IRB before being implemented. 
 


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10.4. 
PROTOCOL AMENDMENT 
With the exception of emergency situations, no changes or deviations in the conduct of this protocol 
will be permitted. Any change to the study must be documented in a protocol amendment. Such 
protocol amendments will be made jointly by the Sponsor and the Investigators. Both parties will sign 
the protocol amendment.  
The Investigators will submit the protocol amendment for review by the independent EC/IRB if the 
change or deviation from the original protocol could increase the risks to the studied patients, or could 
adversely affect the validity of the investigation, or the rights of the human patients; they have to 
obtain approval from the independent EC/IRB before such change(s) or deviation are implemented.  
If the change(s) or deviation to the original protocol eliminate or reduce the risk to the study patients, 
the protocol amendment can be implemented before approval has been received from the independent 
EC/IRB. In such cases, the Investigators will notify the independent EC/IRB within ten working days 
after implementation and will submit the protocol amendment as soon as possible for information/ 
favorable opinion from the independent EC/IRB.  
If the protocol amendment is of the administrative kind, it will be sent to the EC/IRB for information.  
 
 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
GOOD CLINICAL PRACTICE (GCP) 
The trial will be conducted with respect to the protocol, GCP-ICH and the European directives 
(EMA), and the local legal requirements.  
In conformity with GCP (ICH E6), the Investigator should provide direct access to source data/ 
documents for trial-related monitoring, audits, IRB/IEC review and regulatory inspection. Any 
authorized party with direct access should take all reasonable precautions within the constraints of 
the applicable regulatory requirement(s), to maintain the confidentiality of patient’s identities and 
Sponsor’s proprietary information. 
 
11.2. 
MONITORING 
The Sponsor will delegate the monitoring of the study to a Contract Research Organization (CRO). 
Monitoring will be done by personal visits from a representative of the CRO who will review the case 
report against source documents and will ensure that the investigation is conducted according to the 
protocol design, applicable Standard Operating Procedures (SOPs) and regulatory requirements. 
The monitor is responsible for checking that the rights and well-being of clinical trial patients are 
protected and the quality of data is maintained, and ensuring that the investigative site is adhering to 
the study protocol. Additionally, the monitor ensures that the site is following the legal and ethical 
requirements as stated in local laws and the principles of GCP. 
Source data verification is an essential part of the monitoring process and the Investigator must grant 
direct access to the original patient’s source documents. The Investigator will cooperate with the 
monitor to ensure that any discrepancies between source data and eCRF are resolved. 
 
11.3. 
INVESTIGATOR QUALIFICATIONS AND RESPONSIBILITIES 
The Investigator should provide a signed and dated copy of his/her current curriculum vitae describing 
his/her experience, qualifications and training prior to the beginning of the study. He/She should 
comply with the following conditions: 
‐ 
Be experienced in neurology, particularly in the management of Huntington’s Disease patients 
and to study procedures/testing facilities adequate for participation in study trial. Notably 
qualified to assess patients according to UHDRS®.  
‐ 
Have a sufficient number of HD patients who meet the enrolment goals. 
‐ 
Have previous clinical research experience with training to Good Clinical Practices. 
‐ 
Be willing to comply with the study the protocol and to complete all CRFs (eCRF) promptly, 
and to answer to any query according to the specificities and guidelines provided by the monitor 
for using the electronic interface. 
‐ 
Be willing to spend time to complete the administrative work involved in the study. 


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‐ 
Be willing to spend time with the Sponsor monitors (Clinical Research Associates; CRAs) or 
delegates during the monitoring visits, and to ensure to them direct access to source documents. 
The Investigator may appoint such other individuals as he/she may deem appropriate as sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial protocol. 
All sub-investigators shall be appointed and listed in a timely manner. The sub-investigators will be 
supervised by and work under the responsibility of the Investigator. The Investigator will provide 
them with a copy of the clinical trial protocol and all necessary information. 
 
11.4. 
QUALITY CONTROL AND AUDIT 
The study may also be subject to a quality assurance audit performed by the Sponsor or its designees, 
as well as inspection by appropriate regulatory authorities. 
The original documents generated in the course of the study will be controlled at each step of the 
study, both by the Sponsor’s representative and the Investigator, in order to guarantee the accuracy 
of the analyzed data. Auditors should have access to any study records (CRFs, site files, trial master 
files) and sources (e.g. patients’ medical documentation), being understood that these personnel are 
bound by professional secrecy, and as such will not disclose any personal identity or personal medical 
information. Investigators accept the possibility to be audited and agree to dedicate necessary time to 
the proper conduct of the audit at their sites. It will enable to check that the study is being run in 
conformity to the protocol and to current rules and regulations.  
 
11.5. 
PROTOCOL DEVIATION 
A protocol deviation is any noncompliance with the clinical trial protocol, International Council for 
Harmonization Good Clinical Practices (ICH-GCP), or Manual of Procedures (MOP) requirements. 
The noncompliance may be either on the part of the patient, the Investigator, or the study site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented promptly.   
The Investigator is responsible for ensuring that the study is conducted in accordance with the 
protocol. No modifications to the protocol, other than those that are deemed necessary to protect the 
safety, rights, or welfare of patients by the Investigator are to be made without prior, written approval 
by the Sponsor. The nature and reasons for the protocol deviation will be recorded where appropriate 
and indicated. The Sponsor must be notified of all protocol deviations. Significant protocol deviations 
(e.g. inclusion/exclusion criteria) will be reported to the Sponsor and to the IRB/IEC in accordance 
with its reporting policy. 
 
 
 


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12. 
DATA HANDLING AND RECORD KEEPING 
12.1. 
DATA ENTRY IN THE ECRF 
Electronic data capture will be used for the purpose of the study. The eCRF will be developed and 
validated by the CRO, representative of the Sponsor. The access to the electronic case report form 
will be provided by the Sponsor to the Investigator. All protocol-required information collected 
during the study must be entered by the Investigator, or designated representative, in the eCRF.   
Details of case report form completion and correction will be explained to the Investigator. If the 
Investigator authorizes other persons to make entries in the eCRF, the names, positions, signatures, 
and initials of these persons must be supplied to the Sponsor. 
The Investigator, or designated representative, should complete the eCRF pages as soon as possible 
after information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be completed 
immediately after the final examination. An explanation should be given for all missing data. 
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF.  
A source data location list will be prepared and updated during the study. This list will be filed in 
both the trial master file and the Investigator study file. 
The completed case report form must be reviewed and signed by the Investigator named in the study 
protocol. At the end of the study, the Sponsor will retain all case report forms. The Investigator will 
retain a record of all completed case report forms. 
The informed consent form will include a statement by which the patient allows the Sponsor’s duly 
authorized personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct 
access to original medical records which support the data on the eCRFs (e.g. patient's medical file, 
appointment books, original laboratory records, etc.). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to the 
technology used), designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF and allow 
remote monitoring. 
The computerized handling of the data by the Sponsor when available in the eCRF may generate 
queries to which the Investigator is obliged to respond by confirming or modifying the data 
questioned. The queries with their responses will be managed through the eCRF. 
 


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12.2. 
DATA MANAGEMENT 
The data will be entered into a validated FDA 21 CFR part 11 compliant database maintained by the 
Sponsor or designee. The data management group will be responsible for data processing, in 
accordance with agreed procedures. The Principal Investigator will electronically sign and date the 
appropriate eCRF page when instructed to do so by the study CRA. This signature will indicate that 
the Principal Investigator inspected or reviewed the data in the database, the data queries, and the site 
notifications, and agrees with the content. The standard procedures for handling and processing eCRF 
records will be followed per GCP and the Sponsor’s (or designee’s) SOPs. Complete details of data 
management will be described in a separate Data Management Plan. 
 
12.3. 
RECORD RETENTION 
The Investigator must maintain confidential all study documentation, and take measures to prevent 
accidental or premature destruction of these documents.  
In order to constitute evidence with respect to product safety or regulatory or legal compliance, the 
Investigators, investigational sites and Ethics Committees agree to retain study related documents in 
a location that is secure and to which access can be gained if required. The following documents must 
be archived: the Investigator’s file containing all required GCP documents, including signed Informed 
Consent forms and patient-related records, and copy of the CRFs. The Investigator and the site should 
retain records at least 25 years after the completion or discontinuation of the clinical trial. If 
the Investigator's personal situation is such that archiving can no longer be ensured by him/her, the 
Investigator shall inform the Sponsor and the relevant records shall be transferred to a mutually agreed 
upon designee. The Investigator must notify the Sponsor prior to destroy any study essential 
documents following the clinical trial completion or discontinuation.  
These documents must be available for inspection by authorized representative of the Sponsor or 
regulatory authorities. Audits may be performed for quality insurance of data handling. 
 
12.4. 
DATA PROTECTION 
The data collected in this study will only be used for the purpose(s) of the study and to document the 
evaluation of the benefit/risk ratio, efficacy and safety of the tested product SOM3355.  
The patient's personal data, which are included in the Sponsor database, shall be treated in compliance 
with all applicable laws and regulations. When archiving or processing personal data pertaining to 
the Investigator and/or to the patients, the Sponsor shall take all appropriate measures to safeguard 
and prevent access to this data by any unauthorized third party. 
The Sponsor also collects specific data regarding investigator as well as personal data, from any 
person involved in the study which may be included in the Sponsor’s databases, shall be treated by 
both the Sponsor and the Investigator in compliance with all applicable laws and regulations. 


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Patient race or ethnicity will be collected in this study. Differences in response to medical products 
have already been observed in racially and ethnically distinct subgroups of the U.S. population. These 
differences may be attributable to intrinsic factors (e.g., genetics, metabolism, elimination), extrinsic 
factors (e.g. diet, environmental exposure, sociocultural issues), or interactions between these factors. 
Race and ethnicity information will be collected according to the FDA Guidance for Industry - 
Collection of Race and Ethnicity Data in Clinical Trials (2005), and in accordance of local laws in 
the different participating countries. 
 
12.5. 
CONFIDENTIALITY AND PROPERTY RIGHTS 
All documents that concern the studied medication and the company’s operations belonging to the 
Sponsor such as patent applications, formulas, manufacturing processes, basic scientific data and 
analysis bulletins, and any information supplied by the company and not previously published are 
considered confidential and shall remain the sole property of the Sponsor. The information included 
in this protocol, along with the Investigator’s brochure of the product, the eCRF and the results of the 
present study are considered as confidential and should not be divulged unless such disclosure is 
required by law or regulations. The Investigator agrees to use this information only in accomplishing 
this study and they will not use it for other purposes without written consent from the Sponsor. 
In any event, any persons to whom the information is disclosed such as sub-investigators must be 
informed that the information is confidential and may not be further disclosed by them. The signature 
of the present protocol by the Investigator is equivalent to a confidentiality agreement. 
It is understood by the Investigator that the information from the clinical study will be used by the 
company in connection with the development of the tested drug and, therefore, may be disclosed as 
required, to other clinical investigators or to government agencies. 
 
 


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13. 
FINANCES AND INSURANCE 
13.1. 
FINANCING  
The Sponsor will cover the additional costs related to this study. These costs will be defined and 
agreed upon, before the start of the study. A financial agreement will be made between the parties: 
institution, investigator and Sponsor, in accordance with each administrative procedure. 
 
13.2. 
INSURANCE 
The Sponsor will contract a specific insurance policy to insure the patients enrolled in the study, in 
conformity with the national regulations. An insurance certificate will be provided to the IECs/IRBs 
or regulatory authorities in countries requiring this document. The insurance of the Sponsor does not 
relieve the Investigator and the collaborators from any obligation to maintain their own liability 
insurance policy. 
 
 
14. 
PUBLICATION POLICY 
The Sponsor will be responsible for conducting the statistical analysis and for preparing a Clinical 
Study Report and must provide a summary of study results to the Investigators. 
The Sponsor will publish the results at the end of the study in an international journal on behalf of 
the study group including all the principle investigators of all sites, after validation and agreement of 
the manuscript by the publication committee including the Sponsor and the coordinating investigator.  
The communication or publication of all or part of the results of this study, including ancillary studies, 
will be only permitted after written agreement of the Sponsor. Any manuscript or presentation should 
be submitted at least 30 days before submission to the Sponsor for review and approval. The objective 
is to ensure consistency between data submitted to regulatory agencies and data appearing in 
publications and presentations. In addition, if requested by the Sponsor, any presentation or 
submission for publication shall be delayed for a limited time, not to exceed 90 days, to allow for 
filing of a patent application or such other justified measures as the Sponsor deems appropriate to 
establish and preserve its proprietary rights. The Sponsor has the right at any time to publish the 
results of the study. 
 
 


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15. 
REFERENCES 
• 
Al-Khawaja, IM, Caruana, MP, Prince, H, Whittington, J and Raftery, EB. Once- and twice-
daily bevantolol for systemic hypertension using 24-hour ambulatory intraarterial blood 
pressure recording. Am J Cardiol. 1986; 58:17e-20e. 
• 
Andrich, J, Schmitz, T, Saft, C, Postert, T, Kraus, P, Epplen, JT, et al. Autonomic nervous 
system function in Huntington's disease. J Neurol Neurosurg Psychiatry. 2002; 72:726-31. 
• 
Andrich, J, Saft, C, Ostholt, N and Müller, T. Complex movement behaviour and progression 
of Huntington's disease. Neurosci Lett. 2007; 416:272-4. 
• 
Awad V M, Sakhamuru S, Kambampati S, et al. Mechanisms of Beta-Blocker Induced 
Psoriasis, and Psoriasis De Novo at the Cellular Level. Cureus, 2020;12(7): e8964. DOI 
10.7759/cureus.8964. 
• 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989; 154: 672–676.  
• 
Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: 
twenty-five years of evaluation. Clin Psychol Rev. 1988; 8:77-100. 
• 
Carlozzi NE, Miciura A, Migliore N, Dayalu P. Understanding the Outcomes Measures used 
in Huntington Disease Pharmacological Trials: A Systematic Review. J Huntingtons Dis. 
2014;3(3):233-252. 
• 
Caroff, SN. Risk of Neuroleptic Malignant Syndrome with Vesicular Monoamine 
Transporter Inhibitors. Clin Psychopharmacol Neurosci. 2020;18:322-6. 
• 
Coppen, EM and Roos, RA. Current Pharmacological Approaches to Reduce Chorea in 
Huntington's Disease. Drugs. 2017; 77:29-46. 
• 
Dorsey, ER, Beck, CA, Darwin, K, Nichols, P, Brocht, AF, Biglan, KM, et al. Natural history 
of Huntington disease. JAMA Neurol. 2013;70:1520-30. 
• 
Du, X, Pang, TY and Hannan, AJ. A Tale of Two Maladies? Pathogenesis of Depression with 
and without the Huntington's Disease Gene Mutation. Front Neurol. 2013; 4:81. 
• 
Fahn, S, Jankovic, J and Hallet, M. Huntington disease.  Principles and practice of movement 
disorders. Toronto, Canada: Elsevier; 2011. p. 311-34. 
• 
Frishman, WH, Goldberg, RJ and Benfield, P. Bevantolol. A preliminary review of its 
pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension 
and angina pectoris. Drugs. 198835:1-21. 
• 
Ghosh, R and Tabrizi, SJ. Huntington disease. Handb Clin Neurol. 2018;147:255-78. 
• 
Gluhm S, Goldstein J, Brown D, Van Liw C, Gilbert PE, Corey Blum J. Usefulness of the 
Montreal Cognitive Assessment (MoCA) in Huntington’s disease. Mov Disord. 2013 
October; 28(12): 1744–1747. doi:10.1002/mds.25578. 
• 
Huntington Study Group. 1996. Unified Huntington's Disease Rating Scale: reliability and 
consistency. Mov Disord 1996;11:136–142. 


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• 
Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a 
randomized 
controlled 
trial. 
Neurology. 
2006;66(3):366-372. 
doi:10.1212/01. 
wnl.0000198586.85250.13 
• 
Huntington Study Group. Effect of deutetrabenazine on chorea among patients with 
huntington 
disease: 
a 
randomized 
clinical 
trial. 
JAMA. 
2016;316(1):40-50. 
doi:10.1001/jama.2016.8655 
• 
Johns MW. A new method for measuring daytime sleepiness: The Epworth sleepiness scale. 
Sleep. 1991; 14:540-545. 
• 
Kaplan, HR, Chang, T, Eckerson, HW and Tessman, DK. Bevantolol Hydrochloride. 
Cardiovascular Drug Reviews. 1985; 3:85-97. 
• 
Kaplan, HR. Pharmacology of bevantolol hydrochloride. Am J Cardiol. 1986; 58:3e-7e. 
• 
Kobal, J, Melik, Z, Cankar, K, Bajrovic, FF, Meglic, B, Peterlin, B, et al. Autonomic 
dysfunction in presymptomatic and early symptomatic Huntington's disease. Acta Neurol 
Scand. 2010; 121:392-9. 
• 
Latts, JR. Clinical pharmacokinetics and metabolism of bevantolol. Angiology. 1986;37:221-
5. 
• 
Maclean, D. Bevantolol vs propranolol: a double-blind controlled trial in essential 
hypertension. Angiology. 1988;39: 487-96. 
• 
McColgan, P and Tabrizi, SJ. Huntington's disease: a clinical review. Eur J Neurol. 
2018;25:24-34. 
• 
Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for 
symptomatic treatment in Huntington's disease. Cochrane Database of Systematic Reviews 
2009, Issue 3. Art. No.: CD006456. DOI: 10.1002/14651858.CD006456.pub2. 
• 
Mestre TA, Bachoud-Lévi AC, Marinus J, Stout JC, Paulsen JS, Como P, Duff K, Sampaio 
C, Goetz CG, Cubo E, Stebbins GT, Martinez-Martin P; Members of the MDS Committee 
on Rating Scales Development. Rating scales for cognition in Huntington's disease: Critique 
and recommendations. Mov Disord. 2018 Feb;33(2):187-195. 
• 
Mickes L, Jacobson M, Peavy G, Wixted JT, Lessig S, Goldstein JL,Corey-Bloom J: A 
comparison of two brief screening measures of cognitive impairment in Huntington's disease. 
Mov Disord 2010, 25: 2229–2233. 
• 
Orrillo  SJ, de Dios N, Asad AD, De Fino F, Imsen M,  Romero AC, Zárate S  Ferraris J, 
Pisera D. Anterior pituitary gland synthesises dopamine from l-3,4-dihydroxyphenylalanine 
(l-dopa) J Neuroendocrinol. 2020;32(7):e12885. 
• 
Orth, M, Handley, OJ, Schwenke, C, Dunnett, SB, Craufurd, D, Ho, AK, et al. Observing 
Huntington's Disease: The European Huntington's Disease Network's REGISTRY. PLoS 
Curr. 2010;2: Rrn1184. 
• 
Paulsen, JS, Nehl, C, Hoth, KF, Kanz, JE, Benjamin, M, Conybeare, R, et al. Depression and 


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stages of Huntington's disease. J Neuropsychiatry Clin Neurosci. 2005; 17:496-502. 
• 
Poon, LH, Kang, GA and Lee, AJ. Role of tetrabenazine for Huntington's disease-associated 
chorea. Ann Pharmacother. 2010; 44:1080-9. 
• 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, 
Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: 
Initial validity and internal consistency findings from three multisite studies with adolescents 
and adults. American Journal of Psychiatry. 2011;168: 1266–77.  
• 
Ross, CA and Shoulson, I. Huntington disease: pathogenesis, biomarkers, and approaches to 
experimental therapeutics. Parkinsonism Relat Disord. 2009;15 Suppl 3: S135-8. 
• 
Ross, RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010; 5:40. 
• 
Ross, CA, Aylward, EH, Wild, EJ, Langbehn, DR, Long, JD, Warner, JH, et al. Huntington 
disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014; 
10:204-16. 
• 
Schwab, LC, Garas, SN, Drouin-Ouellet, J, Mason, SL, Stott, SR and Barker, RA. Dopamine 
and Huntington's disease. Expert Rev Neurother. 2015; 15:445-58. 
• 
Stergiou et Al. on behalf of the European Society of Hypertension Council and the European 
Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular 
Variability. 2021European Society of Hypertension practice guidelines for office and out-of-
office blood pressure measurement. Journal of Hypertension 2021, 39:000–000 
• 
Videnovic A, Bernard B, Fan W, et al. The Montreal Cognitive Assessment as a screening 
tool for cognitive dysfunction in Huntington’s disease. Mov Disord. 2010; 25:402–404.  
• 
Vuong, K, Canning, CG, Menant, JC and Loy, CT. Gait, balance, and falls in Huntington 
disease. Handb Clin Neurol. 2018; 159:251-60. 
• 
Wang YP, Gorenstein C. Psychometric properties of the Beck Depression Inventory-II: a 
comprehensive review. Revista Brasileira de Psiquiatria. 2013; 35:416–431 
• 
Wheelock, VL, Tempkin, T, Marder, K, Nance, M, Myers, RH, Zhao, H, et al. Predictors of 
nursing home placement in Huntington disease. Neurology. 2003; 60:998-1001. 
 


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16. 
APPENDICES 
All appendices will be provided in a separate document. 
16.1. 
UHDRS® - MOTOR PART INCLUDING TOTAL MOTOR SCORE (TMS) AND TOTAL 
MAXIMAL CHOREA (TMC), DYSTONIA AND GAIT SUB-SCORES 
16.2. 
UHDRS® - TOTAL FUNCTIONAL CAPACITY (TFC)  
16.3. 
UHDRS® - FUNCTIONAL ASSESSMENT (FA) 
16.4. 
CLINICAL GLOBAL IMPRESSION (CGI-S AND CGI-C) 
16.5. 
PATIENT GLOBAL IMPRESSION (PGI-S AND PGI-C) 
16.6. 
EQ-5D-5L 
16.7. 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
16.8. 
BECK’S DEPRESSION INVENTORY (BDI) 
16.9. 
EPWORTH SLEEPINESS SCALE (ESS) 
16.10. BARNES AKATHISIA RATING SCALE (BARS)  
16.11. MONTREAL COGNITIVE ASSESSMENT (MOCA) 
16.12. PROBLEM BEHAVIOR ASSESSMENT SHORT FORM (PBA-S) 
16.13. GUIDANCE OF THE EUROPEAN SOCIETY OF HYPERTENSION FOR BLOOD 
PRESSURE AND ORTHOSTATIC BP MEASUREMENT 

SAP_001.pdf: 
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Statistical Analysis Plan Version 1.0 
 
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CONFIDENTIAL 
 
Statistical Analysis Plan (SAP) 
Sponsor: 
SOM Biotech 
Protocol No 
SOMCT03                                       NCT number: NCT05475483    
Study Title: 
Phase IIb, randomized, double-blind, placebo-controlled study in 
parallel groups assessing the efficacy and safety of two doses of 
SOM3355 in patients suffering from Huntington’s Disease with 
choreic movements.  
Protocol 
Version/Date: 
V1.1, Spain 2022-02-24 
V1.1, UK 2022-05-19 
V1.1, Italy 2022-05-17 
V1.1, France 2022-05-20 
V1.1, Germany 2022-07-25 
V1.1 Switzerland 2022-08-03 
SAP 
Version/Date: 
Version 1.0, 2024-07-12 
Supersedes SAP Ver-
sion: 
Version 0.5 
Appendices 
(external documents): 
1. 
List of Tables, Listing, Figures (TLFs) 
2.  
Additional details on statistical methods 
 
 
 
Revision history 
 
SAP Version 
Version date 
Reason(s) for change 
0.1 
2023-03-31 
1st draft 
0.2 
2023-05-15 
2nd draft for sponsor review 
0.3 
2023-08-04 
3rd draft for sponsor review 
0.4 
2024-06-05 
4th draft for sponsor review 
0.5 
2024-07-09 
5th draft for sponsor review 
1.0 
2024-07-12 
Final version 
 
 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ......................................................................................................................... 4 
1 Study information ........................................................................................................................................ 6 
1.1 Primary objective .......................................................................................................................................... 6 
1.2 Secondary objective ...................................................................................................................................... 6 
1.3 Study design.................................................................................................................................................. 7 
1.4 Planned sample size ...................................................................................................................................... 8 
2 General Information .................................................................................................................................... 8 
2.1 Background details ....................................................................................................................................... 8 
2.2 Deviations from the trial protocol with regard to statistical analyses ........................................................... 8 
2.3 Individual protocol deviations ...................................................................................................................... 9 
3 Analysis Populations .................................................................................................................................... 9 
3.1 Screen failures ............................................................................................................................................ 10 
3.2 Intention-to-Treat (ITT) population ............................................................................................................ 10 
3.3 Safety (SAF) population ............................................................................................................................. 10 
3.4 Modified Intention-to-Treat (mITT) population ......................................................................................... 10 
3.5 Per-protocol (PP) Population ...................................................................................................................... 10 
3.6 Subgroup analyses ...................................................................................................................................... 11 
4 Statistical Analyses ...................................................................................................................................... 11 
4.1 Conventions ................................................................................................................................................ 12 
4.1.1 
Baseline definition ......................................................................................................................... 12 
4.1.2 
Missing data ................................................................................................................................... 13 
4.1.3 
Pooling of centres ........................................................................................................................... 14 
4.1.4 
End of Study ................................................................................................................................... 14 
4.2 Patient disposition ....................................................................................................................................... 14 
4.3 Demographic and other background data ................................................................................................... 15 
4.3.1 
Basic description ............................................................................................................................ 15 
4.4 IMP exposure and compliance .................................................................................................................... 16 
4.5 Medical history, physical examination ....................................................................................................... 16 
4.6 Prior and concomitant medication .............................................................................................................. 16 
4.7 Efficacy ....................................................................................................................................................... 17 
4.7.1 
Primary endpoint ............................................................................................................................ 17 
4.7.2 
Secondary endpoints ...................................................................................................................... 20 
4.7.2.1 Clinical Global Impression ............................................................................................................ 20 
4.7.2.2 Percentage of responders on TMC score ....................................................................................... 21 
4.7.2.3 The percentage of change in TMC score ....................................................................................... 21 
4.7.2.4 Patient Global Impression ............................................................................................................. 22 
4.7.2.5 Motor part of UHDRS® (Total Motor Score, Gait and Dystonia sub-scores) .............................. 22 
4.7.2.6 EQ-5D-5L measuring quality of life ............................................................................................. 23 
4.8 Pharmacokinetics (PK) ............................................................................................................................... 24 
4.9 PK-PD assessments..................................................................................................................................... 24 
4.10 Safety .......................................................................................................................................................... 24 
4.10.1 
Adverse events ............................................................................................................................... 25 
4.10.2 
Vital signs ...................................................................................................................................... 26 
4.10.3 
ECG ................................................................................................................................................ 26 
4.10.4 
Laboratory variables ....................................................................................................................... 27 
4.10.5 
Physical examination...................................................................................................................... 28 
4.10.6 
Concomitant Medications .............................................................................................................. 28 
4.10.7 
C-SSRS assessing suicidality ......................................................................................................... 28 
4.10.8 
BDI scale assessing depression ...................................................................................................... 29 
4.10.9 
ESS assessing sleepiness ................................................................................................................ 29 
4.10.10 TFC of the UHDRS® assessing functioning .................................................................................. 30 
4.10.11 Functional Assessment of the UHDRS® ....................................................................................... 30 


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4.10.12 BARS assessing akathisia .............................................................................................................. 30 
4.10.13 MoCA scale to assess cognitive disturbances ................................................................................ 30 
4.10.14 PBA-s to assess behavioral symptoms in HD ................................................................................ 31 
4.11 Other variables ............................................................................................................................................ 31 
4.12 Interim analyses .......................................................................................................................................... 31 
5 Quality Control ........................................................................................................................................... 32 
6 Derivations and Transformations ............................................................................................................... 32 
6.1 Formulas for derived variables ................................................................................................................... 32 
6.2 Transformations to be applied .................................................................................................................... 33 
7 References ................................................................................................................................................... 33 
8 Standards used in Preparation of Statistical Outputs ................................................................................ 34 
8.1 Programming .............................................................................................................................................. 34 
8.2 Layout ......................................................................................................................................................... 34 
8.3 Headers, Titles and Footnotes ..................................................................................................................... 34 
8.4 General Conventions................................................................................................................................... 35 
Appendices ..................................................................................................................................................... 37 
1. 
List of Tables, Listings, Figures ................................................................................................................. 37 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Description 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area under the Curve 
ATC 
Anatomic, Therapeutic, Chemical (Classification System for Drugs) 
BARS 
Barnes Akathisia Rating Scale 
BDI 
Beck Depression Inventory 
BID 
Twice daily 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per minute 
CAG 
Cytosine-Adenine-Guanine 
CGI 
Clinical Global Impression 
CI 
Confidence Interval 
Cmax 
Maximum observed plasma concentration 
CPMP 
Committee for Propriety Medicinal Products 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTC 
Common Toxicity Criteria 
DBP 
Diastolic Blood Pressure 
DD 
Drug Dictionary (WHO Coding Thesaurus) 
deuTBZ 
Deutetrabenazine 
DMP 
Data Management Plan 
DRM 
Data Review Meeting 
DVP 
Data Validation Plan 
ECG 
Electrocardiogram 
ESS 
Epworth Sleepiness Scale 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HD 
Huntington's Disease 
HPLC 
High Performance Liquid Chromatography 
HR 
Heart rate 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
ITT 
Intention-to-treat 
LOD 
Level of Detection 
LOQ 
Level of Quantification 
LSmeans 
Least Square Means 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCA 
Montreal Cognitive Assessment 
NCS 
Non-Clinically Significant 


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Abbreviation 
Description 
PBA-s 
Problem Behavior Assessment-short form 
PD 
Pharmacodynamics 
PGI 
Patient Global Impression 
PK 
Pharmacokinetics 
PP 
Per-protocol 
PPA 
Per-protocol Analysis 
PPS 
Per-protocol Set 
PT 
Preferred Term 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis Software Package 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class 
SOM3355 
Bevantolol hydrochloride (racemate) 
SOP 
Standard Operating Procedure 
SP 
Statistical Programmer 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBZ 
Tetrabenazine 
TEAE 
Treatment Emergent Adverse Event 
TFC 
Total Functional Capacity 
TLFs 
Tables, Listings, Figures 
Tmax 
Time corresponding to occurrence of Cmax 
TMC 
Total Maximal Chorea 
TMS 
Total Motor Score 
TS 
Trial Statistician 
UHDRS® 
Unified Huntington's Disease Rating Scale 
VMAT2 
Vesicular monoamine transporter type 2 
WHO 
World Health Organization 
 
 
 


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1 STUDY INFORMATION 
Huntington’s disease (HD) is an inherited progressive neurodegenerative disease. Chorea, 
an involuntary jerky movement that is purposeless and abrupt, is one of the most promi-
nent symptoms in HD. No effective disease-modifying therapies exist for HD, and treat-
ment is symptomatic relief. Chorea is treated by tetrabenazine (TBZ), approved in Europe 
and the United States (US), and the long-acting derivative deutetrabenazine (deuTBZ), 
approved in the US only. Both drugs are vesicular monoamine transporter type 2 
(VMAT2) inhibitors depleting monoamines in presynaptic neurons. It is thought that the 
consequent modulation of dopamine signalling across neural synapses reduces the dyski-
netic movements, such as chorea.  
SOM3355 provided functional inhibition of the VMAT2 with similar potency to that of 
TBZ but different binding properties that may provide less risk of severe side effects. Re-
lying on its VMAT2 inhibition activity, and the good tolerability shown in previous trials 
at doses from 100 to 600 mg/day administered once or twice daily (OD or BID), SOM 
Biotech is now developing SOM3355 for the treatment of the dyskinetic movement disor-
ders related to HD. 
 
1.1 Primary objective 
The primary objective of the study is to assess the efficacy of two doses of SOM3355 (200 
mg taken twice daily [BID]  i.e. 400 mg/day and 300 mg BID i.e. 600 mg/day over at least 
8 weeks at maintenance dose) compared to placebo to reduce chorea in HD patients meas-
ured by the change from baseline in total maximal chorea (TMC) score (primary efficacy 
endpoint). 
 
1.2 Secondary objective 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of two doses of SOM3355 (400 mg/day and 600 
mg/day) compared with placebo in HD patients, with particular attention to depression 
and suicidality and to the cardiovascular hemodynamic parameters. 
• To evaluate the efficacy of the two doses of SOM3355 (400 mg/day and 600 mg/day) 
compared with placebo on: 
o the change of Clinical Global Impression (CGI-C), 
o the change of Patient Global Impression (PGI-C), 
o the percentage of responders based on the improvement ≥2 in TMC score, 
o the percentage of change of TMC score. 
• A pharmacokinetic (PK) sub-study in a subset of 24 patients will allow to determine 
the PK profile of the two doses of SOM3355 (200 mg BID and 300 mg BID) at steady 
state and to model PK-PD assessments of hemodynamic and cardiac parameters. Anal-
ysis of these data will be described in a separate document and the results will be also 
presented in a separate report.   
 
 


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1.3 Study design 
This is an international, multicenter, double-blind, randomized, placebo-controlled, paral-
lel-group Phase IIb study assessing two doses of SOM3355 (400 or 600 mg/day), taken as 
200 mg BID or 300 mg BID, in patients presenting choreic symptoms related to HD. 
Patients will be randomized at the inclusion visit (Visit 1) to one of 3 treatment arms to 
receive either SOM3355 400 mg/day, SOM3355 600 mg/day, or placebo, all given BID. 
Dosing will start with an up titration in the first 3 weeks and will be maintained at a fixed 
dose for 7 weeks. After 10 weeks, patients will down titrate to 1 capsule 200mg / day of 
study drug for 1 week, followed by 1 capsule / day of placebo to assess the effect of drug 
interruption. 
The study will enroll 129 patients with a genetically proven diagnosis of Huntington’s 
Disease (confirmed by HTT gene CAG repeats ≥36), of mild to moderate severity (TFC 
score ≥7) with choreic symptoms (TMC score ≥10). The patients will be recruited in in-
vestigating sites in various European countries. Ambulatory patients will be recruited by 
reference centers for HD in collaboration with patient advocacy groups and the EHDN.  
A sub-study will characterize the PK profile of the 2 doses (400 mg/day or 600 mg/day) 
given twice daily for at least one week in a subset of patients (n = 24) who consent to be 
hospitalized for 24 hours for blood sampling and cardiac and hemodynamic assessments. 
Figure1 


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The flowchart/schedule of events can be found in Table 1: Schedule of Activities by Visit 
of the protocol. 
An independent data safety monitoring board (DSMB) will be established by the Sponsor. 
DSMB will assess at intervals the progress of the clinical trial and the safety for partici-
pants in reviewing accumulated data on safety, tolerability, and efficacy outcomes. 
 
1.4 Planned sample size 
Power calculation is based on results from previous trials that tested VMAT2 inhibitors 
(TBZ and deuterbenazine) on chorea in HD patients with TMC score as primary endpoint, 
which showed a standard deviation of 3.5 and 3.9 respectively, and a treatment effect 
compared to placebo in TMC score of -3.5 and -2.5 respectively. 
The sample size will be a total of 129 patients. Eligible patients will be randomized in 
blinded fashion in a 1:1:1 ratio i.e. 43 patients in each arm (SOM3355 400 mg/day, 
SOM3355 600 mg/day, or placebo). Assuming a treatment difference of -2.5 points in the 
change from baseline of TMC score compared to placebo and a standard deviation of 3.5 
(to ensure a clinically relevant effect of at least -2 in the study), 39 patients per arm will 
provide at least 80% power that at least 1 dose of SOM3355 will be significantly superior 
to placebo at the 2-sided 0.025 significance level. This is based on the use of a two-sided 
t-test for the mean TMC score change. For the primary endpoint, the overall type I error 
will be controlled using a Holm procedure. To account for a 10% dropout rate, 43 patients 
per arm (i.e., a total of 129 patients) will be enrolled. 
 
2 GENERAL INFORMATION 
 
2.1 Background details 
All study data will be transferred to a SAS database (version 9.4 or later) for statistical 
analysis purposes. Data will be imported from a Data Capture System OPVerdi and exter-
nal data vendors (cf. Data Management Plan) via validated SAS programs. 
The SAP will be finalized before database lock after agreement with the Sponsor on pa-
tient disposition and coding. 
 
2.2 Deviations from the trial protocol with regard to statistical analyses 
The following deviations from the protocol were identified as being important for the sta-
tistical analysis: 
For the key secondary efficacy endpoint (Change from baseline in the Clinical Global 
Impression (CGI-C)) multiplicity adjustment will be applied.  
Original text in protocol: The type I error will be set at 0.05 (two-sided) and the cover-
age level of confidence intervals to 95% for all secondary efficacy analyses. No multi-
plicity adjustment will be applied for the statistical inferences of the secondary efficacy 
endpoints. 


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The revised definition in SAP only for key secondary endpoint: To preserve the family-
wise error rate at the 0.05 level when comparing the two doses of SOM3355 versus 
placebo and comparing a primary endpoint and key secondary endpoint, statistical test-
ing will be carried out using the Holm procedure for CGI-C if the primary endpoint is 
significant for both doses. The smallest p-value of the two comparisons will be first 
compared at the two-sided 0.025 level and if statistically significant, the other p-value 
will be compared at the two-sided 0.05 level. 
 
2.3 Individual protocol deviations 
Apart from violations of inclusion or exclusion criteria the table below lists conditions that 
may affect the evaluation of patient data and the proposed actions: 
Condition 
Decision Rule 
Informed consent not given 
Exclude from all data analyses. 
Violation of any inclusion or exclu-
sion criteria 
Potentially exclude from Per Protocol Population 
(PP)  
Patients not exposed to IMP 
Exclude from Safety Analysis Population (SAF), 
Modified Intent-to-Treat Population (mITT) and 
Per Protocol Population (PP) 
Premature discontinuation during the 
treatment period 
Potentially exclude from Per Protocol Population 
(PP) 
Less than 80% or more than 120%  
compliance with IMP intake 
Potentially exclude from Per Protocol Population 
(PP) 
No post-baseline assessment of the 
TMC score 
Exclude from Modified Intent-to-Treat Population 
(mITT) and Per Protocol Population (PP) 
Patients receiving prohibited treat-
ments 
Potentially exclude from Per Protocol Population 
(PP) 
Patient received a treatment which 
the patients was not randomized for 
Exclude from Per Protocol Population (PP)  
 
A detailed review of all documented and derived deviations from protocol will be part of 
the Blinded Data Review Meeting (BDRM) before database lock. During this BDRM the 
impact of protocol deviations on the analysis will be assessed and the conclusions rec-
orded. Also, additional deviations could be identified during the meeting. 
A complete listing of documented and derived protocol deviations and the judgment for 
assessment of patient disposition will be signed before database lock. A description of 
protocol violations that led to exclusion from any analysis sets will be included in the CSR. 
 
3 ANALYSIS POPULATIONS 
In general, the disposition of patients will be displayed for following populations, if appli-
cable: 
• All screened population (having signed ICF) 
• Screening failures 


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• Intention-to-Treat (ITT) population 
• Safety (SAF) population 
• Modified Intention-to-Treat (mITT) population 
• Per-Protocol (PP) population 
Population assignment of patients will be decided upon in a treatment-blinded DRM with 
the Sponsor before database lock. The proper flags for analysis sets exclusion (e.g., exclu-
sion from PP set), will be included in the analysis datasets. The protocol deviation list 
should be finalized before database lock. 
 
3.1 Screen failures 
Screen failures are patients who have consented to participate in the clinical trial by signing 
the Informed Consent. Form before performing the screening assessments but who did not 
meet all the selection criteria to be randomized at the inclusion visit V1, by consequence 
they are not eligible to be subsequently randomly assigned to the study intervention or 
entered in the study. 
 
3.2 Intention-to-Treat (ITT) population 
The ITT Population will include all randomized patients whether they received the study 
treatment or not. Patients will be analysed in the treatment group to which they were ran-
domized, regardless of the treatment that was actually received or if they withdrew prior 
to first dosing. 
 
3.3 Safety (SAF) population 
The Safety Analysis Set (SAF) includes all patients who were administered at least one 
dose of any study drug. Patients who are randomized and assigned a treatment but with-
drew prior to dosing will not be included in the safety population. Patients will be included 
in the treatment group based on the treatment actually received. The analysis of all safety 
variables will be based on the SAF. 
 
3.4 Modified Intention-to-Treat (mITT) population 
The mITT Population will include all patients from the ITT Population who were random-
ized to treatment, received at least one dose of study drug and had at least one post-baseline 
assessment of the TMC score. The primary efficacy analysis will be conducted on the 
mITT Population. Patients will be included in the treatment group to which they were 
randomized, regardless of the treatment that was received. 
 
3.5 Per-protocol (PP) Population 
The Per-Protocol Population (PP) is a subset of patients in the mITT.  


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It includes all randomized patients who completed the study without important deviations 
from the protocol. The decision of the membership in the PP Population will be made 
during a blinded Data Review Meeting prior to database lock, reviewing all deviations 
occurred. 
 
3.6 Subgroup analyses 
Subgroup analyses of the primary efficacy (change in Total Maximal Chorea (TMC) score 
from baseline to the end of maintenance therapy at V5) are planned for the following sub-
groups: 
• patients not taking neuroleptics during the study vs patients taking neuroleptics as 
concomitant medication during the study 
• gender: male, female 
• age: < median, ≥ median 
• country: France, Spain, UK, Poland, Italy, Germany 
• baseline TMC: < median, ≥ median 
• baseline TMS: < median, ≥ median 
This analysis will be performed on the mITT population, except the neuroleptics subgroup, 
which will also be repeated on the PP population. 
Additional subgroup, correct versus incorrect down titration phase between Visit 5 and 
Visit 6, is defined as: 
• patients who have performed a correct down titration phase i.e. who correctly took 
the IMP at half dose (1 capsule/ day) for a week and then capsules from placebo 
bottle for at least 4 days. 
• patients who did incorrect down titration  
o who took 2 capsules/day of IMP so remaining at full dose with no down 
titration, and then placebo with abrupt IMP discontinuation 
o or who took the IMP at half dose (1 capsule/ day) for 2 weeks with no 
placebo wash out or less than 4 days under placebo      
For this subgroup, only descriptive statistics on visits for the TMC score will be repeated 
on the mITT population to show the evolution of the TMC score between V5 and V6 after 
IMP interruption. In addition, time profiles of the mean TMC scores with standard error 
of the mean (SEM) will be presented. 
 
4 STATISTICAL ANALYSES 
All statistical analyses will be performed using the SAS® software (Version 9.4 or later). 
It will be based on data according to CDISC standards, SDTM (SDTM IG v3.3) and 
ADaM (ADaM IG v1.3). 
Descriptive statistics will be given by treatment group and overall, where appropriate. 


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If not stated otherwise, the following standard types of descriptive analyses will be pre-
sented:  
− Descriptive statistics for continuous data 
N, mean, SD, min, median and max will be presented. These descriptive statistics will 
be determined for measured values and for changes from baseline. 
− Descriptive statistics for categorical data 
Absolute frequencies and percentages will be presented. Percentage bases (denomina-
tors) will be identified in the table title or footnote (i.e. all patients at risk, all non-
missing cases, all cases). For changes from baseline, shift tables may be generated.  
− Inferential statistics 
Unless otherwise stated, all statistical tests will be performed two-sided and at a type I 
error probability of =0.05. The p-values will be printed consistently with 4 decimals 
(p<0.0001 will be displayed, if the p-values are less than 0.0001 and p>0.9999 will be 
displayed, if the p-values is more than 0.9999). 
Unless otherwise stated, all confidence intervals (CIs) will be derived two-sided and at 
a confidence probability of 1-α=0.95.  
− Listings 
All recorded data will be listed by patient (sorted by treatment group Placebo, 200 mg 
BID, 300 mg BID). Identification variables are centre number, patient number and 
treatment group.  
Derived data will be stored in special analysis data sets and will be calculated as outlined 
in section 6.1. 
 
4.1 Conventions 
4.1.1 Baseline definition 
Baseline is defined according to the endpoint as follows: 
• For the Total Maximal Chorea score (TMC), and motor part of Unified Hunting-
ton’s Disease Rating Scale (UHDRS-TMS) the baseline is defined as the average 
of the values for Visit 0 and Visit 1. 
• The severity of choreic symptoms is assessed at Visit 1 with Clinical Global Im-
pression-severity (CGI-S) scale and Patient Global Impression-severity (PGI-S) 
scales. Score of these 2 scales is assessed at baseline but cannot be used as baseline 
value when calculating changes to baseline, since change is already assessed at each 
visit (Visit 2 to Visit 6) with Clinical Global Impression of Change (CGI-C) and 
Patient Global Impression of Change (PGI-C). 
• For EQ-5D, Barnes Akathisia Rating Scale (BARS), Montreal Cognitive Assess-
ment (MoCA) scale and Problem Behavior Assessment short form (PBA-s) base-
line is the value at Visit 1. 


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• For the Total Functional Capacity score (TFC), Columbia Suicide Severity Rating 
Scale (C-SSRS), Beck Depression Inventory (BDI), Epworth Sleepiness Scale 
(ESS), ECG and vital signs, baseline is defined as the value at Visit 1. 
• For Functional Assessment (FA) of the UHDRS baseline is at Visit 0. 
• For laboratory data (haematology and clinical chemistry), baseline is at Visit 0. 
• For any other parameter, baseline is defined as the last available measurement be-
fore the first administration of study drug, i.e., the value of the parameter at Visit 0 
or at Visit 1. 
 
4.1.2 Missing data 
In case of premature discontinuation, values collected at the end of study visit (EOS) or 
Unscheduled Visit (if it is the last visit) will be imputed to the first missing visit of the 
patients. For example, a patient withdrew between V3 and V4 (i.e. V4 is missing), then 
the value recorded at EOS will be imputed to V4. If a patient discontinues exactly at the 
time of a visit, but the value is recorded in the EOS page, this value will be imputed to the 
visit when the discontinuation occurred.  
Partial dates are allowed on the eCRF for adverse event (AE) onset and resolution dates, 
concomitant medication start and stop dates, and concomitant procedure dates. An entry 
for the year is required in the eCRF system for each of these dates. Only the month and 
day may be entered as unknown. Dates from these forms will be reported in listings as 
collected. Every effort will be made to query missing dates particularly to clarify the onset 
day and time of AE occurring at visit 1 to determine if the AE is treatment emergent or 
not.  
For records with missing AE onset date, the following procedure will be employed for use 
in determining whether the AE is treatment emergent: 
• AE onset dates with missing day and non-missing month will be assumed to occur 
on the first day of the non-missing month, except for AEs occurring in the first 
month of dosing, in which case the date will be set to the first day of dosing. 
• AE onset dates with missing month will be assumed to occur on the first day of the 
non-missing year (i.e., January 1), except for AEs occurring in the first year of 
dosing, in which case the date will be the first day of dosing.  
For records with a missing medication start and/or stop date, the following procedure will 
be employed for use in determining whether the medication is prior or concomitant: 
• Medication start dates with a missing day and non-missing month will be assumed 
to occur on the first day of the non-missing month, except for medications occur-
ring in the first month of dosing, in which case the date will be the first day of 
dosing. 
• Medication start dates with missing month will be assumed to occur on the first 
day of the non-missing year (i.e., January 1), except for medications occurring in 
the first year of dosing, in which case the date will be the first day of dosing.  


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• Medications that are not ongoing and have a medication stop date with a missing 
day and non-missing month will be assumed to occur on the last day of the non-
missing month. 
• Medications that are not ongoing and have a medication stop date with a missing 
month will be assumed to occur on the last day of the non-missing year (i.e., De-
cember 31). 
For records with a missing procedure date, the following procedure will be employed for 
use in determining whether the procedure is prior or concomitant: 
• Procedure dates with a missing day and non-missing month will be assumed to 
occur on the first day of the non-missing month, except for procedures occurring 
in the first month of dosing, in which case the date will be the first day of dosing. 
• Procedure dates with missing month will be assumed to occur on the first day of 
the non-missing year (i.e., January 1), except for procedures occurring in the first 
year of dosing, in which case the date will be the first day of dosing. 
 
4.1.3 Pooling of centres 
No pooling of centres will be performed.   
 
4.1.4 End of Study 
A patient is considered to have completed the study if he/she has completed all visits of 
the study (until visit 6). 
The end of the study is defined as the date of the last visit of the last patient in the study. 
 
4.2 Patient disposition 
The disposition of patients will be summarized using the following tabulations: 
• the number of all screened subjects (included in Visit 0 - ICF signed) 
• the number of screening failures with reasons of exclusion  
• the number of randomised subjects (at Visit 1) 
• the number of subjects who took at least one dose of IMP 
• the number of subjects who prematurely discontinued the study i.e. withdrawals 
with reasons  (Adverse Events, non-compliance to IMP, Protocol selection criteria 
violation, Consent withdrawn, others) 
• the number of patients who completed V5 (primary endpoint assessment at the 
end of maintenance dose)  
• the number of subjects having completed the entire study until Visit 6 
 
Then this will define the number of subjects in the ITT, Safety, mITT and PP population. 
Frequencies or different reasons for exclusions from analysis sets (as defined in section 3) 
will be tabulated and listed.  
A CONSORT flow diagram on patient disposition, will be created in the CSR. 


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Also, the disposition by country and centre will be presented. 
A by-patient listing of the randomisation scheme and codes will be provided. 
 
4.3 Demographic and other background data 
4.3.1 Basic description 
 
Demographic and baseline characteristics will be summarized in frequency or sampling 
statistics tables for Safety population (SAF) and mITT, if not identical.  
Screen failure demographic data will be also listed. 
Demographic variables: 
• Age 
• Sex  
• BMI  
• Ethnic origin 
• Country and centre  
• Females only: childbearing potential (Yes/No) 
 
Disease specific patient characteristics measured at screening/baseline: 
• Number of Cytosine-Adenine-Guanine (CAG) repeats 
• Total Functional Capacity (TFC) score at baseline 
• Level of chorea at baseline (TMC score) 
• Total Motor score (TMS) at baseline  
• Age at diagnosis: Year of HD diagnosis - Year of Birth, where year of birth will be 
calculated as: Year of inform consent - Age 
• Age at first symptoms: Year of first symptoms - Year of Birth, where year of birth 
will be calculated as: Year of inform consent - Age 
• Documented evidence on any other HD-related symptom(s) available such 
o Presence of depression 
o Presence of Behaviour disorders or aggressiveness  
o Presence of Cognitive disturbance 
• Neuroleptic treatment in co-medications to treat behaviour disorder (accepted by 
Steering Committee) 
• Antidepressant treatment in co-medications 
Antidepressant and neuroleptic treatments will be identified by the Sponsor and Med-
ical Monitor. 
 


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4.4 IMP exposure and compliance 
Exposure:  
- 
Total number of patients with at least one dose of study treatment: overall and per 
treatment periods (W1 (200mg once daily (OD) or Placebo), W2 (200mg BID or Pla-
cebo), W3 (200 or 300mg BID or Placebo), W4-W10 (200 or 300mg BID or Placebo), 
W11 (200mg OD or Placebo), W12 (Placebo))  
- 
Total number of days with at least one dose of study treatment: overall and per treat-
ment periods (W1 (200mg OD or Placebo), W2(200mg BID or Placebo), W3, W4-
W10 (200 or 300mg BID or Placebo), W11(200mg OD or Placebo), W12 (Placebo)).  
The earliest date of study withdrawal/completion or product withdrawn (AE) will be se-
lected and the day before this date will be defined as the last treatment intake. The first 
date of administration is collected by visit in the eCRF. Within visits, the intake of study 
treatment will be defined according to the study protocol and is theoretical. 
Compliance: 
Compliance will be evaluated by calculating at each visit the number of capsules used 
(capsules dispensed minus capsules returned) divided by the expected number of capsules 
to be used x 100. A patient will be deemed compliant if the patient has taken ≥80% but 
≤120% of the expected tablets of study drug. 
Total dose taken per patient and per bottle can be calculated as: 
Total dose (mg) for each bottle = (total number of capsules in the bottle – number of 
capsules returned) x dose for the given bottle  
Compliance (%) will be assessed during the whole study and by study period (up-titration 
period W1-W3 (from V1 to V2), maintenance period W4-W10 (from V2 to V5), and 
down-titration period W11-W12 (from V5 to V6). 
A summary of the total dose by study period and IMP compliance (%) by study period 
will be presented per treatment group for the SAF.  
A by patient listing of IMP compliance by period will be provided. 
 
4.5 Medical history, physical examination 
All medical history and physical examination data will be listed.  
Analysis of physical examination is described in Section 4.10.5. 
 
4.6 Prior and concomitant medication 
Prior and concomitant medications will be coded using the WHO Drug Global thesaurus 
version Q1 2022. Coding will be performed by Ergomed and agreed upon with the sponsor 
before data base lock (cf. DMP).  
Prior medications are defined as medications which were taken before the study and 
stopped before the start of study treatment. For some drugs they should be stopped 1 or 3 
months before the randomization as stated in protocol §5.3.1. 


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Concomitant medications are defined as medications which were taken during the study 
with the investigational treatment (regardless of the start time).  
Prior medications and Concomitant medications will be listed separately. Summaries will 
show the frequencies of patients by WHO Drug Global INN. 
All details of concomitant medications will also be listed including the route, dose, fre-
quency, start and stop date and indication. 
Analysis of concomitant medications is described in Section 4.10.6. 
 
4.7 Efficacy 
The primary efficacy analysis will be conducted on the mITT population including all 
patients who were randomized to treatment, received at least one dose of study drug and 
had at least one post-baseline assessment of the TMC score. Patients will be included in 
the treatment group to which they were randomized, regardless of the treatment that was 
received.  
Additional analyses for the primary endpoint will also be performed for the ITT population 
and PP population. The latter analyses serve as sensitivity analysis to explore the robust-
ness (cf. Section 2.1). 
 
4.7.1 Primary endpoint 
 
The primary endpoint is  the change in Total Maximal Chorea (TMC) score from baseline 
(defined for each patient as the average of values at the screening visit (Visit 0) and the 
inclusion visit (Visit 1)) to the end of maintenance therapy (defined for each patient as the 
average of values at the end of Week 9 (Visit 4) and the end of Week 10 (Visit 5)). 
As a result, the different factors included in the MMRM model (below) will be defined as 
following:  
- Baseline TMC: calculated as (TMC V0 + TMC V1)/2,  
- TMC at each following Visits: V2 (week 3), V3 (week 6), V4 (week 9), V5 (week 10)),  
- Change from baseline TMC: [(TMC V4 + TMC V5)/2 – Baseline TMC]  
If the value at V5 is missing and V4 is not missing, then the value at V4 will be used for 
the calculation. If the value at V4 is missing and V5 is not missing, then the value at V5 
will be used for the calculation. If both V4 and V5 values are missing, change from base-
line TMC will be treated as missing. 
The estimand of the primary efficacy analysis is defined according to ICH-E9-R1. The 
estimand reflects a mixed strategy for the inter-current events as presented in the table 
below. 
Estimand 
attribute 
Primary definition 
Rationale (as needed) 
Population 
Patients with Huntington’s disease with cho-
reic movements 


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Estimand 
attribute 
Primary definition 
Rationale (as needed) 
Endpoint 
Change from baseline (Visit 0 and Visit 1) 
to end of maintenance dose (Visit 4 and 
Visit 5) in TMC score 
Inter-current 
events 
Event 
Strategy 
Rationale (as needed) 
Receipt of assigned 
study treatment 
Treatment policy 
This strategy applied to align the esti-
mand with the application of the ITT 
principle. 
Prohibited concomitant 
neuroleptic treatment 
during the treatment 
period 
While on treat-
men 
This strategy applied up to the time of the 
prohibited concomitant treatment.  
 
Discontinuation from 
study 
Hypothetical pol-
icy 
This strategy applied for randomized and 
treated patients using a MMRM approach 
under MAR assumptions. 
Summary 
measure 
Difference in the change of TMC score from baseline to end of maintenance visit adjusted 
LS means between active arms and placebo  
 
The primary analysis of the primary efficacy endpoint will be based on a mixed-effect 
linear model for repeated measures (MMRM) to compare each active treatment group to 
placebo. The model will include the following factors: treatment group, visit, and treat-
ment-by-visit interaction as fixed effects, and baseline TMC score as covariate. An un-
structured (UN) variance-covariance matrix will be used to model the within-patient er-
rors. If no reliable results under the UN assumption can be obtained, the Toeplitz (TP) 
covariance structure, followed by the autoregressive (AR1) and Compound Symmetry 
(CS) covariance structure will be used. The Kenward-Roger method will be used to esti-
mate the denominator degree of freedom. 
The SAS code for the primary analysis is as follows: 
PROC MIXED data=dataset method=REML; 
CLASS subject treatment visit; 
MODEL changeTMC = treatment visit treatment*visit baselineTMC / ddfm=KR; 
REPEATED visit / subject = subject type = UN; 
LSMESTIMATE treatment*visit “TMC change 200 mg vs Placebo” 0 0 -1   0 0 1   0 
0 0 / cl elsm; 
LSMESTIMATE treatment*visit “TMC change 300 mg vs Placebo” 0 0 -1   0 0 0  0 0 
1/ cl elsm; 
RUN; 


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The least squares mean (LSM) estimate for each treatment group and difference in LSM 
estimates at end of maintenance dose between active treatments and placebo group with 
their confidence intervals will be provided. For the lowest p-value 97.5% CI will be pro-
vided and for the highest p-value 95% CI will be provided. 
To preserve the family-wise error rate at the 0.05 level when comparing the two doses of 
SOM3355 versus placebo, statistical testing will be carried out using the Holm procedure. 
The smallest p-value of the two comparisons will be first compared at the two-sided 0.025 
level and if statistically significant, the other p-value will be compared at the two-sided 
0.05 level. 
Descriptive statistics will be presented for the TMC score and changes from baseline by 
treatment group and by visit (including V6), on imputed data (as described in 4.1.). In 
addition, time profiles of the mean TMC scores with standard error of the mean (SEM) 
will be presented. 
 
Sensitivity analyses on the primary efficacy endpoint will be conducted as follows: 
Sensitivity #1 
A sensitivity analysis will be performed to assess the robustness of the primary analysis 
based on MMRM. Intermittent missing values will first be imputed using the Markov 
Chain Monte Carlo (MCMC) method which assumes a joint multivariate normal model 
for variables in the imputation model. Then a control-based pattern imputation is applied 
to the monotone missing data under the assumption of data missing not at random 
(MNAR). PROC MI using the MCMC statement will be used to implement the first step. 
Then PROC MI using the MONOTONE and MNAR statements will be used to create the 
complete data sets. MNAR will be imputed using Copy Reference method and number of 
imputations will be 30. The same MMRM analysis as defined for the primary analysis will 
be performed on the complete data sets, and the results will be combined using PROC 
MIANALYZE. This analysis will be performed on the mITT population. 
Sensitivity #2 
Primary endpoint will be analysed using the observed cases (no imputations) using an 
analysis of covariance (ANCOVA) model including treatment as fixed factor and baseline 
score as covariate. Results for the outcome of the primary endpoint will be presented for 
the least square means estimates and 95% CIs. This analysis will be performed on the 
mITT population. 
Sensitivity #3 
Primary efficacy analysis will be repeated for the PP Population. 
Sensitivity #4 
The primary efficacy analysis will be repeated using data without imputation for the visits 
of discontinued patients for the mITT population. 
Subgroup analysis as defined in section 3.6 will be performed for the primary endpoint 
across all predefined groups, with a particular focus on comparing patients taking neuro-
leptics as concomitant medication during the study versus patients not taking neuroleptics 
during the study. For this subgroup, descriptive statistics for the TMC score and changes 


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from baseline by treatment group and by visit (including V6) will be presented, as well as 
time profiles of the mean TMC scores with standard error of the mean (SEM) will be 
provided. 
For the subgroup analysis assessing patients with correct versus incorrect down titration 
phase between V5 and V6, only descriptive statistics for TMC score on visits will be re-
peated on the mITT to show the evolution of the TMC score between V5 and V6 after 
IMP interruption. 
 
4.7.2 Secondary endpoints 
Key secondary endpoint: 
• CGI change (CGI-C) at V5 (end of maintenance)  
The key secondary efficacy endpoint will be analysed for the mITT and PP Population. 
To preserve the family-wise error rate at the 0.05 level when comparing the two doses of 
SOM3355 versus placebo and comparing a primary endpoint and key secondary endpoint, 
statistical testing will be carried out using the Holm procedure for CGI-C if the primary 
endpoint is significant for both doses. The smallest p-value of the two comparisons will 
be first compared at the two-sided 0.025 level and if statistically significant, the other p-
value will be compared at the two-sided 0.05 level. 
Other secondary endpoints: 
They will be assessed in the following order: 
• TMC-response defined as improvement ≥ 2 in TMC score between the baseline 
and the end of maintenance dose  
• The percentage of change in TMC score 
• The PGI change  
• Total Motor Score (TMS) of the motor part of UHDRS® 
• Gait sub-score of the motor part of UHDRS® 
• Dystonia sub-score of the motor part of UHDRS® 
• EQ-5D-5L measuring quality of life  
Secondary efficacy endpoints will be analysed for the mITT Population. 
The type I error will be set at 0.05 (two-sided) and the coverage level of confidence inter-
vals to 95% for all secondary efficacy analyses. No multiplicity adjustment will be applied 
for the statistical inferences of the secondary efficacy endpoints. 
 
4.7.2.1 Clinical Global Impression  
The CGI-Severity (CGI-S) assessed at baseline is a 7-point Likert Scale that asks the cli-
nicians to rate, considering their total experience with this type of patients, the level of 
illness due to chorea on the illness severity ranging from normal (1) to extremely ill (7) 
(CGI-Severity).  


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Then, after therapy initiation, the CGI-Change (CGI-C) asks the clinician to assess the 
overall global change in the choreic symptoms since the start of study drug dosing, in a 7-
point Likert Scale ranging from very much worse (7) to very much improved (1). 
CGI-S will be assessed at the inclusion (Visit 1 at Day 0), and CGI-C at each following 
visit (from V2 to V6). For the CGI-C, patients with a score of 1 (very much improved), 2 
(much improved) or 3 (minimally improved) will be defined as ”Improved” and patients 
with a score of 4 (No change), 5 (Minimally worse), 6 (Much worse) and 7 (Very much 
worse) will be defined as “Not improved”.  
CGI-S (baseline characteristic) and CGI-C results will be analysed descriptively at each 
visit. 
A logistic regression model will be performed for CGI-C at V5 (end of maintenance dose) 
including the treatment group as the main factor in the model. Estimates along with 95% 
confidence intervals for the difference in response proportion and the odds ratio of re-
sponse will be derived from this model.  
In addition, histogram will be presented.  
 
4.7.2.2 Percentage of responders on TMC score  
TMC score is assessed at each visit from V0 to V6.  
V0 and V1 values are used to calculate the baseline (mean of the 2 values), and V4 V5 
values for the end of maintenance dose.  
Assessment at V6 occurs after the drug interruption with one week at 200 mg OD and the 
last week under placebo. 
TMC score evolution will be assessed at each visit.  
 
The number and percentage of responders with an improvement of at least 2 points in the 
TMC score will be calculated in each treatment group at each visit. 
The TMC response status (“Responder” vs. “Not responder”) will be described at each 
visit. 
Logistic regression model will be performed for responders on TMC score at V5 (end of 
maintenance dose) including the treatment group as the main factor in the model. Esti-
mates along with 95% confidence intervals for the difference in response proportion and 
the odds ratio of response will be derived from this model.  
In addition, histogram will be presented. 
This analysis will be repeated on the PP population. 
 
 
4.7.2.3 The percentage of change in TMC score 
The percentage of change in TMC score is defined as: 
100 * (TMC score at Visit x – TMC score at Baseline) / TMC score at Baseline. 


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“Baseline” is the average score between V0 and V1, “Visits x” are V2, V3 and the average 
score between V4 and V5 or V4, V5 in case of missing visit.  
For the analysis of the percentage of change in TMC score, descriptive statistics and the 
same MMRM model, as described for the primary endpoint will be used.  
 
This analysis will be repeated on the PP population. 
 
4.7.2.4 Patient Global Impression 
The PGI-Severity (PGI-S) is a 7-point Likert Scale that asks the patients to assess the 
severity of their choreic symptoms at baseline ranging from not present (1) to extremely 
severe (7). 
Then, after therapy initiation, the PGI-Change (PGI-C), asks the patients to assess the 
overall global change in their choreic symptoms and their quality of life since the start of 
study drug dosing, in a 7-point Likert Scale ranging from very much worse (7) to very 
much improved (1). 
PGI-S will be assessed at the inclusion (Visit 1 at Day 0), and PGI-C at each following 
visit (from V2 to V6). For the PGI-C, patients with a score of 1 (very much improved), 2 
(much improved) or 3 (minimally improved) will be defined as ”Improved” and patients 
with a score of 4 (No change), 5 (Minimally worse), 6 (Much worse) and 7 (Very much 
worse) will be defined as “Not improved”. 
PGI-S and PGI-C results will be analysed descriptively at baseline and post-baseline visit 
respectively.  
Logistic regression models will be performed for PGI-C at V5 (end of maintenance dose) 
including the treatment group as the main factor in the model. Estimates along with 95% 
confidence intervals for the difference in response proportion and the odds ratio of re-
sponse will be derived from this model. In addition, histogram will be presented. 
 
This analysis will be repeated on the PP population. 
 
 
4.7.2.5 Motor part of UHDRS® (Total Motor Score, Gait and Dystonia sub-scores) 
The motor part of the UHDRS® is assessed at each visit from V0 to V6, including the 
TMC score and the following other scores:  
The Total Motor Score (TMS) is made of all 31 items The items are rated from 0 to 4, 
with 0 indicating normal findings and 4 indicating severe abnormalities. The range of the 
Total Motor Score (TMS) is 0 to 124, with higher scores indicating more severe motor 
impairment. If 7 or more item scores are missing for a given assessment, the TMS will not 
be calculated. If 6 or fewer item scores are missing, the last non missing score for any 
missing item will be used in calculating the TMS. 
The gait sub-score of the UHDRS questionnaire measures the severity of gait disturb-
ances in individuals with Huntington's disease and it is made from 3 items: gait, tandem 
walking and retropulsion pull test. To obtain the gait sub-score all 3 items need to be 


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summed up. The gait sub-score ranges from 0 to 12, with higher scores indicating greater 
impairment. 
The dystonia sub-score of the UHDRS questionnaire is used to evaluate the severity of 
dystonia in individuals with Huntington's disease and it consists of four items: trunk (in-
voluntary movements of the trunk), right upper extremity (involuntary movements of the 
right arm and hand), left upper extremity (involuntary movements of the left arm and 
hand), right lower extremities (involuntary movements of the right leg and feet), left lower 
extremities (involuntary movements of the left leg and feet). The severity of dystonia is 
rated on a scale of 0 to 4 for each item, where 0 represents no dystonia and 4 represents 
severe dystonia. The scores for each item are summed to obtain the dystonia sub-score, 
which ranges from 0 to 20. 
The analysis of the Total Motor Score (TMS) endpoint, sub-scores of gait and sub-
scores of dystonia will be similar to the analysis of the primary endpoint.  
Descriptive statistics for each score by visit will be presented. 
The analysis of those endpoints will be based on a mixed-effect linear model for repeated 
measures (MMRM) to compare each active treatment group to placebo. The model will 
include the following factors: treatment group, visit, and treatment by-visit interaction as 
fixed effects, and baseline TMS score/ sub-scores of gait/ sub-scores of dystonia as co-
variate, depending what is analysed. An un-structured (US) variance-covariance matrix 
will be used to model the within-patient errors. If no reliable results under the US assump-
tion can be obtained, the Toeplitz (TP) covariance structure, followed by the autoregres-
sive (AR1) and Compound Symmetry (CS) covariance structure will be used. The Ken-
ward-Roger method will be used to estimate the denominator degree of freedom. 
The least squares mean (LSM) estimate for each treatment group and difference in LSM 
estimates at end of maintenance dose between active treatments and placebo group with 
their 95% confidence intervals will be provided. 
 
For TMS, this analysis will be repeated on the PP population. 
 
 
 4.7.2.6 EQ-5D-5L measuring quality of life  
EQ-5D is a standardised instrument for use as a measure of health outcome. The EQ-5D 
measure is designed in two parts: one descriptive part (EQ-5D) containing five dimensions 
of health; mobility, self-care, usual activities, pain/discomfort and anxiety/depression (5 
categories, each) and a visual analogue scale (EQ-5D VAS) ranging from ‘Best imaginable 
health state’=100 to ‘Worst imaginable health state’=0.  
The EQ5D is rated at the inclusion (Visit 1 at Day 0) and at the end of maintenance dose 
(Visit 5 at end of Week 10). 
The EQ5D ratings at baseline will be compared to those after the treatment by presenting 
descriptive statistics for the entire questionnaire and for the difference between V1 and V5 
and also for the VAS.  
EQ5D dimensions  and VAS will be analysed using an analysis of covariance (ANCOVA) 
model including treatment as fixed factor and baseline score as covariate. Results for the 


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outcome of the primary endpoint will be presented for the least square means estimates 
and accompanying 95% CIs. 
 
4.8 Pharmacokinetics (PK) 
For plasma concentration of SOM3355 and Prolactin plasma concentration measured in all 
patients at each visit from Visit 1 to Visit 6 (before dosing at each visit and 2 hours after dosing at 
Visit 2 and Visit 4), analysis will be described in a separate Statistical Analysis Plan and results 
will be reported in a separate report. 
PK analysis for the PK sub-study conducted in a sub-set of 24 patients (8/per arm) with 
12-hours PK samples performed at Visit 2 (H0 before dosing, H0.5, H1, H1.5, H2, H3, 
H5, H8, H12) analysis will be described in a separate Statistical Analysis Plan and results 
will be reported separately. 
 
4.9 PK-PD assessments 
PK-PD analysis is described in a separate Statistical Analysis Plan and results will be re-
ported separately. 
 
4.10 Safety 
The Safety Analysis Set (SAF) will be used for the analysis of safety data. SAF includes 
all patients who were administered at least one dose of any study drug. Patients who are 
randomized and assigned a treatment but withdrew prior to dosing are not included in the 
safety population. Patients are included in the treatment group based on the treatment ac-
tually received. 
Safety endpoints include: 
• Incidence, frequency, and severity of AEs in each treatment group. 
• Values and change from baseline in: 
o Vital signs: blood pressure (BP) (including orthostatic measurement), and heart 
rate (HR), weight.  
o ECGs parameters (separately analysed by Banook/Phinc Development) 
o Clinical laboratory test results (chemistry, hematology) 
o Physical examination findings,  
o Concomitant medications 
o C-SSRS assessing suicidality 
o BDI scale assessing depression and suicidality (item #9) 
o ESS assessing sleepiness 
o TFC of the UHDRS® assessing functioning 


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o FA of the UHDRS® assessing disabilities 
o BARS assessing akathisia 
o MoCA scale to assess cognitive disturbances 
o PBA-s to assess behavioural symptoms in HD. 
Tolerability and safety data will be listed by patient (CSR section 16.2) and summarized 
descriptively by treatment group. Also, differences to Baseline will be presented whenever 
appropriate. 
 
4.10.1 Adverse events 
Adverse events (AEs) will be presented by MedDRA System Organ Class (SOC) and Pri-
mary Term (PT). Coding of verbatim terms will be performed by Ergomed and all relevant 
codes are stored in the database and it will be approved by the Sponsor before database 
lock (cf. DMP).   
Only treatment-emergent adverse events (TEAE) will be analysed, i.e. all new and wors-
ened pre-existing adverse events occurring on or after the initiation of IMP. It is assumed 
that for each change in intensity, relationship, or seriousness of an AE a new entry of the 
AE was recorded in the data capture database; hence such cases will be analysed like dif-
ferent phases of the same AE. 
An overall summary of TEAEs will be presented including both the number and percent-
age of patients with a given AE category and the number of events: 
• All TEAEs 
• Serious TEAEs (STEAEs) 
• Treatment-related TEAEs 
• Treatment-related Serious TEAEs 
• Severe TEAEs 
• TEAEs leading to study drug discontinuation 
• Fatal TEAEs  
A descriptive analysis will be performed. Global incidences of primary system organ clas-
ses (SOC) and preferred terms (PT) will be calculated for: 
• All TEAEs irrespective of the causality assessment 
• Serious TEAEs (STEAEs) 
• TEAEs by relationship  
• STEAEs related to study drug 
• TEAEs by maximum severity 
• TEAEs leading to discontinuation 
• Fatal TEAEs 


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These tables will be presented by treatment group and also include summary lines for all 
SOCs and the occurrence of any event of the specified type. SOC terms will be presented 
according to the Internationally Agreed Sorting Order (MedDRA).  
Multiple counts within a PT or SOC (repeated or different included terms or changes in 
descriptors) will be counted only once for the calculation of incidences. In addition to the 
incidences, the number of reported AEs (within a PT or SOC) will be included in the 
summaries. 
Detailed listings of all fatal and other serious events will be provided (for section 14.3.2). 
All adverse events (i.e. TEAEs as well as non-treatment emergent events) will be listed in 
section 16.2. 
 
4.10.2 Vital signs 
The following vital signs parameters will be assessed at each of the visits (from Visit 0 to 
Visit 6) as per schedule of assessment (except height only at Visit 0).  
• Systolic blood pressure (SBP) 
• Diastolic blood pressure (DBP) 
• Heart rate 
• Body weight 
Four sequential measures of Blood Pressure should be performed as follows: sitting posi-
tion for at least 5 minutes, supine position at least 5 minutes, standing position for 1 minute 
and 3 minutes. Orthostatic BP is calculated as change from supine to standing position 
after 1 and 3 minutes. 
The following summaries will be provided: 
• A summary of the observed absolute values and change from baseline in each vital 
sign parameter by treatment group and time point separately for sitting, supine, 1 min 
standing and 3 min standing 
• A time profiles of the mean values for each vital sign parameter by treatment group 
separately for sitting, supine, 1 min standing and 3 min standing with SEM 
A summary of the incidence of drop in SBP of ≥ 20 mmHg or drop in DBP of ≥ 10mm 
Hg will be presented, where drop in BP is calculated as orthostatic BP. 
 
4.10.3 ECG  
All ECGs will be performed after at least 5 minutes’ rest in a supine or semi-supine posi-
tion. To assess safety 12-lead ECGs will be recorded at Screening visit (Visit 0), inclusion 
visit (Visit 1), Visit 2, Visit 3 (in some countries Spain, UK & Germany), Visit 4, and 
Visit 6. At the inclusion, the ECG will be triplicated i.e., 3 successive records at 5 minutes 
of intervals and the average of all parameters will be calculated for baseline reference. All 
ECG are tele transmitted to a central reading centre (Banook) and analyzed within 48 
hours by a cardiologist.  


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ECG analysis is described in a separate Statistical Analysis Plan and results will be re-
ported separately. 
 
4.10.4 Laboratory variables 
The following laboratory measurements will be taken at the Visit 0 (screening visit), at 
Visit 3 (interim visit at the end of Week 6), and at Visit 5 (end of maintenance dose at end 
of Week 10).  
 
Hematology 
Red blood cell count 
Hematocrit  
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular volume  
Platelet count 
Reticulocytes 
White blood cell count with differ-
ential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Clinical  chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Albumin 
C-reactive protein 
Calcium 
Total Protein 
Creatine kinase (CPK) 
Phosphate 
Bicarbonate 
Creatinine 
Chloride 
Bilirubin, direct and total 
Urea 
Potassium 
Gamma glutamyl transpeptidase 
Glucose 
Sodium 
Other 
Pregnancy test in women of childbearing potential 
Continuous laboratory data: 
• Continuous data laboratory safety data (original values and change from baseline) 
will be summarized using descriptive statistics per visit and treatment group. 
• Frequencies of high and low values with respect to the normal range will be dis-
played by visit and treatment group 
• Shift tables comparing each post-baseline visit with baseline with respect to nor-
mal range will be displayed by treatment group 
• In addition, abnormal values outside reference ranges (with assessment by inves-
tigator, NCS/CS) will be summarized in a listing per visit and per patient. 
Vertical boxplot of laboratory values per parameter and per visit with outliers will be pre-
sented. 
The lab values may be transformed to common units before analysis and summaries and 
analyses will only be performed on values converted to common units. However, original 
values and units can be found in laboratory listings. If repeated determinations at the same 


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sampling times were performed (e.g., due to sample clotting) the values of the latest sam-
ple will be used in the analysis. However, all measurements will be included in laboratory 
listings. 
The incidence of abnormal values out of ranges will be summarized for laboratory tests 
using descriptive statistics. These summaries will include all post baseline values (includ-
ing scheduled, unscheduled, and early termination visits). Listing with outliers greater or 
lower than upper normal range will be presented. 
 
4.10.5 Physical examination 
Physical examination will be performed at each visit. Results of physical examination will 
be listed by patient and summarised in a frequency table displaying the absolute and rela-
tive frequency for normal/abnormal findings for each body system by treatment group and 
visit.  
 
4.10.6 Concomitant Medications  
Concomitant medications, including medications that are taken on an as needed basis and 
occasional therapies, will be monitored during the study. All concomitant medications will 
be coded using the WHO drug Global thesaurus. 
The incidence of concomitant medications will be summarized using descriptive statistics 
by WHO Drug Global Preferred Term (INN). Patients are counted only once in each PT 
category. In addition to the incidences, the number of reported CMs (within PT) will be 
included in the summaries. Concomitant medications will include all medications taken 
from the first day of study drug administration up to the end of study as defined in the 
study protocol. 
 
4.10.7 C-SSRS assessing suicidality 
The C-SSRS is a questionnaire performed by trained study personnel that should be done 
at baseline and at each visit during the study to assess the status of the patient regarding 
suicide ideation and the risk of suicide attempt. The “Baseline/Screening” C-SSRS form 
provided at Screening collects the history of suicide attempts, while for subsequent visits 
the C-SSRS form termed “Since the Last Visit” should be used. 
C-SSRS will be assessed at each visit.  
The Columbia-Suicide Severity Rating Scale Screening/Baseline Version (C-SSRS-BL) 
is assessed at Visit 0 and Visit 1. The Columbia-Suicide Severity Rating Scale Since Last 
Visit (C-SSRS-SLV) is assessed at each visit after randomisation (Visit 2, Visit 3, Visit 4, 
Visit 5 and Visit 6). 
Frequency counts and percentages of the C-SSRS outcomes: Suicidal Behavior or Suicidal 
Ideation at Baseline, Suicidal Behavior or Suicidal Ideation Post Dosing, and shifts from 
baseline will be summarized as categorical data using descriptive statistics. 
 


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4.10.8 BDI scale assessing depression 
BDI is 21-question multiple-choice self-report inventory. The questionnaire is composed 
of items relating to symptoms of depression such as hopelessness and irritability, cogni-
tions such as guilt or feelings of being punished, as well as physical symptoms such as 
fatigue, weight loss, and lack of interest in sex. 
Each item has four possible degree of severity rated from 0 to 3, and the patient is asked 
to choose the one that is closest to how he/she feels. The 21 items are summed linearly to 
create a score which ranges from 0 to 63. It can be administered as an interview by the 
clinician or as a self-report instrument. 
The item #9 assessing suicidality includes the following: 
0. “I don't have any thoughts of killing myself.” 
1. “I have thoughts of killing myself, but I would not carry them out.” 
2. “I would like to kill myself.” 
3. “I would kill myself if I had the chance.” 
The Total Score shows the severity of depression as following:  
0 to 9: No depression or minimal depression 
10 to 18: Mild to moderate depression 
19 to 29: Moderate to severe depression 
30 to 63: Severe depression 
BDI will be assessed at each visit from V0 to V6. 
Descriptive statistics for BDI total score as well as changes to baseline and 95 % confi-
dence intervals will be presented at each visit. In addition, time profiles of the mean values 
with SEM will be created. 
For BDI item #9 frequency table and shift table to baseline will be presented. 
 
4.10.9 ESS assessing sleepiness 
The ESS is a self-administered questionnaire comprised of eight questions that provides a 
measure of a patient’s general level of daytime sleepiness. The ESS asks respondents to 
rate, on a 4-point Likert scale (0 – 3), their usual chances of dozing off or falling asleep in 
different situations or activities that most people engage in as part of their daily lives. The 
total ESS score is the sum of 8 item scores and can range between 0 and 24 with a higher 
score indicating a higher level of daytime sleepiness.  
ESS will be assessed at each visit. 
Descriptive statistics for the ESS as well as changes to baseline and 95% confidence in-
tervals will be presented at each visit. In addition, time profiles of the mean values with 
SEM will be created. 
 


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4.10.10 
TFC of the UHDRS® assessing functioning 
The UHDRS®-TFC scale is a tool used by clinicians to assess the stage of HD and the 
level of functional capacity in patients on five items: patients' ability to work, manage 
finances, run a house, take care of themselves, and live at home independently. The TFC 
score ranges from 0 (worse) to 13. 
TFC will be assessed at screening (Visit 0), at the inclusion (Visit 1), and at the end of 
maintenance dose (Visit 5 at end of Week 10). 
Descriptive statistics for TFC as well as changes to baseline and 95% confidence intervals 
will be presented at each visit. In addition, time profiles of the mean values with SEM will 
be created. 
 
4.10.11 
Functional Assessment of the UHDRS® 
The UHDRS®-FA scale includes 25 yes/no questions about common daily tasks (total 
range 0 – 25).  
FA will be assessed at screening and at the end of the maintenance dose (Visit 5 at end of 
Week 10). 
Descriptive statistics for the FA as well as changes to baseline and 95% confidence inter-
vals will be presented at each visit. In addition,  time profiles of the mean values with 
SEM will be created. 
 
4.10.12 
BARS assessing akathisia 
The BARS is administered by healthcare providers to assess the severity of drug-induced 
akathisia and is scored as follows: Objective Akathisia, Subjective Awareness of Restless-
ness and Subjective Distress Related to Restlessness are rated on a 4-point scale from 0 – 
3 and are summed yielding a total score ranging from 0 to 9. Then Global Clinical Assess-
ment of Akathisia uses a 5-point scale ranging from 0 – 4. 
BARS will be assessed at inclusion and at end of the maintenance dose (Visit 5 at end of 
Week 10). 
Descriptive statistics for the BARS as well as changes to baseline and 95% confidence 
intervals will be presented at each visit. In addition, time profiles of the mean values with 
SEM will be created. 
 
4.10.13 
MoCA scale to assess cognitive disturbances 
The MoCA scale is a brief screening instrument recommended for the detection of mild 
cognitive impairment that is sensitive to executive dysfunction in a variety of neurological 
conditions. When used in HD, it was more sensitive to detect mild to moderate cognitive 
impairment.  
The items of the MoCA examine attention and concentration, executive functions, 
memory, language, visuo-constructional skills, conceptual thinking, calculations, and ori-
entation. The attention/executive function items include Trail Making Test B, digit span, 
target detection, verbal fluency, abstraction, and serial seven subtraction. The visuospatial 
items include clock drawing and cube copying. The language items include object naming 


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and sentence repetition. The memory items include recall of five previously presented 
words. The orientation items include six orientation-based questions.  
MoCA scores range between 0 and 30. 
MoCA will be assessed at inclusion and at end of the maintenance dose (Visit 5 at end of 
Week 10). 
Descriptive statistics for the MoCA as well as changes to baseline and 95% confidence 
intervals will be presented at each visit. In addition, time profiles of the mean values with 
SEM will be created. 
 
4.10.14 
PBA-s to assess behavioral symptoms in HD 
The PBA short form is the recommended outcome measure for behavioral symptoms in 
HD. It is a semi-structured interview containing 11 items, each designed to measure the 
severity and frequency of behavioral neuropsychiatric symptoms that are frequent in HD: 
depression, suicidal ideation, anxiety, irritability, aggressive behavior, apathy, obsessive-
compulsive symptoms, perseverative thinking, paranoid thinking, hallucinations, and dis-
orientation.  
Severity and frequency during the previous 4 weeks are rated separately for each symptom 
on a 5 point (0–4) scale. Severity and frequency ratings are multiplied to provide an overall 
score for each symptom.  
Worst severity rating will be only listed. 
PBA-s will be assessed at inclusion, at the interim visit (Visit 3 at the end of Week 6), and 
at the end of the maintenance dose (Visit 5 at the end of Week 10). 
Descriptive statistics for the PBA-s as well as changes to baseline and 95% confidence 
intervals will be presented at each visit. 
 
4.11 Other variables 
Not applicable.  
 
4.12 Interim analyses 
An unblinded interim analysis for futility (non-binding) will take place when at least half 
of the total number of planned patients (N = 65) have completed the study or discontinued 
early. The analysis will be prepared by a separate team that will communicate the results 
only to designated recipients, e.g., the Steering Committee, to protect the study blind. The 
primary criterion to assess the futility of the study will be the probability of rejecting the 
null hypothesis conditional on the accumulated data and the planned sample size. In line 
with the chosen Holm-Bonferroni multiplicity adjustment, the decision will focus on that 
hypothesis that yielded the smallest p-value in the interim analysis of the TMC change. A 
non-binding stop for futility will be recommended if the conditional probability is less 
than 0.25. Otherwise, the study shall be continued without modification unless otherwise 
recommended by the SC. 


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If a decision is made to stop the trial, then a complete, final analysis will be performed 
including those patients that were enrolled into the study in the meantime. 
The analyses will be performed using the SAS® software (Version 9.4 or later).  The 
method and SAS code will be the same as for primary endpoint described in Section 4.6.1 
and Appendix 2. 
An unblinded statistician/programmer will perform the unblinded futility analysis. The 
generated documents will be stored on in a separate file area on the file server with re-
stricted access only to the unblinded person(s).  
 
5 QUALITY CONTROL 
The SAP was reviewed by the Trial Statistician (TS) before signature. Particularly the TS 
has checked the consistency of the described methods and outputs with the actual version 
of the study protocol. In addition, a sponsor representative has reviewed the SAP before 
final approval. 
Log files of all SAS® programs used in the analysis will be checked for errors, warnings 
and suspicious notes by the statistical programmer. All findings will be either eliminated 
or commented upon. The final version of each program will be stored along with its log 
file in the electronic archive.  
All programs will be validated by the program author or an independent statistical pro-
grammer depending on the requested validation level selected in the List of TLFs form 
(FRM/BS/001.02) for a particular program.  
The agreement of the program outputs with the SAP, their consistency and plausibility 
will be checked by the TS. Moreover, the TS will review the outputs regarding complete-
ness, readability and comprehensibility. 
The described process is associated with the 'normal' level of program validation. Addi-
tional levels of quality control can be specified in the List of TLFs (see Appendix, 1) for 
individual outputs. 
 
6 DERIVATIONS AND TRANSFORMATIONS 
6.1 Formulas for derived variables 
 
Variable 
Definition / Derivation 
BMI 
Weight [kg] / (height [m])**2 
Year of birth 
Year of inform consent - Age 
Age at HD diagnosis  
Year of HD diagnosis - Year of Birth 
 
Age at first symptoms 
Year of first symptoms - Year of Birth 
 
Compliance 
(Capsules dispensed - capsules returned) / expected number of 
capsules to be used 
CGI-C improvement 
Patients with a score of 1 (very much improved), 2 (much im-
proved) or 3 (minimally improved) 


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Variable 
Definition / Derivation 
TMC improvement  
change of score between the baseline and the end of mainte-
nance dose is ≥ - 2 
PGI-C improvement 
patients with a score of 1 (very much improved), 2 (much im-
proved) or 3 (minimally improved) 
 
 
6.2 Transformations to be applied 
Not applicable. 
 
 
7 REFERENCES 
Not applicable. 
 
 
 


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8 STANDARDS USED IN PREPARATION OF STATISTICAL OUTPUTS 
The below conventions will be followed as agreed with the Sponsor. 
 
8.1 Programming 
• One SAS program should create only one output. 
• One output file can contain different output types (e.g. descriptive and inferential).  
• Individual output files will be created in MS Word format (Rich Text Format, 
RTF). 
• Once delivered to the client, numbering of TLFs will not be altered, unless agreed 
with the client 
 
8.2 Layout 
• TLFs will be produced in landscape format 
• TLFs will have a minimum 2 cm on every side 
• TLFs will be produced using the Courier New font, size 8  
• Section numbering of TLFs will follow ICH E3 guideline. 
• Numbering of TLFs will follow the convention XXX-YY, where XXX stands for 
a (sub-)section number of the ICH E3 guideline and YY represents the sequence 
number of the output within the section. A dash (‘-‘) will always be used to sepa-
rate section numbers from output sequence numbers 
• Titles and footnotes for figures will also be in Courier New font, size 8. 
• Tables and listings will be in black and white (no colour), figures may include only 
colour that can be distinguished when printed on a grey-scale printer  
• Text styles, such as bolding, italics, borders, shading, and superscripted and sub-
scripted text, will be used sparingly in the TLFs 
• The ANSI character set will be used in the TLFs. Certain subscripts and super-
scripts (e.g., m², AUCnorm) will be employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, unless they are derived directly from the data 
 
8.3 Headers, Titles and Footnotes 
• All output will have the following header at the top left of each page showing the 
study ID, the date of output generation and an internal pagination, where Y stands 
for the total number of pages in the pertaining output. 
 
Study ID 
Study description 
ERGOMED, YYYY-MM-DD 
Page [ X / Y ] 


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• Also, all TLFs will have the following footer, identifying the generating SAS pro-
gram (XXX.SAS), a reference to the relevant subject listing and the date of the 
data snapshot: 
 
SAS program: <XXX>.sas 
Ref. list X.X.X-YY 
Data status: YYYY-MM-DD 
 
• Each TLF will bear a title which is repeated on each page of the output. 
• The title at the top of the page will be horizontally cantered in bold font. 
• A blank line will separate the title from the body of the output. 
• The title will consist of an Output number, a descriptive title and a description of 
the presented analysis set (if applicable).  
• The title will have the following general appearance: 
Table / Figure / List XX.X.X-YY 
Descriptive Title line 1 
Descriptive Title line 2 
 (All subjects in the FAS, N=nnn) 
 
• Each new footnote should start on a new line, where possible. 
• Preferably, footnotes should be left justified. When extending beyond a single line, 
a manual linefeed should be inserted to avoid meaning distortion. 
• An automatic footnote ‘(continued)’ will appear at the bottom of TLFs that extend 
over more than one page. 
 
8.4 General Conventions 
• For measured variables column headers should include the unit in their description 
• The order of treatment arms in the TLFs will be consistent throughout the entire 
TLF presentation 
• Alphanumeric values are preferably displayed left-justified; 
• Dates are presented left-justified 
• Integer numbers (e.g., counts) can be centered or right-aligned 
• Numbers containing fractional portions will be decimal-aligned. 
• Fractional numbers with absolute value less than 1 will carry a leading zero, i.e. 
0.123 not .123. 
• Units of measured or derived variables will be included where appropriate 
• Unless otherwise warranted, the estimated mean, median and quartiles for a set of 
values will be displayed with 1 more significant digit than the original values, and 
standard deviations with 2 more significant digits. The minimum and maximum 
should report the same significant digits as the original values.  


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• P-values are output in the format: “0.xxxx”, where xxxx is the value rounded to 4 
decimal places. P-values less than 0.0001 will be presented as <0.0001. 
• Precision of percentages displayed will depend on the total study size. For studies 
with less than 1000 patients values will be presented with one decimal place. For 
studies with more than 1000 patients, values will be presented with two decimal 
places.  
• Tabular display of data for medical history, prior/concomitant medications and all 
tabular displays of adverse event data are generally presented by body system, 
treatment class, or SOC according to the Internationally Agreed Sorting Order of 
the MedDRA, unless otherwise agreed. 
• The percentage of patients is normally calculated as a proportion of the number of 
patients assessed in the relevant treatment group (or overall) for the analysis (sub-) 
population presented.  
• For categorical summaries (number and percentage of patients) where a patient can 
be included in more than one category, an explanatory text will be added to clarify 
that multiple answers were possible. 
• Missing values will be displayed either by a double-dash (“--”) or as “NA” (=’not 
available/applicable’), whichever is appropriate. 
• Dates are displayed in according to ISO date/time format as YYYY-MM-DD, e.g. 
2010 03 24. Missing dates may be represented as “NA”, if not available/applicable. 
• Clock times are displayed as HH:MM or HH:MM:SS based on 24-hour clock 
 
 
 


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APPENDICES 
1. List of Tables, Listings, Figures 
A complete List of tables, listings, figures (TLFs) will be given in a separate document 
which can be updated without updating the SAP. The List will serve as a reference for 
both the Sponsor, the TS and the SP and describes the entire set of statistical output to be 
produced. Therefore, this List will be versioned and approved by both Ergomed and Spon-
sor before commencing the statistical programming. 
Each output page will have an appropriate heading specifying the study ID and abbreviated 
study title. 
Each output page will show a common date and page numbers in the form 'Page [x / y]' 
where x denotes the current page within an output and y the total number of pages of that 
output. The output pages will not contain any other sequential page numbering. 
All statistical output will identify the underlying analysis set(s) and indicate the number 
of patients/events in this set (N) and the number of patients/events actually contributing to 
the particular output (n). 
All patient listings will contain in addition to the patient identification the analysis popu-
lation.