Effects of N-Acetyl-L-Leucine on Ataxia-Telangiectasia (A-T): A Multinational, Multicenter, Open-label, Rater-blinded Phase II Study
Phase: PHASE2
Conditions: Ataxia Telangiectasia
Sponsor: IntraBio Inc

 
 
 
 
Effects of N-Acetyl-L-Leucine on Ataxia-Telangiectasia (A-T):  
A multinational, multicenter, open-label, rater-blinded Phase II study 
 
 
 
 
NCT Number: NCT03759678 
 
 
Version and date of Protocol: Final Global Version 7.0, 05-Oct-2023 
 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
CONFIDENTIAL 
 
Page 3 of 155 
Global Version 7.0 05-Oct-2023 
Principal Investigator Agreement 
I, _______________________________________________, (Investigator’s Name) have read 
this protocol and agree that it contains all necessary details for carrying out this trial. I will 
conduct the trial as outlined herein and will complete the trial within the time designated. 
 
The information contained in this protocol is provided to me in confidence, for review only by 
myself, the ethics committee authorized to review and approve the trial at this trial site, and 
designated trial staff participating in this clinical study.  
 
I agree to the conditions as set out in this protocol and fully accept that any change requires 
prior approval by the trial Sponsor. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible 
to me who assist in the conduct of this trial. I will discuss this material with them to ensure 
they are fully informed regarding the investigational medicinal product (IMP), N-Acetyl-L-
Leucine, and the conduct of the trial. 
 
I will use only the informed consent form approved by the Sponsor or its representative and 
will fulfil all responsibilities for submitting pertinent information to the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) responsible for this trial. 
 
I agree to carry out all terms of this protocol in accordance with the ICH GCP (Good Clinical 
Practice) Guidelines, the Declaration of Helsinki and local regulations. I will ensure that the 
Investigational Medicinal Product is used only as described in the protocol or any subsequent 
amendment. 
 
I understand that the information/technology contained in this protocol is proprietary and may 
not be disclosed to any other party, in any form, without prior authorisation from the trial 
Sponsor except to the extent necessary to obtain informed consent from potential trial patients.  
 
_________________________________________  
__________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
_________________________________________ 
Clinical Trial Site Name 
 
 
 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
CONFIDENTIAL 
 
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Global Version 7.0 05-Oct-2023 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Protocol Version 
Date 
Global Amendment 4 
Global Version 7.0 
05-Oct-2023 
Spain Amendment 2 
Spain Version 6.1 
03-Mar-2021 
Global Amendment 4.0 
Global Version 6.0 
06-Oct-2020 
Spain Amendment 1 
Spain Version 5.1 
02-Sep-2020 
Global Amendment 3 
Global Version 5.0 
30-Dec-2019 
UK Amendment 2 
UK Version 4.1 
07-Oct-2019 
Global Amendment 2 
Global Version 4.0 
25-Jul-2019 
Global Amendment 1 
Global Version 3.0 
09-Jul-2019 
UK Amendment 1 
UK Version 2.1 
12-Jun-2019 
US Amendment 1  
Global Version 2.0 
08-Feb-2019 
Global Protocol  
Protocol Version 1.0 
21-Dec-2018 
The Protocol Amendment Summary of Changes is located in the supplementary document, “IB1001-203 
Protocol Summary of Changes Version 2.0 05Oct2023 
 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
CONFIDENTIAL 
 
Page 5 of 155 
Global Version 7.0 05-Oct-2023 
PROTOCOL SYNOPSIS 
Included as Appendix 1.  

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
CONFIDENTIAL 
 
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TABLE OF CONTENTS 
Protocol Amendment Summary of Changes Table .................................................... 4 
PROTOCOL SYNOPSIS .................................................................................................. 5 
TABLE OF CONTENTS .................................................................................................. 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 12 
1 
INTRODUCTION ............................................................................................... 15 
1.1 
Risk/Benefit Considerations ........................................................................... 16 
1.2 
COVID-19 ........................................................................................................ 19 
2 
STUDY OBJECTIVES ........................................................................................ 21 
2.1 
Primary Objective ........................................................................................... 21 
2.2 
Secondary Objective(s) ................................................................................... 21 
2.3 
Exploratory Objective .................................................................................... 21 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 22 
3.1 
Overview .......................................................................................................... 22 
3.1.1 
Trial Design/Patient Population ........................................................... 22 
3.1.2 
Study Design ........................................................................................ 22 
3.1.2.1 
Baseline Period ............................................................................. 22 
3.1.2.2 
Treatment Period ........................................................................... 24 
3.1.2.3 
Washout Period ............................................................................. 24 
3.1.2.4 
Extension Phase ............................................................................ 24 
3.1.2.5 
COVID-19 Modifications to the Original Study Schema ............ 24 
3.1.2.6 
Interim Analyses ........................................................................... 26 
3.1.3 
Target Number of Patients ................................................................... 26 
3.1.4 
Number of Centers ............................................................................... 27 
3.1.5 
Study Duration ..................................................................................... 27 
3.2 
Discussion of Study Design ............................................................................. 27 
3.2.1 
Study Design ........................................................................................ 27 
3.2.2 
Development of the Primary Endpoint: Clinical Impression of Change 
in Severity (CI-CS) .............................................................................. 28 
3.2.2.1 
Anchor Tests: 9-hole Peg Test Dominant Hand (9HPT-D) or 8-
meter Walk Test (8MWT) ............................................................... 29 
3.2.2.2 
Blinded Raters & Video Assessments ............................................ 29 
3.2.2.3 
Serial Endpoint Evaluation ............................................................ 30 
3.2.3 
Separate Trial Protocols by Indication ................................................. 30 
3.3 
End of Study Definition .................................................................................. 30 
4 
STUDY POPULATION ...................................................................................... 32 
4.1 
Inclusion Criteria ............................................................................................ 32 
4.2 
Exclusion Criteria ........................................................................................... 34 
4.3 
Patient Withdrawal ......................................................................................... 35 
4.4 
Patient Identification ...................................................................................... 36 
5 
STUDY DRUG ..................................................................................................... 37 
5.1 
Identity ............................................................................................................. 37 
5.2 
Administration ................................................................................................. 38 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
CONFIDENTIAL 
 
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5.3 
Modification of Dose Schedule ....................................................................... 38 
5.4 
Packaging, Labeling and Storage .................................................................. 39 
5.5 
Granules for Oral Suspension Sachet – Parent Study ................................. 39 
5.6 
Blinding and Breaking the Blind ................................................................... 39 
5.7 
Drug Accountability ........................................................................................ 39 
5.8 
Investigational Medicinal Product (IMP; ‘study drug’) Compliance ........ 40 
5.9 
Concomitant Medications and Therapies ..................................................... 40 
5.10 
Treatment of Overdose ................................................................................... 41 
6 
PARAMETERS AND METHODS OF ASSESSMENT .................................. 42 
6.1 
Efficacy Parameters ........................................................................................ 42 
6.1.1 
Measurement of Clinical Impression of Change in Severity ............... 42 
6.1.1.1 
Secondary Efficacy Endpoints That Directly Supplement the 
Analysis of the Primary Endpoint .................................................. 42 
6.1.2 
Measurement of Ataxia and Functioning ............................................. 43 
6.1.2.1 
Spinocerebellar Ataxia Functional Index (SCAFI) ........................ 43 
6.1.2.2 
Scale for the Assessment and Rating of Ataxia (SARA) ................. 43 
6.1.3 
Measurement of Health-related Quality of Life ................................... 44 
6.1.4 
Measurement of Global Impression ..................................................... 44 
6.1.5 
Remote Assessments ............................................................................ 45 
6.2 
Safety Parameters ........................................................................................... 45 
6.2.1 
Adverse Events .................................................................................... 45 
6.2.1.1 
Adverse Event Intensity ................................................................ 47 
6.2.1.2 
Adverse Event Relatedness ........................................................... 47 
6.2.2 
Serious Adverse Events ....................................................................... 47 
6.2.2.1 
Reporting Serious Adverse Events ............................................... 48 
6.2.2.2 
Responsibilities of the Sponsor ..................................................... 49 
6.2.3 
Pregnancy ............................................................................................. 49 
6.2.4 
Vital Signs ............................................................................................ 49 
6.2.5 
Electrocardiograms (ECGs) ................................................................. 50 
6.2.6 
Physical Examinations ......................................................................... 50 
6.2.7 
Suicide Ideation ................................................................................... 51 
6.2.8 
Additional Safety Assessments ............................................................ 51 
6.3 
Laboratory Parameters .................................................................................... 51 
6.3.1 
Safety Laboratory Assessments ........................................................... 51 
6.3.2 
Measurement of N-Acetyl-L-Leucine Concentration in Blood ........... 53 
6.3.3 
Measurement of N-Acetyl-D-Leucine Concentrations in Urine .......... 53 
6.3.4 
Additional Laboratory Samples for Research Purposes ...................... 53 
6.3.5 
Sample Processing ............................................................................... 53 
7 
STUDY CONDUCT ............................................................................................. 54 
7.1 
Observations by Visit ...................................................................................... 54 
7.1.1 
Screening (Visit 0 or Visit 1) ............................................................... 54 
7.1.1.1 
“Naïve” Patients Screening ........................................................... 54 
7.1.1.2 
“Non-naïve” Patients: Baseline Period ........................................ 55 
7.1.2 
Baseline Visit (Visit 2) ......................................................................... 57 
7.1.3 
Treatment 1 (Visit 3) ............................................................................ 57 
7.1.4 
Treatment 2 (Visit 4) ............................................................................ 58 
7.1.5 
Washout 1 (Visit 5) .............................................................................. 58 
7.1.6 
Washout Visit 2 (Visit 6) ..................................................................... 59 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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7.1.7 
Early Termination Visit ....................................................................... 60 
8 
STATISTICAL METHODS ............................................................................... 61 
8.1 
General Analysis Plan ..................................................................................... 61 
8.1.1 
Disposition of Patients ......................................................................... 61 
8.1.2 
Analysis Populations ............................................................................ 61 
8.2 
General Considerations .................................................................................. 61 
8.3 
Demographics, Baseline Characteristics and Concomitant Medications .. 61 
8.4 
Treatment Compliance ................................................................................... 62 
8.5 
Efficacy Analyses ............................................................................................. 62 
8.5.1 
Primary Efficacy Endpoint .................................................................. 62 
8.5.2 
Secondary Efficacy Endpoints ............................................................. 63 
8.5.3 
Exploratory Efficacy Endpoints ........................................................... 65 
8.6 
Missing Data .................................................................................................... 65 
8.7 
Blinding ............................................................................................................ 66 
8.8 
Safety Analyses ................................................................................................ 66 
8.9 
Interim Analyses .............................................................................................. 66 
8.10 
Determination of Sample Size ........................................................................ 66 
8.11 
COVID-19 Details ........................................................................................... 66 
9 
DATA HANDLING AND RECORD KEEPING .............................................. 68 
9.1 
Data Collection ................................................................................................ 68 
9.2 
Data Correction ............................................................................................... 68 
9.2.1 
Deviations from the Protocol ............................................................... 68 
9.3 
Data Quality Assurance .................................................................................. 68 
9.3.1 
Retention of Records ............................................................................ 68 
9.4 
Protection of personal data ............................................................................ 68 
9.5 
COVID-19 Protocol Deviations and Missing Data ....................................... 69 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 70 
10.1 
Study Initiation Activities ............................................................................... 70 
10.2 
Training of Site Staff ....................................................................................... 70 
10.3 
Documentation and Filing .............................................................................. 70 
10.3.1 
List of Patients (patient identification log) .......................................... 70 
10.3.2 
Source Data .......................................................................................... 70 
10.3.3 
Investigator Site File / Regulatory Binder ........................................... 70 
10.4 
Alternative Site due to COVID-19 ................................................................. 71 
10.5 
Monitoring ....................................................................................................... 71 
10.6 
Audits and Inspections .................................................................................... 71 
11 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................... 73 
11.1 
Good Clinical Practice .................................................................................... 73 
11.2 
Informed Consent ............................................................................................ 73 
11.3 
Protocol Approval and Amendment .............................................................. 74 
11.4 
Archiving Study Records ................................................................................ 74 
11.5 
Data Safety Monitoring Board ....................................................................... 75 
11.6 
Premature Termination of the Study ............................................................ 75 
11.7 
Confidentiality ................................................................................................. 76 
11.8 
Liability and Insurance ................................................................................... 76 
11.9 
Publication Policy ............................................................................................ 76 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
CONFIDENTIAL 
 
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12 
REFERENCE LIST ............................................................................................. 77 
13 
APPENDICES ...................................................................................................... 81 
13.1 
Appendix 1: Synopsis ...................................................................................... 81 
13.2 
Appendix 2: List of Institutions Involved in the Study .............................. 106 
13.3 
Appendix 3: Schedule of Events ................................................................... 109 
13.4 
Appendix 4: Rationale for the Clinical Impression of Change in Severity 
(CI-CS) Appendix 4: Rationale for the Clinical Impression of Change in 
Severity (CI-CS) ............................................................................................ 117 
13.5 
Appendix 5: Protocol Amendment History ................................................ 118 
13.6 
Appendix 6: Extension Phase ....................................................................... 119 
1 
INTRODUCTION – EXTENSION PHASE .................................................... 120 
1.1 
Risk/Benefit Considerations ......................................................................... 120 
2 
STUDY OBJECTIVES – EXTENSION PHASE ............................................ 123 
2.1 
Primary Objective ......................................................................................... 123 
2.2 
Secondary Objectives .................................................................................... 123 
2.3 
Exploratory Objectives ................................................................................. 123 
3 
OVERALL DESIGN AND PLAN OF THE EXTENSION PHASE ............. 124 
3.1 
Overview ........................................................................................................ 124 
3.1.1 
Trial Design/Patient Population ......................................................... 124 
3.1.2 
Study Design ...................................................................................... 124 
3.1.2.1 
Baseline Visit of the Extension Phase .......................................... 124 
3.1.2.2 
Extension Phase Treatment Period .............................................. 124 
3.1.2.3 
Extension Phase Washout Period ................................................ 125 
3.1.2.4 
Extension Phase Treatment Period II .......................................... 125 
3.1.3 
Centers ............................................................................................... 125 
3.1.4 
Study Duration ................................................................................... 125 
3.2 
Discussion of Study Design ........................................................................... 125 
3.2.1 
Choice of the Primary Endpoint ........................................................ 125 
3.2.2 
Choice of the Exploratory Endpoints ................................................. 125 
3.2.3 
Dose/ Duration of Treatment ............................................................. 125 
3.3 
End of Study Definition ................................................................................ 126 
4 
STUDY POPULATION – EXTENSION PHASE .......................................... 127 
4.1 
Inclusion Criteria .......................................................................................... 127 
4.2 
Patient Withdrawal ....................................................................................... 127 
4.3 
Patient Identification .................................................................................... 127 
5 
STUDY DRUG – EXTENSION STUDY ......................................................... 128 
5.1 
Identity ........................................................................................................... 128 
5.1.1 
N-Acetyl-L-Leucine, 1000 mg powder for oral suspension in 60 mL 
glass bottles (without further excipients) ........................................... 128 
5.1.2 
N-Acetyl-L-Leucine, 1000 mg Granules for oral suspension in sachet129 
5.2 
Administration ............................................................................................... 129 
5.3 
Modification of Dose Schedule and Transition to Sachet Formulation ... 130 
5.3.1 
Modification of Dose ......................................................................... 130 
5.3.2 
Transition from IB1001 in Bottles to Sachet Formulation ................ 131 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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5.4 
Packaging, Labeling and Storage ................................................................ 131 
5.4.1 
N-Acetyl-L-Leucine, 1000 mg powder for oral suspension in 60 mL 
glass bottles (without further excipients) ........................................... 131 
5.4.2 
N-Acetyl-L-Leucine, 1000 mg granules for oral suspension in sachet132 
5.5 
Blinding and Breaking the Blind ................................................................. 132 
5.6 
Drug Accountability ...................................................................................... 132 
5.7 
Investigational Medicinal Product (IMP; ‘study drug’) Compliance ...... 132 
5.8 
Concomitant Medications and Therapies ................................................... 132 
5.9 
Treatment of Overdose ................................................................................. 133 
6 
PARAMETERS AND METHODS OF ASSESSMENT – EXTENSION 
PHASE ................................................................................................................ 134 
6.1 
Updated Efficacy Parameters ...................................................................... 134 
6.1.1 
Primary Endpoint: Measurement of Clinical Impression of Change in 
Severity ................................................ Error! Bookmark not defined. 
6.1.2 
Secondary Efficacy Endpoints That Directly Supplement the Analysis 
of the Primary Endpoint ....................... Error! Bookmark not defined. 
6.1.3 
Measurement of Global Impression ................................................... 134 
6.2 
Exploratory Endpoints for the Washout Phase .......................................... 136 
The exploratory endpoints in this Extension Phase are based on:Error! Bookmark not 
defined. 
6.3 
Safety Parameters ......................................................................................... 136 
6.3.1 
Adverse Events .................................................................................. 136 
6.3.2 
Serious Adverse Events ..................................................................... 136 
6.3.3 
Pregnancy ........................................................................................... 136 
6.3.4 
Vital Signs .......................................................................................... 136 
6.3.5 
Electrocardiograms (ECGs) ............................................................... 136 
6.3.6 
Physical Examinations ....................................................................... 136 
6.3.7 
Medical History ................................................................................. 136 
6.4 
Laboratory Parameters ................................................................................ 137 
6.4.1 
Safety Laboratory Assessments ......................................................... 137 
6.4.2 
Measurement of N-Acetyl-L-Leucine Concentration in Blood on 
FULL PK days ................................................................................... 137 
6.4.3 
Measurement of N-Acetyl-D-Leucine Concentration in Urine ......... 138 
6.4.4 
Additional Laboratory Samples for Research Purposes .................... 138 
6.4.5 
Total Blood Volume .......................................................................... 138 
7 
STUDY CONDUCT – EXTENSION PHASE ................................................. 139 
7.1 
Observations by Visit .................................................................................... 139 
7.1.1 
Visit 7: Extension Phase Baseline Visit ............................................. 139 
7.1.2 
Visit 8: Day 180 (+/- 14 days: First assessment of the Extension Phase 
treatment period I ............................................................................... 140 
7.1.3 
Visit 9:  Day 365 (+/- 14 days): Final assessments of the Extension 
Phase treatment period I ..................................................................... 140 
7.1.3.1 
Visit 9, Part A:  Day 365 (+/- 14 days) of the treatment period .. 141 
7.1.3.2 
Visit 9, Part B ............................................................................... 141 
7.1.4 
Visit 10: Washout Visit ...................................................................... 141 
7.1.5 
Visit 11: Day 587 (+/- 14 days): Interim Extension Phase visit 
treatment period II .............................................................................. 142 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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7.1.6 
Visit 12 Day 767: Final assessments of the Extension Phase treatment 
period II with N-Acetyl-L-Leucine .................................................... 143 
7.1.7 
Extension Phase Early Termination (ET) .......................................... 143 
8 
STATISTICAL METHODS – EXTENSION PHASE ................................... 145 
8.1 
General Analysis Plan ................................................................................... 145 
8.1.1 
Disposition of Patients ....................................................................... 145 
8.1.2 
Analysis Populations .......................................................................... 145 
8.2 
General Considerations ................................................................................ 145 
8.3 
Demographics, Baseline Characteristics and Concomitant Medications 145 
8.4 
Treatment Compliance ................................................................................. 145 
8.5 
Efficacy Analyses ........................................................................................... 146 
8.5.1 
Primary Efficacy Endpoint ................................................................ 146 
8.5.2 
Secondary Efficacy Endpoints ........................................................... 146 
8.5.3 
Exploratory Efficacy Endpoints Relating to the Washout Phase . Error! 
Bookmark not defined. 
8.6 
Missing Data .................................................................................................. 148 
8.7 
Blinding .......................................................................................................... 148 
8.8 
Safety Analyses .............................................................................................. 148 
8.9 
Interim Analyses .................................................. Error! Bookmark not defined. 
8.10 
Determination of Sample Size ...................................................................... 148 
9 
DATA HANDLING AND RECORD KEEPING – EXTENSION PHASE .. 149 
10 
QUALITY CONTROL AND QUALITY ASSURANCE – EXTENSION 
PHASE ................................................................................................................ 150 
11 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS – EXTENSION 
PHASE ................................................................................................................ 151 
12 
LIST OF REFERENCES – EXTENSION PHASE ........................................ 152 
  
Tables in Text 
Table 5.1: Prohibited Medications .............................................................................................................. 40 
Table 6.1: Safety Laboratory Tests ............................................................................................................. 52 
 
Figures in Text 
Figure 3-1: Study Schema for “Naïve” Patients ........................................................................................... 22 
Figure 3-2: Study Schema for Non-naïve Patients ....................................................................................... 24 
Figure 4-1: Sample ID Format for IB1001-203 Subject ................................................................................ 36 
 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
8MWT 
8-meter walk test 
9HPT-D 
9-hole peg test of the dominant hand 
9HPT-ND 
9-hole peg test of the non-dominant hand 
AE 
Adverse event 
AEMPS 
Spanish Agency of Medicines and Medical Devices  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
A-T 
Ataxia-Telangiectasia 
ATC 
Anatomic Therapeutic Chemical 
CFR 
Code of Federal Regulations 
CGI 
Clinical global impression  
CGI-C 
Clinical global impression of change 
CGI-S 
Clinical global impression of severity 
CHMP 
Committee for Medicinal Products for Human use 
CHO 
Chinese hamster ovary 
CI-S 
Clinical impression of severity 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EQ 
EuroQol 
ET 
Early termination 
FAS 
Full analysis set 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GMP 
Good manufacturing practice 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISPOR 
International Society for Pharmacoeconomics and Outcomes Research 
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone releasing system 
LAM 
Lactational amenorrhoea method 
LOCF 
LPLV 
Last observation carried forward 
Last patient last visit 
MASAP 
Meta-analysis statistical analysis plan 
mDRS 
Modified disability rating scale 
MEB 
Dutch Medicines Evaluation Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
United Kingdom Medicines and Healthcare Products Regulatory 
Agency 
mITT 
Modified intention to treat 
MoCA 
Montreal Cognitive Assessment 
NCS 
Not clinically significant 
NPC  
Niemann-Pick disease type C 
NPCCSS 
NPC clinical severity scale 
PI 
Principal investigator 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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PK 
Pharmacokinetic(s) 
PPS 
Per protocol set 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SARA 
Scale for the assessment and rating of ataxia  
SCAFI 
Spinocerebellar ataxia functional index 
SD 
Standard deviation 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analogue scale 
WHO 
World Health Organization 
 
 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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1 
INTRODUCTION 
The goal of this study is to demonstrate that N-Acetyl-L-Leucine is efficacious in improving 
symptoms, functioning, and quality of life against the defined endpoints in patients with 
Ataxia-Telangiectasia (A-T) for the purpose of establishing the benefit/risk balance of 
investigational medicinal product in the proposed clinical setting.  
A-T is a rare, devastating, autosomal-recessive cerebellar ataxia that causes progressive 
degeneration to the cerebellum, central nervous system (CNS), and immune system, resulting 
in cognitive and physical decline and premature death [van Os et al, 2016]. In general, patients 
with neurological onset early in life have more severe symptoms, deteriorate faster, and die 
sooner [Jacobi et al, 2011]. A-T is estimated to affect 1:40,000 to 1:100,000 live births 
[Rothblum-Oviatt et al, 2016]. No medication has been proven effective for the treatment of 
inherited cerebellar ataxias, like A-T and there are no authorized treatments approved for A-T 
[Ilg et al, 2013]. Therefore, there is a strong need for the development of novel and more 
effective therapies to treat these intractable diseases.  
N-Acetyl-L-Leucine is the L-enantiomer of N-Acetyl-DL-Leucine, a modified amino acid that 
has been available in France since 1957 under the trade name Tanganil® (Pierre Fabre 
Laboratories) as a treatment for acute vertigo and is available as a solution for injection and as 
a tablet. N-Acetyl-L-Leucine is not currently authorized anywhere in the world for the 
treatment of any condition.   
 
The Sponsor’s (IntraBio Ltd.) development of Acetyl-Leucine for A-T began with the 
investigation of the commercially available racemic mixture, N-Acetyl-DL-Leucine 
(Tanganil®). Published case studies are available in the literature describing the effect of acute 
treatment with the racemate N-Acetyl-DL-Leucine in patients with inherited cerebellar ataxias 
[Strupp et al, 2013; Schniepp et al, 2016] as well as Niemann-Pick disease type C (NPC) 
[Bremova et al, 2015]. An additional case series is available in the literature describing the 
neuroprotective, disease modifying effect of long-term treatment with N-Acetyl-DL-Leucine 
for NPC [Cortina-Borja et al, 2018]. The potential clinical utility of N-Acetyl-DL-Leucine has 
been observed in compassionate use studies for A-T, as well as related inherited cerebellar 
ataxias and neurodegenerative diseases [Dr Michael Strupp, MD, Professor of Neurology LMU 
Munich, Personal Communication]. In all studies, the compound was well-tolerated with no 
discernible serious side effects. 
 
Recent in vitro and in vivo studies have demonstrated that the L-enantiomer mediates the 
therapeutic effect and has potential clinical benefits over the racemic mixture [Platt, 2018; 
Mann, 2018]. IntraBio therefore intends to focus further development on N-Acetyl-L-Leucine 
without the presence of D-enantiomer. The safety profiles of both N-Acetyl-DL-Leucine and 
N-Acetyl-L-Leucine have been characterized in both preclinical and clinical studies. In 
addition, the safety profile of N-Acetyl-DL-Leucine has been characterized on the basis of 
compassionate use experience in A-T (as well as in patients with other lysosomal storage 
disorders, neurodegenerative and genetic diseases, and further indications).  
Based on these findings, IntraBio is conducting this Phase II study investigating the efficacy 
and safety of N-Acetyl-L-Leucine for the treatment of A-T.  
The Parent Study drug is formulated as 1000 mg Powder for suspension in 40 mL Ora-Blend® 
and oral administration . Patients enrolled into the trial under protocol Version 5.1 or later may 
be dosed in the Parent Study with 1000 mg Granules for Oral Suspension in Sachet, suspended 
in 40 mL water. Patients aged ≥13 years will receive a total daily dose of 4 g/day (administered 
as 3 doses per day). Patients 6 to 12 years of age will receive weight-tiered doses.  

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The investigator will monitor the degree of stress to patients and the risk threshold throughout 
the trial. Patients will be instructed to report any AEs that they experience to the Investigator 
and the Investigator will ask about the occurrence of AEs at each visit. As described in 
Section 11.6, if the Investigator (or the Sponsor or Medical Monitor) becomes aware of 
conditions or events that suggest a possible hazard to patients if the study continues, the clinical 
study may be terminated after appropriate consultation between the involved parties. 
 
In addition, as described in Section 11.5, the Data Safety Monitoring Board (DSMB), in 
conjunction with the study Medical Monitor and/or Sponsor, will monitor the level of risk on 
a regular basis throughout the study. The DSMB is a multidisciplinary group consisting of 
clinicians with pediatric experience and a biostatistician. The DSMB has been set up to 
safeguard the interests of study participants by providing an independent review of patient 
safety data to monitor that no undue harm is occurring to patients due to their participation. 
The DSMB may recommend changes in the conduct of the studies to IntraBio, if needed, to 
ensure the safety of patients in the study and the proper conduct of the studies. The DSMB may 
also recommend suspending recruitment or terminate the study early because of undue safety 
risks to patients or any issues concerning the rights of patients. For this purpose, the DSMB 
will receive regular updates of safety and review all safety data on a regular basis.  
 
Based upon the nature of the drug, the available non-clinical and clinical data for N-Acetyl-L-
Leucine and N-Acetyl-DL-Leucine, the current lack of effective treatments A-T, and in the 
context of a marketed racemate, this clinical trial is concluded to pose acceptable levels of risk 
and burden on participants.  
 
1.2 
COVID-19 
This study is ongoing during the COVID-19 epidemic. Coronavirus (COVID-19) outbreaks 
have been recorded in all countries with study sites and subjects participating in IntraBio’s 
clinical trials and have significantly impacted the IB1001-203 clinical trial. 
 
Protocol Version 5.0, 30-December-2020 was approved in all active countries  (UK, USA, 
Germany) prior to the widespread outbreak of COVID-19 in the US and Europe. Protocol 
deviations, urgent safety measures, and modifications to this protocol have been necessary to 
prioritize and ensure the safety of trial participants, their families, and study site teams, and 
maintain the integrity of the study.  
 
New or modified processes / contingency measures enacted due to the outbreak of COVID-
19 are described throughout the Parent Study Protocol, including a risk/benefit assessment 
when applicable. All measures and actions that have been implemented due to COVID-19 
were first reviewed and agreed by the Data Safety Monitoring Committee (DSMB), the 
Medical Monitor, and applicable Principal Investigators.  
 
These new or modified processes enacted due to the outbreak of COVID-19 are consistent 
and permitted per the guidance’s issued from applicable regulatory bodies regarding the 
management of clinical trials in relation to COVID-19. In addition, applicable competent 
authorities (CA), research ethic committees (REC), and institutional review boards (IRBs) 
were notified and provided with copies of the applicable guidance’s issued by the Sponsor to 
participating Study Sites regarding the management of the COVID-19 pandemic (including 
IntraBio 2020a).  

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Note: This protocol amendment (Version 6.0 06-Oct-2020) has been made to include changes 
to protocol procedures which have been enacted due to COVID-19 at this time. However, 
because COVID-19 is an evolving situation, the ultimate impact of COVID-19 on the IB1001-
203 clinical trial remains unknown. Therefore, the protocol and related study documents may 
be updated as applicable. Any measures implemented in relation to COVID-19 will be in 
accordance with Guidance’s issued from applicable National Competent Authorities. The 
Data Safety Monitoring Board (DSMB) will also be consulted as applicable to ensure the 
safety of trial participants and clinical trial site study teams, as well as maintain the integrity 
of the clinical study.  All protocol deviations related to COVID-19 will be well-documented to 
enable appropriate evaluation of the IB1001-203 clinical trial.   
 

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2 
STUDY OBJECTIVES 
This study is ongoing during the COVID-19 outbreak. The impact of the global pandemic on 
the overall design and plan of the study is described in section 3.1.2.5. 
2.1 
Primary Objective 
The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded 
raters’ clinical impression of change in severity (CI-CS) in the treatment of A-T. 
2.2 
Secondary Objective(s) 
The secondary objectives are: 
o To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms of ataxia, 
functioning, and quality of life for patients with A-T; 
o To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in patients 
with A-T, including patients aged ≥13 years, and weight-tiered doses in patients 6 
to 12 years of age . 
2.3 
Exploratory Objective 
The exploratory objective is: 
To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with A-T 

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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
3.1.1 Trial Design/Patient Population 
This is a multinational, multicenter, open-label, rater-blinded Phase II study that will enroll 
male or female patients aged ≥6 years with a confirmed diagnosis of A-T at the time of signing 
informed consent.  
3.1.2 Study Design 
Patients will be assessed during three study phases: a baseline period (with or without a study 
run-in), a treatment period, and a washout period. It is not uncommon for symptoms and 
functioning to fluctuate over a week, so to help account for intra-patient variability, patients 
will be assessed twice during each period. Section 7 contains more detailed information on 
which study assessments and procedures will be conducted for each study phase and visit.  
At the initial screening visit, patients will be classified as either “naïve” or “non-naïve” patients 
depending on their use of prohibited medications within the past 42 days. The schedule of 
events during the initial screening visit and throughout the baseline period (through Visit 1) 
will vary depending on the patient’s classification as either “naïve” or “non-naïve”. 
3.1.2.1  Baseline Period 
Baseline: “Naïve” Patients (Figure 3-1). 
(See Appendix 3A for “naïve” patients schedule of events) 
“Naïve” patients are defined as patients who, at the initial screening visit, confirm (or whose 
legal representatives confirm on behalf of the patient) that they have not used any prohibited 
medications within the past 42 days. For these patients, the initial screening visit will be treated 
as Visit 1 (Baseline 1). 
A urine sample will be taken at Visit 1 to detect N-Acetyl-D-Leucine. Provided the patient’s 
levels of N-Acetyl-D-Leucine are below the permitted threshold, the initial screening visit will 
be confirmed as Visit 1 (Baseline 1). Visit 2 (Baseline 2/ Start of treatment period) will take 
place 14-days (+7 days) after Visit 1. 
 
Figure 3-1: 
Study Schema for “Naïve” Patients 
 
 
 

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Reclassifying “Naïve” Patients to “Non-naïve” Patients 
Visit 1 will not be confirmed for “naïve” patients whose urine sample test unexpectedly detects 
levels of N-Acetyl-D-Leucine above the permitted threshold. Provided the treating physician 
believes the patient will indeed comply with the pre-treatment washout and complete study the 
protocol1, these patients will be given the option to undergo a minimum of 42 days washout 
before returning for Visit 1 (Baseline 1). Provided the patient (or legal representative on behalf 
of the patient) consents, the patient will be reclassified as “non-naïve” and will return for a 
repeat Visit 1 after the study run-in washout period.   
Baseline: “Non-Naïve” Patients (Figure 3-2). 
(See Appendix 3B for “non-naïve” patients schedule of events) 
“Non-naïve” patients are defined as patients who confirm (or whose legal representatives on 
behalf of the patient confirm) they have used, or are unable to confirm or deny if they have 
used, any prohibited medication within the past 42 days2.  
Provided the treating physician believes the patient will comply with the pre-treatment 
washout and complete the study protocol, the “non-naïve” patient will be given the 
opportunity to undergo a minimum of 42 days washout before returning for Baseline 1. 
Provided the patient (or their legal representatives on behalf of the patient) consent, the initial 
screening visit will be treated and confirmed as Visit 0 (Figure 3-2). 
Visit 0 will commence study the run-in period where patients undergo a washout from 
prohibited medications. Patients are eligible to return for Baseline 1 after a minimum of 42 
days washout. For patients (or their legal representatives on behalf of the patient) who confirm 
they have not used any prohibited medications for a minimum of 42 days, the second visit will 
be treated as Visit 1 (Baseline 1)3.  
A urine sample will be taken at Visit 1 to assess the level of N-Acetyl-D-Leucine. Provided 
the level of N-Acetyl-D-Leucine is below the permitted threshold, the second visit will be 
confirmed as Visit 1 (Baseline 1). Visit 2 (Baseline 2/ Start of treatment period) will take place 
14 days (+7 days) after Visit 1.  
 
 
1 If the treating physician has reason to believe the patient will not comply with the study run-in washout or the complete 
study protocol, the patient will be notified they are ineligible for the study.  
2 As described, “non-naïve” patients can also be defined as patients who were initially classified as “naïve,” but whose initial 
urine sample unexpectedly detected levels of N-Acetyl-D-Leucine above the permitted threshold. Provided they are eligible, 
patients will be reclassified as “non-naïve” and return for a second screening visit after a minimum of 42 days washout.  
3 At Visit 1, patients who confirm (or whose legal representatives confirm) they have used, or are unable to confirm or deny 
if they have used, any prohibited medication within the past 42 days are ineligible to continue in the study.   
 

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Figure 3-2: 
Study Schema for Non-naïve Patients  
 
3.1.2.2 Treatment Period 
From Visit 2 onward, all visits will be the same for all patients regardless of whether they were 
considered to be “naïve” or “non-naïve” at the time of screening. 
During the treatment period, all patients will receive N-Acetyl-L-Leucine for 42 days 
(+7 days). Visit 3 (Treatment 1) will occur at Day 28 (+7 days) of the treatment period and 
Visit 4 (Treatment 2) will occur after the full 42 days (+7 days) of treatment. 
3.1.2.3 Washout Period 
A 42-day (+7 days) washout period will be performed following treatment with N-Acetyl-L-
Leucine. Visit 5 (Washout 1) will occur on Day 28 (+7 days) of the washout period and Visit 6 
(Washout 2) will occur after the full 42 days (+7 days) of washout. 
3.1.2.4 Extension Phase 
Patients who have participated in the study will be offered the opportunity to participate in a 
planned Extension Phase if the safety and tolerability during the 42-day (+7 days) treatment 
are considered to be acceptable by the Investigator for each specific patient, and the 
Investigator determines further treatment with IB1001 to be in the patient’s interest. Provided 
the patient (or their legal representative on their behalf) subsequently consent to participate, 
the Extension Phase is planned to allow patients to have further access to IB1001 for one year. 
Following a 6-week post Extension Phase treatment washout (Visit 10 of the Extension Phase), 
patients will have further access to IB1001 for an additional one-year in the Extension Phase 
Treatment Period II. 
See Appendix 6 for the Protocol for Extension Phase.  
3.1.2.5 COVID-19 Modifications to the Original Study Schema 
COVID-19 has significantly impacted study subjects’ ability to attend study visits due to 
government-ordered lockdowns or the closure of state (domestic) and/or national borders. In 
addition, the issuance of site-specific policies limiting or halting the conduct of non-essential 
study visits, the conversion of study-sites into COVID-19 wards, and site staff not on duty or 
reassigned to other priorities at the hospitals have affected the feasibility of conducting study 
visits. Finally, considering GM2 patients are already classified as a vulnerable patient 
population, patients may be self-isolating. 
 
If, per the reasons above, in-person visits cannot be carried out in accordance with the 
schedule of events, the following departures from the original study schema are allowed:  
 

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3.1.2.5.1 Non-Essential In-Person Visits: Treatment Visit 3/ Washout Visit 5 
- 
Visit 3 and Visit 5 are “interim” visits of the treatment and washout phases, 
respectively.  
- 
The Sponsor’s Medical Expert, Medical Monitor, the DSMB, Biostatistician and 
Principal Investigators consider that missing the in-person Visit 3 and / or Visit 5 
would not compromise the safety of the patient or the integrity of the study, and that 
the patient could continue with medication (Visit 3) or the post-treatment washout 
phase (Visit 5) without attending the in-person Visit 3 and / or Visit 5. This risk 
assessment was based on the previously established safety profile of IB1001 (see 
Section Error! Reference source not found.), the observed very good tolerability 
shown to date in this ongoing, open-label study, including that no related serious 
adverse reactions had been reported with IB1001 (in any ongoing trial ), that these 
visits are not critical to the primary outcome assessment, and that the integrity of the 
clinical trial could be maintained if these visits were not performed due COVID-19 
restrictions. 
- 
Therefore, in-person Visit 3 and Visit 5 have been classified as non-essential visits 
and may be skipped if they are not feasible to conduct in-person due to national, local, 
or site-specific restrictions, or necessary to safeguard the site staff, patients, and their 
families. If the in-person Visit 3 and / or Visit 5 is skipped, a remote visit should be 
conducted in lieu of the in-person visit (see Section 3.1.2.5.3 below).  
 
3.1.2.5.2 Essential In-Person Visits: End of Treatment Visit 4/ Washout Visit 6 
- 
Visit 4 and Visit 6 are the final visits of the treatment/washout phase (respectively) 
- 
The Sponsor’s Medical Expert, Medical Monitor, the DSMB, and each Principal 
Investigator determined that the in-person Visit 4 and Visit 6 are necessary visits 
needed to fully assess the safety of trial participants, the primary endpoint, and 
maintain the integrity of the clinical trial.  
- 
However, it was determined (if they are not feasible to conduct in-person due to 
national, local, or site-specific restrictions, or necessary to safeguard the site staff, 
patients, and their families) postponing the in-person Visit 4 and/or Visit 6 would not 
compromise the safety of the patient, and that the patient could continue with 
medication / be dosed longer than the planned 42 days (+7 days) treatment period 
(Visit 4).  This risk assessment was based on the previously established safety profile 
of IB1001 (see Section Error! Reference source not found.), the observed good 
tolerability shown to date in this ongoing, open-label study, including that no related 
serious adverse reactions had been reported with IB1001 (in any ongoing clinical 
trial), that the Extension Phase (including one-year treatment period with IB1001) had 
been approved in all countries, and that data collected from these postponed in-person 
Visit 4 and/or Visit 6 was acceptable for the purpose of assessing a true treatment-
related effect. 
- 
Therefore, Visit 4 and Visit 6 have been classified as essential study visits which may 
be postponed (if they are not feasible to conduct in-person due to national, local, or 
site-specific restrictions, or necessary to safeguard the site staff, patients, and their 
families) but cannot be skipped. If Visit 4 and / or Visit 6 is postponed, a remote visit 
should be conducted at the time of the original the in-person visit (see Section 
3.1.2.5.3 below) 
 

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3.1.2.5.3 Remote Visits 
For any (i) skipped in-person Visit 3/5; (ii) postponed in-person Visit 4/6: based on the 
availability of the patient/ the study team, within approximately  +/- 3 days of the originally 
scheduled visit, the study team/ principal investigator (PI) should contact the patient (and as 
applicable, their parents/caregiver/legal representative) via phone/Skype4 to collect 
information in order to monitor adverse or serious adverse events, and provide study 
oversight (hereafter referred to as “remote visits”).  
 
Assessments which may be able to be performed remotely (as feasible) may include: 
• 
Documentation of (changes in) frequency of therapy (hours per week) 
• 
Documentation of (changes in) concomitant medication 
• 
Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• 
Clinical Global Impression of Severity (CGI-S)  
• 
Clinical Global Impression of Change (CGI-C)  
• 
Documentation of changes in or new adverse events / serious adverse events 
• 
Discuss if additional study drug is needed (V3 only) 
• 
PATA Speech Test 
• 
Modified Disability Rating Scale  
• 
Scale for the Assessment and Rating of Ataxia  
• 
Additional Protocol Assessments which the Investigator/ Patient mutually agree to 
perform/assess  
 
Assessments collected at a remote Visits 3 and/or Visit 5 should be entered into the electronic 
case report form (eCRF) under Visit 3 and/or Visit 5. 
 
Assessments collected from remote Visit 4 and/or Visit 6 should be entered into eCRF as an 
Unscheduled Visit. When the postponed, in-person Visit 4 and/or Visit 6 is performed, all 
assessments collected at this visit should be entered into the eCRF as Visit 4 and/or Visit 6.  
 
See Section 9.5 for additional information on how contingency measures/protocol deviations 
related to COVID-19 will be captured in the electronic case report form (eCRF)/ documented 
in the Parent Study Clinical Study Report (CSR). 
 
3.1.2.6 Interim Analyses  
No interim analyses are planned throughout the Parent Study.  
3.1.3 Target Number of Patients 
• To be enrolled: Approximately 39 patients  
 
• To be analyzed according to the modified Intention to Treat (mITT) analysis: 
Approximately 36 patients 
 
• To be analyzed according to the Per Protocol Analysis: Approximately 30 patients 
 
 
4 As feasible; Skype is used as a generic term for videoconferencing, telemedicine but other software’s may be used. No video recordings 
should be made of these remote visits.  

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3.1.4  Number of Centers 
The trial will be conducted in a total of approximately 6 centers in the United States, the United 
Kingdom, Germany, Spain, or an additional European site, which must meet the structural and 
personnel requirements for performing the planned regular trial-related investigations.  
If necessary, additional countries may be included in the trial. 
3.1.5 Study Duration 
The treatment and washout duration for all patients, from the first day of dosing with the study 
drug (Visit 2) to the final follow-up visit after washout (Visit 6), is expected to be 
approximately 84 days.  
For “naïve” patients, there is a 14-day (+7 days) baseline period between Visit 1 and Visit 2. 
For “non-naïve” patients, there is a 42-day (+7 days) run-in period before Visit 1, and a 14-day 
(+7 days) baseline period between Visit 1 and Visit 2.  
COVID-19 will impact the duration of the study for patients whose Visit 4 and/or Visit 6 are 
postponed. 
3.2 
Discussion of Study Design 
3.2.1 Study Design 
Open-label rater-blinded study 
IntraBio initially proposed to investigate the safety and efficacy of N-Acetyl-L-Leucine for 
NPC, Tay-Sachs disease, and inherited Cerebellar Ataxias in a randomized, double-blind, 
placebo-controlled, crossover study. This design was discussed with regulators in the United 
States and Europe, including the United States Food and Drug Administration (US FDA; July 
2018), the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA), 
the Dutch Medicines Evaluation Board (MEB), and the Spanish Agency of Medicines and 
Medical Devices (AEMPS).  
Following these meetings, a formal feasibility study was initiated by IntraBio that demonstrated 
that a randomized, double-blind, placebo-controlled, crossover study would be difficult to 
recruit and commence without changes to the study design for the following reasons: 
- 
 IntraBio discussed these findings with A-T clinical experts and the heads of 
multinational A-T patient organizations, who believe that given the relentless and often 
rapid progression, invariably fatal outcome, and –the common use of unlicensed 
treatments/therapies by patients, families/caregivers would be reluctant to enroll 
patients in the planned placebo-controlled study where patients would be on treatment 
for 6 weeks (42 days), but without study drug for 18 to 24 weeks (depending on whether 
they are considered as “naïve” or “non-naïve” patients).   
- 
Moreover, both A-T clinical experts and the heads of multinational A-T patient 
organizations have questioned the appropriateness of initiating randomized, double-
blind, controlled studies for ultra-orphan indications like A-T, and strongly 
recommended the trial design be amended so that it is (a) feasible to enroll and retain 
the trial subjects and (b) appropriate in view of the size of the patient population with 
A-T and their need to have the rapidly progressing and fatal condition properly 
managed. This feedback was similar to a concern raised by the US FDA, who 
recommended that a crossover design should not be used in a study intended to 
demonstrate the effectiveness and controlled safety data because of the potential for 

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missing data caused by dropouts [United States Department of Health and Human 
Services, 2018b]. 
Therefore, the current proposed multinational, multicenter, open-label, rater-blinded Phase II 
study was designed with regard to an informed assessment based on input from the clinical 
experts and patient representatives. The proposed study now reduces the time patients are asked 
to go without study drug. During the trial, naïve patients will be without study drug for 6 out 
of 12 weeks (compared previously to 18 out of 24 weeks) and non-naïve patients will be 
without study drug for 14 of 20 weeks (compared previously to 24 out of 30 weeks). 
To reduce bias in an open-label clinical study, and especially in the clinical assessment of the 
trial subjects against the pre-defined variables, the primary analysis will be based on two 
independent raters’ blinded assessment of videos documenting the patients’ performance on 
the 9-Hole Peg Test of the Dominant Hand (9HPT-D) or 8-meter Walk Test (8MWT) (for 
details see Section 8.5.1). 
Two Study Schemas during Baseline Period 
As A-T is has an ultra-small patient population, and the number of eligible patients is already 
restricted, the study will permit patients who have used prohibited medications over the past 
42-days to enroll provided they meet the inclusion/exclusion criteria and agree to perform a 
minimum 42-day washout from the prohibited medication prior to Visit 1. 
3.2.2 Development of the Primary Endpoint: Clinical Impression of Change in Severity 
(CI-CS) 
As a consequence of the weaknesses of the current validated ataxias scales (e.g., Scale for 
Assessment and Rating of Ataxias; SARA) and the fact that no drug has been approved for 
A-T, IntraBio proposes a novel primary endpoint based on the Clinical Impression of Change 
in Severity (CI-CS) assessed by two blinded raters to evaluate the efficacy of N-Acetyl-L-
Leucine as a treatment for A-T. At the recommendation of the US FDA, the novel CI-CS 
endpoint is used in lieu of the traditional SARA scale as the primary outcome measure 
because it has been developed to assess and reflect a clinically meaningful change in function 
[United States Department of Health and Human Services, 2018b]. 
The development of the CI-CS follows the recommendation of the US FDA and was designed 
in accordance with the FDA PRO Guidance and International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR) Task Force papers [ISPOR, 2018] to assist in establishing a 
well-defined and reliable blinded-clinician reported outcome assessment for use in the planned 
clinical studies [United States Department of Health and Human Services, 2018a].  
The conceptual framework and description of the CI-CS methodology is provided 
 
. 
A manual will be provided to each clinical site which provides instructions for the 
administration of the CI-CS [
]. Similarly, a video-acquisition manual will be 
provided, which provides instructions for making standardized videos of the 8MWT and 9HPT-
D anchor tests [
 2019]. 
 

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Based on the US FDA recommendation, the assessments and recordings will be made in the 
clinic rather than in the patient’s home to standardize assessments across the diversity of 
patients’ home environments [United States Department of Health and Human Services, 
2018a]. 
In addition to adding blinded control to the primary assessment, at the recommendation of the 
US FDA, videos will be used to increase reliability and minimize testing burden on patients. 
Video recordings allow repeated viewings without the necessity for repetition and patient 
fatigue, and permit the blinded rater to control the pace of the movement analysis [Lord et al, 
1998]. Finally, at the recommendation of the US FDA, basing the primary assessment on videos 
minimizes the recall bias that can be associated with the traditional Clinical Global Impression 
of Change (CGI-C) scale [United States Department of Health and Human Services, 2018a]. 
Each site will have the same video-recording devices and receive the same standardized 
training and instructions to create homogeneity in the video recordings. 
The CI-CS will also be performed for the anchor test (9HPT-D or 8MWT) that was not selected 
as the patient’s primary anchor test (i.e., the non-primary anchor test). This will enable the 
evaluation of both of the possible anchor tests, and to assess the appropriateness of the chosen 
primary anchor test with regard to its ability to function as a clinically meaningful outcome 
measure for the patient. 
The blinded raters will be independent senior raters, who have ideally performed the 9HPT, 
8MWT, and Clinical Global Impression (CGI) in a clinical setting. At the recommendation of 
the US FDA, definitions of disease severity and components for blinded raters to assess and 
rate the patients’ change in severity will be provided [United States Department of Health and 
Human Services, 2018a]. The blinded raters will receive the same standardized training and 
instructions to create homogeneity in the assessments of patient’s clinical change in severity 
while performing the 9HPT-D/8MWT. 
3.2.2.3 Serial Endpoint Evaluation 
Three additional visits have been added to the study so that patients will be assessed twice 
during each period (baseline, treatment, washout) based on the US FDA recommendation to 
have more frequent primary endpoint evaluations given the high degree of variability within 
these patient populations and in small sample sizes generally. These additional visits are 
intended to allow serial endpoint evaluations to mitigate against within-patient heterogeneity 
and missing data [United States Department of Health and Human Services, 2018a]. 
3.2.3 Separate Trial Protocols by Indication 
Initially it was proposed to include patients with NPC, Tay-Sachs disease, and cerebellar ataxia 
patients in a single, basket trial. Based on the recommendation of the US FDA [United States 
Department of Health and Human Services, 2018a] and the Dutch MEB [MEB, 2018], separate 
trials will be conducted for NPC, as well as for GM2-Gangliosidosis (Tay-Sachs and Sandhoff 
Disease) and ataxia-telangiectasia (an inherited cerebellar ataxia subtype), to investigate the 
safety and efficacy of N-Acetyl-L-Leucine for the treatment of each indication. At the 
recommendation of the UK MHRA [MHRA, 2018] there will be a series of meta-analyses that 
will bring together the data from the three studies for the primary and secondary endpoints. 
Further details will be provided in a meta-analysis statistical analysis plan (MASAP).  
3.3 
End of Study Definition 
A patient is considered to have completed the Parent Study if he/she has completed all phases 
of the Parent Study including the last visit (Visit 6). 

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The end of the Parent Study is defined as the date of the last visit of the last patient in the Parent 
Study globally.  
A complete Clinical Study Report (CSR) will be written when the last visit of the last patient 
in the Extension Phase has been completed (see Section 3.3 of the Extension Phase in 
Appendix 6).   

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4 
STUDY POPULATION 
The study population comprises patients with A-T. To be eligible, patients must satisfy the 
following entry criteria:   
4.1 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible to participate in the study: 
1. Written informed consent signed by the patient and/or their legal representative/ parent/ 
impartial witness 
2. Male or female aged ≥6 years with a genetically confirmed  diagnosis of A-T at the 
time of signing informed consent.   
3. Females of childbearing potential, defined as a premenopausal female capable of 
becoming pregnant, will be included if they are either sexually inactive (sexually 
abstinent5 for 14 days prior to the first dose and confirm to continue through 28 days 
after the last dose) or using one of the following highly effective contraceptives (i.e. 
results in <1% failure rate when used consistently and correctly) 14 days prior to the 
first dose continuing through 28 days after the last dose: 
a) intrauterine device (IUD); 
b) surgical sterilization of the partner (vasectomy for 6 months minimum); 
c) combined (estrogen or progestogen containing) hormonal contraception associated 
with the inhibition of ovulation (either oral, intravaginal, or transdermal); 
d) progestogen only hormonal contraception associated with the inhibition of 
ovulation (either oral, injectable, or implantable); 
e) intrauterine hormone releasing system (IUS);  
f) bilateral tubal occlusion. 
4. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
 
 
5 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. In this trial abstinence is only 
acceptable if in line with the patient’s preferred and usual lifestyle. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. As well, female 
condom and male condom should not be used together. 
 

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a) hysteroscopic sterilization; 
b) bilateral tubal ligation or bilateral salpingectomy; 
c) hysterectomy; 
d) bilateral oophorectomy; 
OR be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. 
FSH analysis for postmenopausal women will be done at screening. FSH levels should 
be in the postmenopausal range as determined by the central laboratory. 
5. Non-vasectomized male patient agrees to use a condom with spermicide or abstain from 
sexual intercourse during the study until 90 days beyond the last dose of study 
medication and the female partner agrees to comply with inclusion criteria 3 or 4. For 
a vasectomized male who has had his vasectomy 6 months or more prior to study start, 
it is required that they use a condom during sexual intercourse. A male who has been 
vasectomized less than 6 months prior to study start must follow the same restrictions 
as a non-vasectomized male. 
6. If male, patient agrees not to donate sperm from the first dose until 90 days after their 
last dose. 
7. Patients must fall within: 
a) A SARA score of 5 ≤ X ≤ 33 points (out of 40)  
AND 
b) Either: 
i. 
Within the 2-7 range (0-8 range) of the Gait subtest of the SARA scale   
OR  
ii. 
Be able to perform the 9-Hole Peg Test with Dominant Hand (9HPT-D) (SCAFI 
subtest) in 20 ≤ X ≤150 seconds. 
8. Weight ≥15 kg at screening. 
9. Patients are willing to disclose their existing medications/therapies for (the symptoms) 
of A-T, including those on the prohibited medication list. Non-prohibited 
medications/therapies (e.g., concomitant speech therapy, and physiotherapy) are 
permitted provided: 
a) The Investigator does not believe the medication/therapy will interfere with the 
study protocol/results 
b) Patients have been on a stable dose/duration and type of therapy for at least 42 days 
before Visit 1 (Baseline 1)  
c) Patients are willing to maintain a stable dose/do not change their therapy throughout 
the duration of the study. 

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10. An understanding of the implications of study participation, provided in the written 
patient 
information 
and 
informed 
consent 
by 
patients 
or 
their 
legal 
representative/parent, and demonstrates a willingness to comply with instructions and 
attend required study visits (for children this criterion will also be assessed in parents 
or appointed guardians).  
4.2 
Exclusion Criteria 
Individuals who meet any of the following criteria are not eligible to participate in the study: 
1. Asymptomatic patients 
2. Patient has clinical features of A-T, but a completely negative result on a previous 
genetic test for A-T 
3. Patients who have any of the following: 
a) Chronic diarrhea; 
b) Unexplained visual loss; 
c) Malignancies; 
d) Insulin-dependent diabetes mellitus. 
e) Known history of hypersensitivity to the Acetyl-Leucine (DL-, L-, D-) or 
derivatives. 
f) History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, 
sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, 
dimethicone, methylparaben, and potassium sorbate). 
4. Simultaneous participation in another clinical study or participation in any clinical 
study involving administration of an investigational medicinal product (IMP; ‘study 
drug’) within 6 weeks prior to Visit 1. 
5. Patients with a physical or psychiatric condition which, at the investigator’s discretion, 
may put the patient at risk, may confound the study results, or may interfere with the 
patient’s participation in the clinical study.  
6. Known clinically-significant (at the discretion of the investigator) laboratories in 
hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to: 
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x 
upper limit of normal (ULN); 
b. Total bilirubin >1.5x ULN, unless Gilbert’s syndrome is present in which case 
total bilirubin >2x ULN. 
7. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol. 
8. Current or planned pregnancy or women who are breastfeeding. 
9. Patients with severe vision or hearing impairment (that is not corrected by glasses or 
hearing aids) that, at the investigator’s discretion, interferes with their ability to perform 
study assessments. 
10. Patients who have been diagnosed with arthritis or other musculoskeletal disorders 
affecting joints, muscles, ligaments, and/or nerves that by themselves affects patient’s 
mobility and, at the investigator’s discretion, interferes with their ability to perform 
study assessments. 

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11. Patients unwilling and/or not able to undergo 42 day washout period from any of the 
following prohibited medication prior to Visit 1 (Baseline 1) and remain without 
prohibited medication through Visit 6. 
a) Aminopyridines (including sustained-release form); 
b) N-Acetyl-DL-Leucine (e.g., Tanganil®); 
c) N-Acetyl-L-Leucine (prohibited if not provided as IMP); 
d) Riluzole; 
e) Gabapentin; 
f) Varenicline; 
g) Chlorzoxazone; 
h) Sulfasalazine; 
i) Rosuvastatin. 
4.3 
Patient Withdrawal  
Patients may withdraw from the study at any time at their own request without stating the 
reason(s) for withdrawal. If a patient withdraws early from the study after start of treatment an 
early termination (ET) visit should be arranged, preferably 7-14 days after the last dose of study 
drug. 
“Non-naïve” patients (including “naïve” patients reclassified as “non-naïve”) will be 
withdrawn from the study if their urine sample from Visit 1 (Baseline 1) detects levels of N-
Acetyl-D-Leucine above the permitted threshold.  
The treating physician may decide that a patient should be withdrawn from the study or from 
the study drug. Reasons for withdrawal from the study or the study drug may include, but are 
not limited to, the following: 
• Development of any adverse event (AE), serious AE (SAE), laboratory abnormality, 
condition, intercurrent illness, injury, medical condition, or use of a medication that is 
likely to interfere with patient safety, the overall assessment, or the study procedures, 
such that continued participation in the study would not be in the best interest of the 
patient. 
• Consent withdrawal. 
• The patient becomes pregnant or plans to become pregnant. 
• Significant patient noncompliance, defined as an unwillingness to complete the 
procedures defined in the schedule of events. 
• Patient lost to follow-up (i.e., staff unable to contact patient after several attempts). 
• Investigator, Medical Monitor, and/or Sponsor decision for any other reason not listed 
above that may invalidate the results of the study or jeopardizes the health and/or safety 
of a patient. 
• Complications related to pandemics such as COVID-19. 
 
Patients who discontinue study drug prior to completing the full treatment period, should be 
asked to complete the remaining study visits as far as possible and complete safety assessments 
at a minimum. If unwilling to complete the remaining study visits, regardless of the reason for 
withdrawal, best efforts should be made to have the patient take part in early termination (ET) 

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procedures, preferably 7-14 days following the last dose of the study drug, unless the patient is 
lost to follow-up or has withdrawn his/her consent to further study participation. Due to 
COVID-19, the ET visit may need to be postponed or conducted remotely, after discussion 
with the PI and the Sponsor. 
The reason for withdrawal will be recorded in the electronic case report form (eCRF). Adverse 
event follow-up procedures will be required if the patient is withdrawn from the study as a 
result of an AE/SAE. Data collected before withdrawal will be evaluated for safety and efficacy 
(if possible).  
If the Investigator, Sponsor, or Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to patients if the study continues, the clinical study may be terminated 
after appropriate consultation between the involved parties. The clinical study may also be 
terminated at the Sponsor’s discretion in absence of such a finding. The reasons will be 
explained should the situation arise. 
Conditions that may warrant termination of the study include (but are not limited to): 
• The discovery of an unexpected, relevant, or unacceptable risk to patients; 
• Failure to enroll patients at the required rate; 
• A decision of the Sponsor to suspend or discontinue development of the study drug. 
Recruitment will continue until approximately 30 patients complete dosing and Visit 6 or 
approximately 39 patients are enrolled.  
 
4.4 
Patient Identification  
All patients (also referred to as “subject”) will be assigned a unique, seven-digit identification 
number at screening, the “patient number”. The first 4 digits will refer to the site: the first 2 
numbers refer to the country (e.g., 49 for Germany, 34 for Spain, etc.) and the second 2 digits 
refer to the site number (e.g., 01 for the first site in Germany, 02 for the second site in Germany, 
etc.) (Figure 4-1). 
The next 3 digits will refer to the indication/patient: the first digit will refer to the study (3 for 
the Ataxia-Telangiectasia study). The final 2 digits refer to the patient number. 
The site and patient digits will be separated by a dash, e.g., 4901-201, 4301-105. 
This unique patient number will not be replaced by an enrollment number if the patient is 
eligible and will start treatment. 
 
 
Figure 4-1: Sample ID Format for IB1001-203 Subject 

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- 
carrageenan 
- 
calcium sulfate 
- 
trisodium phosphate 
- 
citric acid and sodium phosphate as buffers 
- 
dimethicone antifoam emulsion 
- 
preserved with methylparaben and potassium sorbate 
5.2 
Administration 
All patients are to receive N-Acetyl-L-Leucine (IB1001) in this single-arm study; there will be 
no comparator or placebo.  
The 40mL of Ora-Blend® will be combined into the powder and must be shaken vigorously 
for 2 minutes so that it fully mixes before being administered.  
The study drug should be taken 30 minutes before, or at least two hours after a meal. 
During the treatment period of this study, the dosing of the study drug is as follows: 
• Patients aged ≥13 years will take 4 g per day: 2 g in the morning, 1 g in the afternoon, 
and 1 g in the evening. 
• Patients aged 6-12 years weighing 15 to <25 kg will take 2 g per day: 1 g in the morning 
and 1 g in the evening. 
• Patients aged 6-12 years weighing 25 to <35 kg will take 3 g per day: 1 g in the morning, 
1 g in the afternoon, and 1 g in the evening. 
• Patients aged 6-12 years weighing ≥35 kg will take 4 g per day: 2 g in the morning, 1g 
in the afternoon and 1 g in the evening (as per patients aged ≥13). 
The planned maximum dosage for patients ≥13 years, or aged 6-12 weighing ≥35 kg is 4 g per 
day for 42 days (+7 days). 
Patients aged 6 to 12 years and <35 kg will receive 2 g or 3 g per day for 42 days (+7 days), in 
accordance with their body weight (see above).  
5.3 
Modification of Dose Schedule 
On visit days, patients should keep to their usual dosing schedule.  
If a patient misses a dose of study drug, the patient should wait and take the next dose according 
to the treatment schedule.  
Compliance will be assessed upon a review of the inventory of IB1001 bottles returned from 
patients.   
The patient’s total daily dose may be reduced by up to one-half of their assigned dose at the 
discretion of the investigator. 
In the event a patient turns 13 years old, or a patient aged 6-12 years old changes weight 
category over the course of the study, their daily dose will not change from the initial dosing 
regimen prescribed at Visit 2, the start of IMP.  
 Study drug will be taken during the 42-day (+7 days) treatment period. After the 42-day 
(+7 days) treatment period, patients will enter a 42-day (+7 days) washout period, which 
includes efficacy and safety assessments.  

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6 
PARAMETERS AND METHODS OF ASSESSMENT 
The primary and secondary parameters used during the study are described below.  
Section 3 describes the Overall Design and Plan of Study for “naïve” and “non-naïve” patients. 
See Appendix 3A for “naïve” patients’ schedule of events and Appendix 3B for “non-naïve” 
patients’ schedule of events. 
Section 7 contains more detailed information on which study assessments and procedures will 
be conducted for each study phase and visit. 
6.1 Efficacy Parameters 
6.1.1 Measurement of Clinical Impression of Change in Severity  
The primary endpoint is defined as the clinical impression of change in severity (CI-CS) 
comparing end of treatment with N-Acetyl-L-Leucine (Visit 4) with baseline (Visit 2) minus 
the CI-CS comparing the end of washout (Visit 6) with the end of treatment with N-Acetyl-L-
Leucine (Visit 4) based on the primary anchor test.  
This primary endpoint will assess the efficacy of N-Acetyl-L-Leucine for the treatment of A-
T, based on blinded raters’ CI-CS of patient’s change in performance over 6 weeks on either 
the 9-hole peg test of the dominant hand (9HPT-D) or the 8-meter walk test (8MWT). See for 
a full discussion on the development and the appropriateness of the primary endpoint. A manual 
will be provided to each clinical site, which provides instructions for the administration of the 
CI-CS [
]. Similarly, a video-acquisition manual will be provided, which provides 
instructions for making standardized videos of the 8MWT and 9HPT-D anchor tests 
 
. 
At Visit 1, the treating physician will evaluate each patient’s clinical symptoms and select 
either the 9HPT-D or 8MWT as the primary anchor around which the CI-CS assessment will 
be based. The primary evaluation of the CI-CS will be performed by two independent raters 
whose assessments will be based on videos of the anchor test taken at each visit. The raters will 
be blinded to the treatment phases to reduce detection and performance biases and for each pair 
of visits will make an assessment based on a 7-point Likert scale, e.g., -3 = ‘significantly 
worse’, 0 = ‘no change’ to +3 = ‘significantly improved’ (see Section 8.5.1 for further details 
on the primary efficacy analysis).  
6.1.1.1 Secondary Efficacy Endpoints That Directly Supplement the Analysis of the Primary 
Endpoint 
Supportive secondary endpoints will be evaluated that directly supplement the analysis of the 
primary endpoint as follows (see Section 8.5.2 for further details): 
• The individual components of the primary endpoint, that is the CI-CS from Visit 2 to 
Visit 4 and the CI-CS from Visit 4 to Visit 6. 
• Differences in the blinded rater’s Clinical Impression of Severity (CI-S) values from 
baseline to end of treatment and from end of treatment to end of washout. The two CI-S 
values at each of these periods (Visit 1 and Visit 2 for baseline, Visit 3 and Visit 4 for 
end of treatment and Visit 5 and Visit 6 for end of washout) will be averaged. 
• Sensitivity measurement of change in performance on either the 9HPT-D or the 8MWT 
on a 3-point scale. Using the CI-CS outcome for the primary anchor test based on the 
data for Visits 2 and Visit 4, any patient given a score of -1, -2, or -3 on the CI-CS will 
be classified as worsened (-1). Any patient classified as 0 on the CI-CS will be classified 
no change (0). Any patient given a score of +1, +2, +3 on the CI-CS will be classified 
as improved (+1). A similar classification will use the CI-CS comparing the end of 

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treatment with N-Acetyl-L-Leucine with end of washout based on the data for Visits 4 
and Visit 6 and the difference between these scores calculated. 
• An evaluation of the CI-CS for the test (9HPT-D or 8MWT) that was not selected as 
the primary anchor test will also be undertaken. This will enable the separate analysis 
of CI-CS for both the 9HPT-D and the 8MWT.  
 
There will also be an investigation of the intra-rater correlation in relation to Videos from Visits 
1 and 2, Visits 3 and 4, and Visits 5 and 6 to help investigate the stability of the outcome 
evaluation and the disease itself. Pearson rank correlation coefficients will be calculated for 
each of these pairings for each of the two raters. 
Other secondary endpoints include the Spinocerebellar Ataxia Functional Index (SCAFI) and 
Scale for Assessment and Rating of Ataxia (SARA) scores, based on the changes from baseline 
(Visit 2) to the end of treatment with N-Acetyl-L-Leucine (Visit 4), as well as from the end of 
treatment with N-Acetyl-L-Leucine (Visit 4) to the end of post-treatment washout (Visit 6). 
See Section 8.5.2 for further details on the analysis of the secondary efficacy endpoints. 
6.1.2 Measurement of Ataxia and Functioning 
6.1.2.1 Spinocerebellar Ataxia Functional Index (SCAFI) 
The SCAFI consists of a timed 8MWT to be carried out at maximum speed, the 9-hole peg test 
with both dominant and non-dominant hands (9HPT-D; 9HPT-ND) and the “PATA” test to 
measure speech performance. For the 8MWT and 9HPT tests, a lower score/time indicates a 
clinical improvement. A higher “PATA” test score indicates improvement in speech 
performance [Schmitz-Hübsch et al, 2008]. 
The SCAFI represents vital movement features (8MWT;9HPD-D/-ND for evaluation of the 
coordination of the upper extremities; PATA-test for evaluation of speech). After the 
assessment, raw scores are transformed into reciprocals and converted into subtest Z-scores. 
The final SCAFI is then generated as the arithmetic mean of all three Z-scores.  
Two subtests, the 9HPT-D and 8MWT, will be videoed in a standardized format at every visit, 
except Visit 0. 
A subset of the SCAFI, the 9HPT-D, serves as an inclusion criterion for the severity of ataxia 
at the beginning of the study prior to enrollment.  
The complete SCAFI will be performed at the time points designated on the schedule of events 
(Appendix 3A for “naïve” patients and Appendix 3B for “non-naïve” patients). 
The score will be assessed by the investigator or qualified member of the study team.  
6.1.2.2 Scale for the Assessment and Rating of Ataxia (SARA) 
The SARA [Schmitz-Hübsch et al, 2006; Subramony, 2007] is an eight-item clinical rating 
scale (range 0–40, where 0 is the best neurological status and 40 the worst). It is a reliable and 
valid clinical scale with a high internal consistency that measures the severity of ataxia and 
increases with ataxia disease stage. 
The SARA will serve as an inclusion criterion for the severity of ataxia at the beginning of the 
study.  
The complete SARA will be performed at the time points designated on the schedule of events 
(Appendix 3A for “naïve” patients and Appendix 3B for “non-naïve” patients).  
The score will be assessed by the investigator or qualified member of the study team.   

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6.1.3 Measurement of Health-related Quality of Life 
The EuroQol (EQ)-5D-5L is a self-administered questionnaire for evaluating quality of life 
(QoL) introduced in 2009 [EuroQol Group, 2017].  
The EQ-5D-5L is a multiple-choice questionnaire and a visual analogue scale that takes only 
few minutes to complete.  
The EQ-5D-5L is a standardized measure of health status and in order to provide a simple, 
generic measure of health for clinical and economic appraisal and consists of 2 parts - the EQ-
5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive 
system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L will be 
used in patients aged ≥ 18. 
The EQ-5D-Y is a child-friendly version of the EQ-5D, adapted to be appropriate for the 
measurement of health-related quality of life in young respondents [Wille et al, 2010]. It will 
be used in patients aged <18. If a patient turns 18 over the course of the Parent Study, they will 
continue to use the EQ-5D-Y for consistency. 
The EQ-5D-5L/EQ-5D-Y will be assessed at the time points designated on the schedule of 
events (Appendix 3A for “naïve” patients and Appendix 3B for “non-naïve” patients).  
6.1.4 Measurement of Global Impression 
The Clinical Global Impression (CGI) Scale has been long been implemented in 
neurodegenerative disease trials to provide an index of clinical importance that cannot be 
obtained from quantitative assessment measures [Quinn et al, 2008]. The CGI-C has been 
widely validated and used 
 successfully across a range of conditions, including neurological disorders such as 
Alzheimer’s disease [Schneider et al, 1997; Knopman et al, 1994], tardive dyskinesia [Solmi 
et al, 2018], and spinocerebellar ataxia [Monte et al, 2017], and other disorders such as 
radiologic findings in hypophosphatasia [Whyte et al, 2018].  
The Clinical Global Impression of Severity (CGI-S) - physician asks the clinician one question:  
“Considering your total clinical experience with this particular population,  how ill is 
the patient at this time?” which is rated on the following seven-point scale: 1=normal, 
not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely 
ill; 7=among the most extremely ill the patient has been. 
The CGI-S - caregiver asks the caregiver one question:  
“Considering your total experience with this particular patient, how ill is the patient at 
this time?” which is rated on the following seven-point scale: 1=normal, not at all ill; 
2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 
7=among the most extremely ill the patient has been. 
The CGI-S - patient asks the patient (if able) one question:  
“Considering your total experience with this particular indication, how ill are you at 
this time?” which is rated on the following seven-point scale: 1=normal, not at all ill; 
2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 
7=among the most extremely ill I have ever been. 

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The CGI-S will be assessed at the time points designated on the schedule of events (Appendix 
3A for “naïve” patients and Appendix 3B for “non-naïve” patients).  
The Clinical Global Impression of Change (CGI-C) - clinician asks the clinician one question: 
“Compared to the patient's condition (i) Visit 2 (prior to medication) versus (ii) Visit 4 
(end of medication) OR (i) Visit 4 (end of medication) versus (ii) Visit 6 (end of 
washout) OR (i) Early Termination Visit versus (ii) previous visit, this patient's is: 
1=very much improved since the initiation of treatment; 2=much improved; 
3=minimally improved; 4=no change from baseline (the initiation of treatment); 
5=minimally worse; 6= much worse; 7=very much worse since the initiation of 
treatment.” 
The Clinical Global Impression of Change (CGI-C) - caregiver asks the caregiver one question: 
“Compared to the patient’s condition (i) Visit 2 (prior to medication) versus (ii) Visit 4 
(end of medication) OR (i) Visit 4 (end of medication) versus (ii) Visit 6 (end of 
washout) OR (i) Early Termination Visit versus (ii) previous visit, how much has he/she 
changed: 1=very much improved since the initiation of treatment; 2=much improved; 
3=minimally improved; 4=no change from baseline (the initiation of treatment); 
5=minimally worse; 6=much worse; 7=very much worse since the initiation of 
treatment.” 
The Clinical Global Impression of Change (CGI-C) - patient asks the patient (if able) one 
question: 
“Compared to how you were (i) Visit 2 (prior to medication) versus (ii) Visit 4 (end of 
medication) OR (i) Visit 4 (end of medication) versus (ii) Visit 6 (end of washout) OR 
(i) Early Termination Visit versus (ii) previous visit, how much have you changed: 
1=very much improved since the initiation of treatment; 2=much improved; 
3=minimally improved; 4=no change from baseline (the initiation of treatment); 
5=minimally worse; 6=much worse; 7=very much worse since the initiation of 
treatment.” 
The CGI-C – clinician/caregiver/patient will be assessed at the time points designated on the 
schedule of events (Appendix 3A for “naïve” patients and Appendix 3B for “non-naïve” 
patients).  
6.1.5 Remote Assessments 
Due to COVID-19, safety and efficacy parameters may be collected remotely in lieu of in-
person assessments (as feasible).  
 
6.2 Safety Parameters 
The Investigator is responsible for monitoring the safety of patients who have been enrolled 
in this study and for accurately documenting and reporting information as described in this 
section.  
In addition, the investigator will monitor the degree of stress to patients and the risk threshold 
throughout the trial.  
6.2.1 Adverse Events 
Patients will be instructed to report to the Investigator any AE that they experience. 
Investigators will ask about the occurrence of AEs at each visit. Investigators are required to 

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document all AEs occurring during the clinical study, commencing with the signing of the 
informed consent form (ICF) through the End of Study Visit (scheduled at 42 days post last 
IB1001 dose). Adverse event recording will continue for patients who discontinue study 
treatment but remain on-study, until their ET Visit has been completed. 
Adverse events will be recorded on designated eCRF pages. Each AE is to be characterized 
(i.e., verbatim term) and information provided regarding its seriousness, start and stop dates, 
intensity, outcome, and causal relationship with the study drug.  
An AE is any undesirable physical, psychological or behavioral effect experienced by a patient 
during participation in an investigational study, in conjunction with the use of the drug or 
biologic, whether or not product-related. This includes any untoward signs or symptoms 
experienced by the patient from the time of signing of the informed consent until completion 
of the study. 
Adverse events may include, but are not limited to: 
• Subjective or objective symptoms spontaneously offered by the patient and/or observed 
by the Investigator or medical staff 
• Findings at physical examinations 
• Laboratory abnormalities of clinical significance 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of 
the investigational product are not considered AEs after treatment unless they reoccur after the 
patient has recovered from the preexisting condition or, in the opinion of the Investigator, they 
represent a clinically significant exacerbation in intensity or frequency. Clinical significance is 
defined as any variation in signs, symptoms, or testing that has medical relevance and may 
result in an alteration in medical care. The Investigator will continue to monitor the patient 
until the assessment returns to Baseline or until the Investigator determines that follow-up is 
no longer medically necessary. 
 
An AE does not include:   
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an adverse event; Planned surgical measures 
permitted by the clinical study protocol and the condition(s) leading to these measures are 
not adverse events, if the condition(s) was (were) known before the start of study treatment. 
In the latter case, the condition should be reported as part of the subject’s medical history. 
• Pre-existing diseases or conditions present or detected prior to the start of study drug 
administration that do not worsen; 
• Situations where an untoward medical event has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions). 
It is important that Investigators record accurate AE terms on eCRFs. Wherever possible, a 
specific disease or syndrome rather than individual associated signs and symptoms will be 
identified by the Investigator and recorded on the eCRF. However, if an observed or reported 
sign or symptom is not considered a component of a specific disease or syndrome by the 
Investigator, or is atypical, it should be recorded as a separate AE on the eCRF.  

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6.2.1.1 Adverse Event Intensity 
The Adverse Event Intensity refers to the extent to which an AE affects the subject's daily 
activities. Severity will be categorized according to the following criteria:  
 
Mild: 
The AE does not interfere with the subject’s routine activities. 
Moderate: 
The AE interferes with the subject’s daily routine, but usual routine 
activities can still be carried out. 
Severe: 
The AE results in the inability to perform routine activities. 
 
The term "severity" is used to describe the intensity of an event. This is not the same as 
"serious". Seriousness, not severity, serves as the guide for defining regulatory reporting 
obligations. The highest severity grade attained should be reported, for AEs with divergent 
severities. 
 
6.2.1.2 Adverse Event Relatedness 
The Principal Investigator (Investigator) will make a judgment regarding whether or not, in 
his/her opinion, the AE was related to study drug. However, even if the Investigator feels there 
is no relationship to the study drug, the AE MUST be recorded on the adverse event eCRF. 
Below are guidelines for relationship assessment: 
Causality of Adverse Event:  
The Causality of Adverse Events refers to the relationship of the AE to study drug. Causality 
will be categorized according to the following criteria: 
Not 
related: 
Adverse events for which a reasonable explanation for an alternative cause 
is considered plausible, e.g., no study drug taken, plausible clinical 
alternative like accidental injury, expected progression of underlying or 
concomitant 
disease, 
pharmacologically 
incompatible 
temporal 
relationship, or intercurrent illness. 
Related: Adverse events for which a reasonably possible clinical and/or 
pharmacological relationship to study drug cannot be excluded, e.g., 
lacking plausible alternatives. 
 
6.2.2 
Serious Adverse Events 
Serious adverse events will be reportable from the time the patient signs the ICF through their 
last study visit (e.g. Visit 6 or Visit 12) or until the Investigator in collaboration with IntraBio 
Ltd determines that follow-up is no longer necessary. Serious adverse events that are suspected 
to be drug related will be reported even if they occur up to 30 days after the patient has taken 
the last dose of study drug. If a related SAE is ongoing at the end of the study or when a patient 
withdraws from the study, appropriate safety follow-up, including additional laboratory tests 
as required, will continue for 30 days. 
 
An SAE is any AE that results in any of the following outcomes: 

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• Death 
• Life-threatening experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly or Birth Defect 
• Important medical events that, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Life-threatening experience. Any adverse experience that places the patient, in the view of 
the reporter, at immediate risk of death from the adverse experience as it occurred, i.e., does 
not include an adverse experience that had it occurred in a more severe form, might have caused 
death. 
 
Required or prolonged inpatient hospitalization. The adverse experience resulted in an 
initial inpatient hospitalization or prolonged an existing hospitalization of the patient. If a 
patient is hospitalized as part of the clinical use of the product, a period of normal 
hospitalization will be outlined in the protocol or by the judgment of the Investigator. 
Hospitalizations longer than this period will be prolonged hospitalizations. 
 
Persistent or significant disability/incapacity. An adverse experience that resulted in a 
substantial disruption of a person’s ability to conduct normal life functions. 
 
Congenital Anomaly. The exposure of the patient to the drug or biologic during pregnancy 
that is judged to have resulted in the congenital anomaly/birth defect. 
 
Important medical events. Adverse experiences that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse experience 
when, based upon appropriate medical judgment, may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent 1 of the outcomes listed above. 
Important medical events or interventions may be considered an SAE based upon medical 
judgment of the Investigator.  
6.2.2.1 Reporting Serious Adverse Events  
SAEs will be reported promptly once the Investigator determines that the event meets the 
protocol definition of an SAE. The Investigator or designate will fill out the SAE reporting 
form in the eCRF within 24 hours of his/her becoming aware of these events. In addition, 
for fatal and life-threatening events, the Sponsor’s Medical Monitor should be contacted 
immediately. Contact numbers for the Medical Monitor (including after-hours cover) will be 
provided to the site before any patients are screened and upon receipt should be kept in the 
Site’s study binder. 
The SAE Reporting Form of the eCRF will always be completed as thoroughly as possible with 
all available details of the event within the designated time frames. The Investigator will always 
provide an assessment of causality at the time of the initial report as described in Section 
6.2.1.2. 
If the Investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before completing the form. The SAE reporting form will be 

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updated when additional information is received within 24 hours of receipt of such 
information. 
The completion of the SAE Reporting Form in the eCRF is the preferred method for Reporting 
SAEs. Only if a technical failure prevents the ability to report an SAE in the eCRF, then the 
paper SAE Reporting Form provided by the Sponsor must be completed and emailed to 
 
The fax and or email instructions can be found on the paper SAE Reporting Forms, which are 
filed in the Investigator Site File. 
6.2.2.2 Responsibilities of the Sponsor 
The Sponsor or their delegate, is responsible for fulfilling all obligations regarding notification 
of Regulatory Authorities, Independent Ethics Committees (IECs)/ Institutional Review Board 
(IRBs), and investigators according to applicable regulatory requirements (expedited and 
periodic reporting, e.g., serious unexpected suspected adverse reactions, Development Safety 
Update Report).  
6.2.3 
Pregnancy  
Every effort should be made to prevent pregnancy during the study treatment period. All 
patients of reproductive potential involved in the study are required to use highly effective 
methods of contraception during the study and for 28 days after the last IB1001 dose. Female 
patients will be instructed to notify the Investigator immediately if they discover they are 
pregnant. Pregnancy data during the study will be reported using the SAE reporting process 
(see Section 6.2.2). Since it will be necessary to collect detailed information on the course of 
any pregnancy occurring in a patient on study the Investigator will be provided with the 
pregnancy notification forms and specific guidance for completing these forms once the initial 
AE form documenting a pregnancy is received within 24 hours. 
Pregnant patients will discontinue study medication for the duration of the pregnancy. 
The pregnancy will be followed by the Investigator and the outcome of the pregnancy will be 
reported to the Pharmacovigilance group. 
At Visit 0 (non-naïve patients only), Visit 1, Visit 2, Visit 4, Visit 6, and Early Termination 
Visit (if applicable), females of childbearing potential will have a urine dipstick pregnancy test 
(analyzed on site).  
6.2.4 Vital Signs 
Vital signs will be measured and recorded at the time points designated on the schedule of 
events (Appendix 3A for “naïve” patients and Appendix 3B for “non-naïve” patients). The 
following measurements must be performed: systolic/diastolic blood pressure and pulse. 
Orthostatic vital signs will be measured after the patient has been in the supine position for at 
least 5 minutes, and again after the patient has stood for 2 minutes (in patients who are able to 
tolerate standing only). 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.  
Due to COVID-19, vital signs may not be able to be collected at the designated timepoints in 
the schedule of events (e.g. if visits are skipped and replaced by a remote visit or postponed). 
The Sponsor’s Medical Expert, Medical Monitor, and DSMB deem the risk posed by vital 
signs not being collected at the designated timepoints due to COVID-19 is acceptable in the 
context of remote visits where study staff will enquire regarding the health and wellbeing of 

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the patient and assess for adverse events. This decision was based on the nature of the drug, 
the available non-clinical and clinical data for N-Acetyl-L-Leucine and N-Acetyl-DL-
Leucine (see Section Error! Reference source not found.), and the safety profile observed 
to date in this ongoing, open-label study (very well-tolerated) (and also in other ongoing trials 
with IB1001).  
 
6.2.5 Electrocardiograms (ECGs) 
During the study, 12-lead ECGs will be performed approximately at the time points designated 
on the schedule of events (Appendix 3A for “naïve” patients and Appendix 3B for “non-naïve” 
patients). In addition, ECGs may be performed at other visits at the discretion of the 
Investigator if the findings from a previous ECG was clinically relevant. 
The patient must be in a supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted. If the patient is unable to be in the supine position, the 
patient should be in the most recumbent position possible. 
All ECGs should be performed in a standardized method. 
Each ECG must include the following measurements:  
Corrected QT, and whether the ECG is Normal, Abnormal NCS (not clinically significant), or 
Abnormal CS (clinically significant) for the patient. 
The Principal Investigator or designated site physician will review and sign all ECGs. Results 
must be summarized in writing and classified as normal; Abnormal NCS (not clinically 
significant), or Abnormal CS (clinically significant) for the patient. Intervals of the ECG will 
be recorded in the eCRF. Once signed, the original ECG tracing will be retained with the 
patient’s source documents. At the request of the Sponsor, a copy of the original ECG will be 
made available.  
Due to COVID-19, ECGs may not be able to be collected at the designated timepoints in the 
schedule of events (e.g. if visits are skipped and replaced by remote visits or postponed) or if 
qualified study team members/ appropriate equipment are not available/accessible. The 
Sponsor’s Medical Expert, Medical Monitor, and DSMB deem the risk posed by ECGs not 
being collected at the designated timepoints is acceptable in the context of remote visits 
where study staff will enquire regarding the health and wellbeing of the patient and assess for 
adverse events. This decision was based on the nature of the drug, the available non-clinical 
and clinical data for N-Acetyl-L-Leucine and N-Acetyl-DL-Leucine (see Section Error! 
Reference source not found.), and the safety profile (no reports of cardiac issues, including 
QTc prolongation) observed in this ongoing, open-label study (and also in other ongoing 
trials with IB1001). ECGs will be routinely collected at Visit 9 in the Extension Phase, 
allowing for further assessment of any cardiac effects.  
 
6.2.6 Physical Examinations 
At Screening (Visit 0 and Visit 1 for non-naïve patients /Visit 1 for naïve patients), Visit 4 
(end of treatment period), Visit 6 (end of washout period), and Early Termination Visit (if 
applicable), a complete physical examination will be done that is limited to the following 
body systems: general appearance (including skin), head and neck, eyes and ears, nose and 
throat, pulmonary, cardiovascular, gastrointestinal, muscular skeletal, lymphatic, neurological 
and other. 
 

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At Screening, if a significant abnormal condition is detected, the condition will be described 
on the medical history CRF. At study visits, if a new, significant abnormal or worsened 
abnormal pre-existing condition is detected, the condition will be described on the AE eCRF. 
 
Height and weight will be measured at the initial screening visit, Visit 1 (“naïve” patients) or 
Visit 0 (“non-naïve” patients). 
6.2.7 Suicide Ideation 
During the study, the Columbia-Suicide Severity Rating Scale (C-SSRS) (a prospective 
assessment for suicidal ideation and behavior) will be performed at the time points designated 
on the schedule of events (Appendix 3A for “naïve” patients and Appendix 3B for “non-
naïve” patients) to characterize the safety and tolerability of IB1001. 
 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a semi-structured interview that 
captures the occurrence, severity, and frequency of suicide-related thoughts and behavior 
[Posner et al, 2011]. The assessment intends: 
i. 
To ensure that patients in clinical trials who are experiencing suicidal ideation and 
behavior are properly recognized and adequately treated; 
ii. 
To make it easier to detect increases in suicidal ideation and behavior in individual trials 
and in pooled analyses; 
iii. 
To avoid misclassification of ideation and behaviors as suicidal, which can 
overestimate the true risk and result in the overly conservative use of the drug or its 
lack of availability entirely. 
In the event that observation/questioning indicates potential suicidal ideation the 
Investigator will make a judgment as to whether the patient requires treatment 
management outside of the protocol.  
 
6.2.8 Additional Safety Assessments 
Not applicable. 
6.3 Laboratory Parameters 
6.3.1 Safety Laboratory Assessments  
The tests listed in Table 6.1 will be conducted on samples collected and analyzed by standard 
laboratory procedures at the time points designated on the schedule of events (Appendix 3A 
for “naïve” patients and Appendix 3B for “non-naïve” patients). Tests that are not done must 
be reported as such on the eCRFs.  
Due to COVID-19, Safety Laboratory Assessments may not be collected at the designated 
timepoints in the schedule of events (e.g. if visits are skipped, performed remotely or 
postponed). The Sponsor’s Medical Expert, Medical Monitor, and DSMB deem that the risk 
posed by safety laboratory assessments not being collected at the designated timepoints due 
to COVID-19 is acceptable in the context of remote visits where study staff will enquire 
regarding the health and wellbeing of the patient and assess for adverse events. This decision 
was based on to the nature of the drug, the available non-clinical and clinical data for N-
Acetyl-L-Leucine and N-Acetyl-DL-Leucine (see Section Error! Reference source not 
found.), and the safety profile observed in this ongoing, open-label study (and also in other 
ongoing IB1001 trials).   

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- 
Specific gravity  
- 
Ketones 
- 
Bilirubin 
- 
Glucose 
 
As described in Section 6.2.3 females of childbearing potential will have a urine dipstick 
pregnancy test analyzed on site at Visit 0 (non-naïve only), Visit 1, Visit 2, Visit 4, Visit 6, 
and the Early Termination Visit (if applicable). 
6.3.2 Measurement of N-Acetyl-L-Leucine Concentration in Blood 
Blood samples for measurements of N-Acetyl-L-Leucine concentrations will be taken at the 
time points designated on the schedule of events (Appendix 3A for “naïve” patients and 
Appendix 3B for “non-naïve” patients). Sparse PK sampling will be carried out at the same 
times that blood is drawn for the safety blood laboratory tests for possible future modeling 
purposes. This sampling is exploratory/descriptive. 
For these PK analysis, Lithium-Heparin plasma samples will be drawn and frozen at -70ºC or 
below and shipped on dry ice for analysis at 
. Note, for each 
PK blood draw, it is important that the day and exact time of the last dose of N-Acetyl-L-
Leucine before the blood draw and the day and exact time of the blood draw are recorded. 
6.3.3 Measurement of N-Acetyl-D-Leucine Concentrations in Urine 
Urine samples will be collected for concentrations of N-Acetyl-D-Leucine at Visit 1, Visit 2, 
Visit 5, and Visit 6. 
Urine samples for measurement of N-Acetyl-D-Leucine will be frozen at -70ºC or below and 
shipped on dry ice for analysis at 
  
The urine sample provided at Visit 1 will be analyzed after it is received by 
and 
results should be made available before start of the treatment phase to demonstrate that levels 
of N-Acetyl-D-Leucine are below the set threshold. 
The urine samples provided at Visit 2, Visit 5, and Visit 6 will be analyzed in batches and used 
for sensitivity analyses only. 
 
6.3.4 Additional Laboratory Samples for Research Purposes 
Retained samples from the Parent Study may be used for research purposes to provide more 
information on the disease Ataxia-Telangiectasia.  
 
6.3.5 Sample Processing 
IntraBio Ltd (or delegates) will provide a laboratory manual that will detail the logistics and 
handling of all samples taken during this study.  
 
 

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7 STUDY CONDUCT 
Per Section 3.1.2.5, due to COVID-19, changes to existing study procedures have been/ may 
continue to be necessary in order to safeguard participants due to the outbreak of COVID-19 
in the US and Europe, as well as their families and study teams.  
7.1 Observations by Visit 
At the initial screening visit, patients will be classified as “naïve” and “non-naïve” patients 
depending on their history and use of prohibited medications within the past 42 days. The 
schedule of events during the initial screening visit and throughout the baseline period (through 
Visit 1) will vary depending on patient’s classification as “naïve” or “non-naïve”. 
For all patients, Visit 2 (Baseline 2) should occur 14 days (+7 days) days after Visit 1 
(Baseline 1). 
Visits 2 through Visit 6 are the same for all patients and should occur within +7 days of the 
scheduled visit. All times should be recorded using the 24-hour clock (e.g., 23:20, not 
11:20 pm).  
7.1.1 Screening (Visit 0 or Visit 1) 
At the initial screening visit, after written informed consent has been obtained and while 
patients eligibility is being confirmed against the inclusion and exclusion criteria, patients (or 
their legal representative) will be asked to confirm whether the patient has used any of the 
prohibited medications within the past 42 days. This will determine whether the patient is 
classified as “naïve” or “non-naïve” and their respective baseline period before the treatment 
period. 
Patients who confirm that they have not used any prohibited mediations within the past 42 days 
will be classified as “naïve” patients (Section 7.1.1.1).  
Patients who confirm they have used, or are unable to confirm or deny if they have used, any 
prohibited medication within the past 42 days will be classified as “non-naïve” patients 
(Section 7.1.1.2).  
7.1.1.1 “Naïve” Patients Screening 
Screening Visit/Visit 1 (Baseline 1): Written informed consent will be obtained. All patients 
will be screened for inclusion and exclusion criteria. Only patients meeting all the inclusion 
and none of the exclusion criteria will be allocated to the trial. The Screening Visit will be 
treated as Visit 1: the first assessment of the baseline period. 8  
• Informed consent/informed consent form (ICF) signature and patient information 
• Patient demographics9 
• Physical examination 
• Patient weight and height measurements 
• 60-day drug history including documentation of prior therapies/medications, including 
 
 
8 The Screening Visit will be confirmed as Visit 1 as soon as the patient’s eligibility is confirmed and the level of N-Acetyl-
D-Leucine detected in their urine sample is confirmed to be below the permitted threshold. Visit 1 will not be confirmed for 
patients classified as “naïve” but whose urine sample unexpectedly detect levels of N-Acetyl-D-Leucine above the permitted 
threshold. At the treating physician’s discretion, these patients will be given the option to undergo a minimum of 42 days 
washout before returning for a second screening visit. Should they agree, the patient will be reclassified and changed to 
“non-naïve”. 
9 Demographics for each patient will be collected in line with local regulations 

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prohibited medications, concomitant medications/therapies for treatment of study-
specific illness, including frequency of therapy (e.g., physiotherapy, speech therapy) 
(documented in hours per week) 
• Relevant medical history as well as medical history concerning the trial specific illness 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT)   10 
• Scale for Assessment and Rating of Ataxia (SARA)  
• Urine by dipstick: pregnancy test for women of childbearing potential 
• Check for remaining inclusion/exclusion criteria (including confirmation that 
prohibited medications have not been used for the past 42 days) 
• Patient classified as “naïve”  
• Vital signs 
• Cognitive assessment according to standard procedures of the clinical site to assist with 
the Clinical Impression of Change in Severity (CI-CS) primary anchor test selection 
• Determine Clinical Impression of Change in Severity (CI-CS) primary anchor test 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients <18 years 
old  
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient (if able) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 12-lead ECG 
• Urinalysis (done at central lab) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for safety laboratory tests, including FSH for menopausal women (done at 
central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
 
7.1.1.2 “Non-naïve” Patients: Baseline Period 
Screening Visit/Visit 0: Written informed consent will be obtained. All patients will be 
screened for inclusion and exclusion criteria. Patients who confirm they have used or are unable 
to confirm or deny if they have used, any prohibited medications within the past 42 days will, 
at the treating physician’s discretion, remain eligible for enrollment. The Screening Visit will 
be treated as Visit 0. 
• Informed consent/informed consent form (ICF) signature and patient information 
• Patient demographics  
• Physical examination  
• Patient weight and height measurements 
• 60-day drug history including documentation of prior therapies/medications, including 
prohibited medications, concomitant medications/therapies for treatment of trial-
 
 
10 The 9-hole Peg Test of the Dominant Hand (9HPT-D) and 8-meter Walk Test (8MWT) will be videotaped in a 
standardized manner at every visit., except Visit 0.  At Visit 1, these videos are made before the CI-CS primary anchor test is 
determined.  
 

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specific illness, including frequency of therapy (e.g., physiotherapy, speech therapy) 
(documented in hours per week) 
• Relevant medical history as well as medical history concerning the trial specific illness 
• Vital signs 
• Spinocerebellar Ataxia Functional Index (SCAFI)  
• Scale for Assessment and Rating of Ataxia (SARA) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Check remaining inclusion/exclusion criteria  
• Patient classified as “non-naïve”  
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Documentation of adverse events  
 
Visit 1 (Baseline 1): Minimum of 42 days after Visit 0/washout from prohibited medication. 
All patients will be screened for inclusion and exclusion criteria. Only patients meeting the 
inclusion and none of the exclusion criteria will be allocated to the trial. This second visit will 
be treated as Visit 1: the first assessment of the baseline period. 11 
• Check of inclusion/exclusion criteria (including confirmation that prohibited 
medications have not been used within the past 42 days) 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication   
• Physical examination 
• Vital signs  
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording for Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 12 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Cognitive assessment according to standard procedures of the clinical site to assist with 
the Clinical Impression of Change in Severity (CI-CS) primary anchor test selection 
• Determine Clinical Impression of Change in Severity (CI-CS) primary anchor test 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 12-lead ECG  
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site)  
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for safety laboratory tests, including FSH for menopausal women (done at 
central lab) 
 
 
11 This screening visit will be confirmed as Visit 1 provided the patient’s eligibility is confirmed and the level of N-Acetyl-
D-Leucine detected their urine sample is below the permitted threshold. Non-naïve patients whose urine sample after Visit 1 
unexpectedly detect levels of N-Acetyl-D-Leucine above the permitted threshold will be marked as non-compliant and 
withdrawn from the study. 
12 The 9-hole Peg Test of the Dominant Hand (9HPT-D) and 8-meter Walk Test (8MWT) will be videotaped in a 
standardized manner at every visit, except Visit 0. At Visit 1, these videos are made before the CI-CS primary anchor test is 
determined.  

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• Blood draw for sparse PK (done at PK Lab) 
• Documentation of adverse events  
 
7.1.2 Baseline Visit (Visit 2) 
Visit 2 (Baseline 2): Day 14 (+7 days) after Visit 1 (Baseline 1). The final day/ second 
assessment of the baseline period. The start of the treatment period. 
• Reconfirm patient eligibility, including confirmation that prohibited medications have 
not been used since Visit 1 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs  
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording for Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site 
before first dose of study drug is taken) 
• Urine test for N-Acetyl-D-Leucine (test done at PK lab) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
• Dispensing of trial drug + intake of study drug at site  
 
7.1.3 Treatment 1 (Visit 3) 
Visit 3 (Treatment 1) Day 28 (+7 days) of treatment period: First assessment of treatment 
period with N-Acetyl-L-Leucine. 
• Return of trial drug and compliance check (if feasible) 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged <18 
years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 

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• 12-lead ECG 
• Urinalysis (done at central lab) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
• Dispensing of additional study drug if needed 
 
7.1.4 Treatment 2 (Visit 4) 
Visit 4 (Treatment 2): Day 42 (+7 days) of treatment period: the final day/second assessment 
of treatment period with N-Acetyl-L-Leucine. The start of washout period. 
• Return of trial drug and compliance check13 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Physical examination  
• Vital signs 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged <18 
years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on Visit 2 to Visit 4 
• Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 2 to Visit 4 
• Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 2 to 
Visit 4 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
 
7.1.5 Washout 1 (Visit 5) 
Between Visit 4 – Visit 5: Wash-Out 
Visit 5 (Washout 1):  Day 28 (+7 days) of wash-out period: First assessment of wash-out 
period.  
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
 
 
13 Or after Visit 4 if IMP is returned via courier 

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• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 12-lead ECG  
• Urinalysis (done at central lab) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
 
7.1.6 Washout Visit 2 (Visit 6) 
Visit 6 (Washout 2): Day 42 (+7 days) of washout period: the final day/second assessment of 
washout period. 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Physical examination  
• Vital signs 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged <18 
years  
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on Visit 4 to Visit 6 
• Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 4 to Visit 6 
• Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 4 to 
Visit 6 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Medication History: If the patient was classified as “naïve”, confirm if they have used 
N-Acetyl-Leucine (L, DL, D) at any time prior to Visit 1 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for laboratory safety tests (done at central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
• Investigator determines continued treatment with IB1001 in patient’s best interest (if 
applicable) 

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• Informed consent/informed consent form (ICF) signature and patient information for 
Extension Phase (if applicable) 
• Check of inclusion/exclusion criteria for Extension Phase (if applicable) 
 
7.1.7 Early Termination Visit 
• Return of study drug and compliance check14 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Physical examination 
• Vital signs 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged <18 
years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on Previous Visit 
to ET Visit  
• Clinical Global Impression of Change (CGI-C) by caregiver based on Previous Visit 
to ET Visit  
• Clinical Global Impression of Change (CGI-C) by patient if able based on Previous 
Visit to ET Visit 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Medication History: If the patient was classified as “naïve”, confirm if they have used 
N-Acetyl-Leucine (L, DL, D) at any time prior to Visit 1 
• 12-lead ECG   
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for sparse PK (done at PK lab) 
• Documentation of adverse events  
 
 
14  Or after ET if IMP is returned via courier 

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8 STATISTICAL METHODS 
8.1 General Analysis Plan 
8.1.1 Disposition of Patients 
The number of patients enrolled, plus the numbers contained within the Safety Analysis Set 
(SAF), the intention-to-treat analysis set (ITT), the modified intention-to-treat analysis set 
(mITT) and the Per Protocol Set (PPS) will be summarized overall and by country. The number 
of patients discontinuing treatment, together with the primary reason for discontinuation will 
be presented. 
 
Protocol Deviations 
Protocol deviations include but are not limited to: 
• Violation of key inclusion/exclusion criteria 
• Use of Prohibited Medications 
• Inadequate study medication compliance 
• Urgent/ contingency measures implemented due to COVID-19, including delayed or 
missed assessments due to postponed or skipped in-person visits. 
 
Further detail will be provided in the Statistical Analysis Plan (SAP)  
8.1.2 Analysis Populations 
• The Safety Analysis Set (SAF) will consist of all patients who receive at least one dose 
of study drug (N-Acetyl-L-Leucine) 
• The intention-to-treat analysis set (ITT) will consist of all patients in the SAF with a 
video recording at either Visit 1 or Visit 2 (or both) 
• The modified intention-to-treat analysis set (mITT) will consist of all patients in the 
SAF with a video recording at either Visit 1 or Visit 2 (or both) and one video recording 
at either Visit 3 or Visit 4 (or both) 
• The Per Protocol Set (PPS) will consist of all patients with video recordings at baseline 
(Visit 1 or Visit 2), end of treatment (Visit 3 or Visit 4), and end of washout (Visit 5 or 
Visit 6) and without any major protocol deviations that could have influenced the 
validity of the data for the primary efficacy variable. 
8.2 General Considerations 
Statistical analysis will be performed using SAS; the version used will be specified in the SAP. 
All variables will be summarized using descriptive statistics. The number of patients, mean, 
standard deviation (SD), minimum, median, and maximum will be calculated for continuous 
and score variables. Frequency tables will be generated for categorical data. 
A one-sided significance level of 5% will be used throughout for all endpoints as a guide for 
evidence for activity. Conclusions regarding treatment efficacy will not solely rely on detecting 
statistical significance with equal emphasis placed on the magnitude and clinical relevance of 
treatment differences as judged by the point estimates. 
No correction for multiple comparisons will be included.  
8.3 Demographics, Baseline Characteristics and Concomitant Medications 
Demographic data and patient characteristics at baseline will be summarized descriptively. 

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Frequency and percentage of prior and concomitant medication use will be summarized by 
World Health Organization (WHO) Drug dictionary coded terms - Anatomic Therapeutic 
Chemical (ATC) classification and preferred term. 
8.4 Treatment Compliance 
Summary statistics for the number of N-Acetyl-L-Leucine doses taken, based on bottles of 
Study Drug dispensed and return bottle counts, will be calculated for each visit. Overall 
compliance in terms of the percentage of drug taken based on these data will be summarized 
descriptively together with the proportion of patients who take at least 80% of the prescribed 
medication. 
8.5 Efficacy Analyses 
The primary analyses of efficacy will be based on the mITT. Analyses of efficacy based on the 
PPS will also be undertaken to provide supplementary information.  
For each of the primary and secondary endpoints there will be separate analyses within key 
subgroups. The subgroups to be considered will be defined by: 
• Naïve versus non-naïve as determined at screening 
• Age (pediatric versus adult) 
• Age/weight/dosing group  
• Disease severity based on SARA below/ above the median SARA score at Visit 1 
• Gender (male versus female) 
• Region (US versus Europe) 
• Primary Anchor Test (9HPT-D or 8MWT)   
• Individual components of SARA scale: Gait Subtest 
• Composite of SARA Subtests 1-4 (Gait, Stance, Sitting, Speech) 
• Intra-patient variability between SARA score at Visit 1 (Baseline 1) versus Visit 2 
(Baseline 2) (below/above median). 
• Intra-patient variability between CI-S score Visit 1 (Baseline 1) versus Visit 2 
(Baseline 2) (below/above median). 
Additional subgroups can be added at the time of analysis on an exploratory basis. 
Separate trials are planned to be conducted with N-Acetyl-L-Leucine for NPC, GM2-
gangliosidosis, and ataxia-telangiectasia. There will however be a planned series of meta-
analyses that will bring together the data from the studies for the primary and selected 
secondary endpoints. Further details will be provided in an MASAP. 
8.5.1 Primary Efficacy Endpoint 
The primary endpoint for the study is based on blinded raters’ Clinical Impression of Change 
in Severity (CI-CS) comparing videos showing the patient’s change in performance over 42 
days (+7 days) on a pre-defined anchor clinical symptom scale: either the 9 Hole Peg Test of 
the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT). A manual will be provided 
to each clinical site, which provides instructions for the administration of the CI-CS [
 
. Similarly, a video-acquisition manual will be provided, which provides instructions for 
making standardized videos of the 8MWT and 9HPT-D primary anchor tests 
  
The comparison of the Visit 4 video with the Visit 2 video and the comparison of the Visit 6 
video with the Visit 4 video will provide the scores that contribute to the primary endpoint. 

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Each of these comparisons will score change on a 7-point Likert scale (+3=significantly 
improved to -3= significantly worse).  
During the pre-treatment period, the treating physician will evaluate each patient’s clinical 
symptoms and select, at Visit 1, either the 9HPT-D or 8MWT as the primary anchor around 
which the CI-CS assessment will be scored. A cognitive assessment should be performed at 
Visit 1 according to standard procedures of the clinical site to assist with the selection of the 
anchoring functional test appropriate for each patient from both a cognitive and a motor 
perspective. 
The primary evaluation of the CI-CS will be performed by two independent raters whose 
assessments will be based on videos of the anchor test taken at each visit. These raters will be 
blinded to the treatment periods (baseline, treatment, or washout) to reduce detection and 
performance bias.  
The primary endpoint is defined as the CI-CS comparing end of treatment with N-Acetyl-L-
Leucine (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout 
(Visit 6) with the end of treatment with N-Acetyl-L-Leucine (Visit 4) based on the primary 
anchor test.   
The CI-CS assessment will instruct the blinded rater to consider: ‘compared to the first video, 
how has the severity of their performance on the 9HPT-D or 8MWT changed (improved or 
worsened) in 6-weeks as observed in the second video?’ 
Each video pairing (CI-CS) will be read by the two independent raters, and the 
appropriate Likert scale score will be entered onto the eCRF. If there is a difference of 
one (1) point in the two primary blinded reviewers’ CI-CS scores for a specific video 
pairing, the two scores will be averaged. If there is difference greater than one (1) point 
between the two primary blinded reviewers’ CI-CS scores for a specific video pairing, an 
adjudication read will be triggered. In such cases, a third blinded reviewer will review the 
scores given from each of the two primary independent reviewers and determine which 
score is more accurate, that of reviewer A or reviewer B (adjudication by consensus). The 
adjudicator's decision will be the final score for that video assessment.  
The statistical analysis of this endpoint will utilize a single sample t-test comparing the mean 
value of the primary endpoint with zero. This endpoint allows the effect N-Acetyl-L-Leucine 
to be measured both in terms of improvement during treatment followed by any deterioration 
once treatment is removed. 
Summary statistics will in addition be calculated separately according to subgroups defined by 
the primary anchor test  
8.5.2 Secondary Efficacy Endpoints 
A key Secondary Endpoint that will be evaluated to directly supplement the analysis of the 
primary endpoint is based on the independent raters’ Clinical Impression of Severity (CI-S) of 
each video. 
 
The independent raters will be given 6 videos of the patient’s performance of the primary 
anchor test taken at Visit 1 to Visit 6. The videos will be labeled as Video A, B, C, D, E, F. 
The videos will be presented in a random order, and the independent raters will be blinded to 
the timepoint corresponding to each video. 
 
For each video, the independent raters will make their evaluation of the CI-S, which asks: 

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“Considering your total clinical experience with this particular population, how ill is the 
patient at this time?”  
 
The CI-S is rated on a 7-point Likert scale ranging from + 3 (normal, not at all ill) to -3 (among 
the most extremely ill patients). For the CI-S, if there is one (1) point or more difference in the 
two blinded reviewers scores, the two scores will still be averaged.  
 
 
Supportive secondary endpoints will be evaluated that directly supplement the analysis of the 
primary endpoint as follows: 
 
• The CI-CS for end of treatment with N-Acetyl-L-Leucine (Visit 4) versus baseline 
(Visit 2) and end of washout (Visit 6) versus end of treatment with N-Acetyl-L-Leucine 
(Visit 4) will each be summarized descriptively. 
• Improvement in the primary and non-primary anchor test measures will be evaluated 
based on the change in the blinded raters’ Clinical Impression of Severity (CI-S) 
between baseline (average for Visit 1 and Visit 2) and end of treatment with N-Acetyl-
L-Leucine (average for Visit 3 and Visit 4) minus the change in CI-S between end of 
treatment with N-Acetyl-L-Leucine (average for Visit 3 and Visit 4) and end of washout 
(average for Visit 5 and Visit 6). Statistical testing for the primary anchor test CI-S 
endpoint will be as for the primary endpoint. There will be no formal statistical testing 
of the non-primary test. 
• Sensitivity measurement of change in performance on either the 9HPT-D or the 8MWT 
on a 3-point scale. Using the CI-CS outcome for the primary anchor test based on the 
data for Visits 2 and Visit 4, any patient given a score of -1, -2, or -3 on the CI-CS will 
be classified as worsened (<0). Any patient classified as 0 on the CI-CS will be 
classified no change (0). Any patient given a score of +1, +2, +3 on the CI-CS will be 
classified as improved (>0). A similar classification will use the CI-CS comparing the 
end of treatment with N-Acetyl-L-Leucine with end of washout based on the data for 
Visits 4 and Visit 6 and the difference between these scores calculated. The descriptive 
table will be similar to the primary endpoint. No statistical analysis will be performed. 
• An evaluation of the CI-CS for the test (9HPT-D or 8MWT) that was not selected as 
the primary anchor test (i.e., the non-primary anchor test) will also be undertaken. There 
will be no formal statistical testing of these endpoints, however.  
 
Bland-Altman plots in relation to videos from Visit 1 and 2, Visits 3 and 4 and Visits 5 and 6 
will be produced to help inform the stability of the outcome evaluation and the disease itself at 
baseline, end of treatment and end of washout. The scatter plot for videos from Visits 1 and 2 
will place the average CI-S outcome of the videos from Visits 1 and 2 on the x-axis and 
difference between those on the y-axis. A y=0 line will be placed on the plot for reference 
purposes. Similar plots will be produced for videos from Visits 3 and 4 and videos from Visits 
5 and 6.  
Additional secondary endpoints will investigate other measures of symptoms and quality of 
life. Descriptive statistics will be provided for these measures at each visit and also changes 
from baseline (Visit 2) to the end of treatment with N-Acetyl-L-Leucine (Visit 4), as well as 
end of treatment with N-Acetyl-L-Leucine (Visit 4) to the end of post-treatment washout 
(Visit 6) for the following measures: 
 

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• Spinocerebellar Ataxia Functional Index (SCAFI)15 
• Scale for Assessment and Rating of Ataxia (SARA) score 
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y16 for patients aged <18 
years 
• Treating Physician Clinical Global Impression of Severity (CGI-S) at every visit  
• Treating Physician Clinical Global Impression of Change (CGI-C) comparing end of 
treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment 
(Visit 4) 
• Caregiver Clinical Global Impression of Severity (CGI-S) at every visit  
• Caregiver Clinical Global Impression of Change (CGI-C) comparing end of treatment 
(Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4) 
• Patient Clinical Global Impression Scales Impression of Severity (CGI-S) at every visit 
if they are able 
• Patient Clinical Global Impression of Change (CGI-C) comparing end of treatment 
(Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4) 
if they are able 
The SARA total score, the SCAFI total score, the individual SCAFI subtests: 9 Hole Peg Test 
with the Dominant Hand (9HPT-D), 8 Meter Walk Test (8MWT), and PATA test, will be 
evaluated statistically based on a single sample t-test or a single sample Wilcoxon Signed Rank 
test. 
The individual SCAFI subtest: 9 Hole Peg Test with Nondominant hand (9HPT-ND) will be 
evaluated descriptively. 
The CGI-S measures, and caregiver and patient CGI-C measures will be summarized 
descriptively. The physican’s CGI-C measures will be analyzed as for the CI-CS primary 
endpoint. 
The measures of the two indices (-5L and -Y) of the EQ-5D descriptive system and measures 
of the two indices (-5L and -Y) of the EQ-5D visual analogue scale (VAS) will be evaluated 
descriptively. 
8.5.3 Exploratory Efficacy Endpoints 
Sparse PK sampling will be collected to characterize the PK of N-Acetyl-L-Leucine in patients 
with A-T.  
8.6 Missing Data 
The primary endpoint will utilize assessments based on single video recordings at the end 
baseline period (Visit 2), end of the treatment period (Visit 4), and end of the washout period 
(Visit 6). If the Visit 2 video is missing, the Visit 1 video will be used in its place. Similarly, 
if the Visit 4 and Visit 6 videos are missing, Visit 3 and Visit 5 videos will respectively be 
used in their place.  
Analyses based on the mITT analysis set will utilize a last observation carried forward (LOCF) 
approach for missing videos at Visit 5 and Visit 6. For the primary endpoint CI-CS, this implies 
that the CI-CS value for Visit 4 to Visit 6 will be assigned the value 0 (stable) if both videos at 
Visit 5 and Visit 6 unavailable. 
 
 
15The 9 Hole Peg Test of the Dominant Hand (9HPT-D) and the 8 Meter Walk Test (8MWT), will be videoed for every 
patient at every visit except Visit 0 
16 European Sites Only 

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A sensitivity analysis will be undertaken to assess the robustness of the primary analysis of the 
primary endpoint in the mITT analysis set as follows: 
If either video for Visit 3 or Visit 4 is available,  but either video from Visit 5 and Visit 6 are 
unavailable, impute the value -1 (worsening) instead of 0 for the CI-CS for Visit 4 to Visit 6, 
unless the missingness is due to a “technical reason” (e.g. due to machine failure).  
Additional methods to deal with missing data will be detailed in the SAP. Any changes from 
the SAP will be described and justified in the Clinical Study Report. 
8.7 Blinding 
The blinded independent raters will be given each of the 6 videos initially in a random order to 
make their evaluation of CI-S for each video. The blinded independent raters will then be 
provided with 3 pairs of video recordings blinded to information on the visits associated with 
these videos and their order and asked to provide a score for CI-CS for each pair. Further details 
regarding this blinding process will be detailed in the SAP. 
8.8 Safety Analyses 
The SAF will be the basis for all analyses of safety and tolerability.  
8.9 Interim Analyses 
There are no planned interim analyses. Determination of Sample Size 
It is postulated that N-Acetyl-L-Leucine will show effectiveness in 30% of patients and this 
success rate is viewed as being clinically important. Assuming that this group of patients will 
have scores that are evenly distributed across the values 1 and 2 for the primary endpoint and 
further that the remaining 70% of patients will have scores that are evenly distributed between 
the values -1, 0, and 1. The resulting mean score is 0.45 and the standard deviation (SD) for 
the primary endpoint under these assumptions is then 1.02. With 30 patients reporting on the 
primary endpoint, the study will have 76% power to detect a treatment benefit in a 5% 
one-sided one-sample t-test. 
 
 
8.10 
COVID-19 Details 
This study is conducted during the COVID-19 outbreak. The following data capture decisions 
have been taken due to national, local, or site-specific restrictions imposed due to COVID-19, 
with the primary need to prioritize the safety of clinical study teams and patients, and to 
maintain the integrity of the study/data collection. 
 
- 
All protocol deviations relating to COVID-19 are collected 
- 
If in-person visits are not feasible, Visits 3 and / or 5 should be skipped and a remote 
visit conducted (i.e. phone, video conference) 
- 
If in-person visits are not feasible, Visits 4 and / or 6 can be postponed until the in-
person visit is feasible and should be performed in person.  
- 
For skipped in-person Visit 3/5 or postponed in-person Visit 4/6, remote visits should 
occur approximately -/+ 3 days from the original visit (as feasible). 
 
Currently, the complete impact of COVID-19 on the proposed statistical analyses is 
unknown. The statistical analysis plan already includes policies for handling missing data. 
Specific items/changes related to COVID-19 are being detailed in a separate document to the 

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SAP (Addendum 1), which will be maintained throughout the study and adjusted as needed 
based on the duration and extent of the impact of the COVID-19 situation.  
 

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9 DATA HANDLING AND RECORD KEEPING 
9.1 Data Collection 
Study data for all patients will be collected in a confidential fashion using an electronic Case 
Report Form (eCRF). Access to the eCRF is restricted to staff members not involved in any 
aspect of the blinded evaluations. All the information required by the protocol must be 
documented and any omissions explained. The Investigator must review all eCRF entries for 
completeness and accuracy. Source documents, including all demographic and medical 
information, eCRFs and informed consent form for each patient in the study must be 
maintained by the Investigator. All information in the eCRFs must be traceable to the original 
source documents. An audit trail of all changes to this database, including the date, reason for 
the data change and who made the change, will be maintained within the same database. The 
audit trail will be part of the archived data at the end of the study. Concomitant medication and 
AEs will be coded using standardized medical dictionaries. 
Responsible Monitor will review eCRFs entered by investigational staff for completeness and 
accuracy. Checks for data discrepancies in the eCRFs will be performed and the resulting 
queries will be notified to the investigational site. Designated Investigator site staff are required 
to respond to queries and make any necessary changes to the data.  
The complete data management process (data capture, data entry, data validation, checks on 
plausibility, query handling, data editing after entry, coding, data base closure, etc.) will be 
defined within a data handling plan/ data management plan. 
9.2 Data Correction 
Automatic and manual queries will be defined according to the data validation plan. These 
queries will be generated by the assigned Data Management Department and sent through the 
electronic data capture (EDC) system for clarification. Corrections will be entered directly into 
the system. This procedure will be repeated until all queries are resolved. 
9.2.1 Deviations from the Protocol 
Deviations from the protocol will be judged during the study and/or when an individual 
patient’s eCRF is completed (monitored) and documented in the protocol deviations log. 
Protocol deviations will be classified (major/minor protocol deviations) for statistical analysis. 
9.3 Data Quality Assurance 
If applicable, the Sponsor (IntraBio Ltd.) and/or their representative (i.e. Monitor engaged by 
the Sponsor) will conduct a site visit to verify the qualifications of each investigator, inspect 
the site facilities, and inform the Investigator of responsibilities and the procedures for ensuring 
adequate and correct documentation. 
9.3.1 Retention of Records 
All essential documents must be safely retained by the Investigator for at least 2 years following 
the date a marketing application is approved for the drug, for the indication for which it is being 
investigated; or if no application is filed or if the application is not approved for such indication 
for 15 years after the investigation is discontinued and the regulatory authorities are notified.   
9.4 Protection of personal data 
The completion of the Study involves the collection and processing of Personal Data. All 
processing of Personal Data at the clinic and by the Sponsor must be carried out in accordance 
with national legislation concerning the protection of Personal Data. Parties involved in the 

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process will observe the requirements provided under Regulation (EU) 2016/679 concerning 
general personal data protection. 
The Investigator must ensure that the patient’s privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, patients will be identified by a patient ID number only. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent form) should 
be kept in a strictly confidential file by the investigator. 
The Investigator shall permit direct access to patients’ records and source document for the 
purposes of monitoring, auditing, or inspection by the Sponsor, authorized representatives of 
the Sponsor, Regulatory Authorities and IECs and IRBs.  
As part of the required content of the informed consent, patients will be informed that their 
records may be reviewed by the Sponsor’s designee and by regulatory agencies.  Should access 
to medical record require a separate waiver or authorization, it is the Investigator’s 
responsibility to obtain such permission from the patient in writing before the patient is entered 
into the study. 
 
9.5 COVID-19 Protocol Deviations and Missing Data 
Protocol deviations related to COVID-19 are documented. These deviations in protocol-
specific procedures due to COVID-19 (changes in study visit schedules, remote and / or 
missed visits, or patient discontinuations) may lead to missing information.  
For each patient, the eCRF will capture specific information that (as much as possible) 
explains the basis of the missing data, including the relationship to COVID-19 for missing 
protocol-specified information (e.g., from missed study visits or study discontinuations due to 
COVID-19). This information will be summarized in the Parent Study clinical study report. 
 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Study Initiation Activities 
The investigator(s) are informed about study objectives and methods, the inclusion and 
exclusion criteria, the time-schedule, and study procedures at an investigators’ meeting (if 
applicable), and during the Site Initiation Visit by the Sponsor and the monitor. 
10.2 
Training of Site Staff 
The Principal Investigator (PI) is responsible for the conduct of the study at their study site, 
including delegation of specified study responsibilities and training of study staff. The PI shall 
ensure that the study is carried out in accordance with the protocol, ICH/GCP guidelines, and 
local regulations. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). He or she will ensure that appropriate training relevant to the study is given to all 
of these staff, and that any new information of relevance to the performance of this study is 
forwarded to the staff involved. 
10.3 
Documentation and Filing 
10.3.1 List of Patients (patient identification log) 
The Investigator will keep a confidential list of names of all patient participating in the study, 
so that the patients’ records can be identified if necessary.  
In addition, the Investigator will keep a list of all patients screened on a screening log to 
document identification of patients who were consented and entered study screening. If 
someone is not eligible to participate in the study, a reason must be provided. 
10.3.2 Source Data 
Per ICH, source data are defined as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. Source data are contained in 
source documents which comprise clinical documentation, data, and records (e.g., hospital 
records, clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, patient files, and records kept at the pharmacy, 
at the laboratories and at medico-technical departments involved in the clinical study). When 
a copy is used to replace an original document, the copy should fulfil the requirements for 
certified copies. 
10.3.3 Investigator Site File / Regulatory Binder 
Before site initiation, an Investigator Site File (ISF) will be provided to each site. The ISF will 
include essential documents as defined by the ICH GCP guideline and applicable local 
requirements that are required for study initiation at the investigational site. 
From that point onwards, the Investigator will be responsible for the update and maintenance 
of the ISF, which will be reviewed periodically by the monitor(s). These documents will be 
reviewed during an audit by the Sponsor or an inspection by the Regulatory Authorities. 
All study-related documents are to be archived and stored according to the local regulatory 
requirements and agreement with the study Sponsor. 
Details pertaining to the retention and archiving of study documents are found in Section 11.4. 

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10.4 
Alternative Site due to COVID-19 
Based on the exceptional circumstances of the COVID-19 pandemic and need to minimize 
risk (i.e. exposure to COVID-19) study visits may be conducted at alternative locations 
provided: 
• The PI determines it is justified based on the personal benefit-risk ratio for the 
individual trial participant; 
• The (i) patient and/or their family/ legal representative; (ii) PI / other applicable 
members of the study team; and, (iii) personnel at the alternative location (if 
applicable) consent to this alternative location  
• Conducting the study visit at the alternative location does not pose an unacceptable 
safety risk (as agreed by (i) patient and/or their family/ legal representative; (ii)PI / 
other applicable members of the study team; and, (iii) personnel at the alternative 
location (if applicable) 
• Traveling to/from this alternative location is permitted by national or local legislation 
and allowed by the alternative site and arrangements are made to provide adequate 
transportation (for applicable persons) 
• If a study assessment cannot be performed at the alternative location, this should be 
documented and captured in the eCRF.  
 
10.5 
Monitoring 
The monitor is responsible for checking the quality of data 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. 
The interval between monitoring visits will depend on the recruitment rate and the complexity 
of the study. 
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. 
Due to COVID-19, alternative monitoring measures may be required if on-site monitoring is 
not permitted and deviations to the study monitoring schedule are necessary. If it is not 
possible to follow the IntraBio recommended monitoring schedule of onsite visits due to 
national, local, or site-specific restrictions, possible temporary, alternative measures may be 
implemented to maintain proper oversight of the clinical trials [IntraBio Ltd 2020b]. All 
monitoring deviations related to COVID-19 should be well-documented to enable appropriate 
evaluation of the clinical trials. 
 
Remote source data verification (SDV) may be performed only in countries where it is 
allowed per national and local law, and subsequently, if the site and Principal Investigator 
agree to this method of monitoring. If remote SDV is allowed per the 
aforementioned requirement, all applicable trainings (monitors, sites, etc) on remote SDV 
procedures should be performed in accordance with the national/local regulations. Site staff 
should be available to respond to monitors questions during the remote monitoring visit. 
 
10.6 
Audits and Inspections 
The Sponsor’s or designated vendor’s Quality Assurance Department may visit the 
investigative site to audit the performance of the study, as well as all study documents. Audits 
may also be performed by contract auditors who will be instructed about the timing and extent 

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of the audits. In the event of an audit at the investigational site, the monitor will usually 
accompany the auditor(s).  
Inspections by Regulatory Authority representatives and IECs/IRBs are possible at any time, 
even after the end of the study. The Investigator is to notify the Sponsor immediately of any 
such inspection. The Investigator and institution will permit study-related monitoring, audits, 
reviews by the IEC/IRB and/or Regulatory Authorities and will allow direct access to original 
source documents for monitoring, audits, and inspections. 

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11 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
11.1 
Good Clinical Practice 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP 
(E6 Consolidated Guidance). 
11.2 
Informed Consent 
A sample Informed consent form (ICF) will be provided to each site. No major deviations may 
be made from the sample ICF other than country- or region-specific formatting or 
requirements. The Sponsor and its advisors will review the draft ICF before it is finalized, and 
the final IRB/EC-approved documents must be provided to the Sponsor for regulatory 
purposes. 
 
As required, approved IRB/EC patient facing documents like the ICF will be made available 
in the patients/ parent/ legal guardian’s native language.  
The ICF must be signed by the patient or the patient’s legal guardian before his or her 
participation in the study. The Principal Investigator (PI) at each site will determine whether 
or not each patient has the capacity to give consent. When the patient is an adult (aged 16 or 
older in the UK) and mentally impaired, and not able to give consent to confirm their 
willingness to participate in the study, a legal representative will be asked to decide on behalf 
of the patient if they will participate in the study.  
The PI will determine a participant’s capacity to consent according to the Mental Capacity Act 
(MCA). The PI will use a two-stage test of capacity to determine if a subject has the capacity 
to make a decision for themselves by considering:  
 
• Does the patient have an impairment of the mind or brain (temporary or 
permanent), or is there some sort of disturbance affecting the way their mind 
or brain works?   
• If so, does that impairment or disturbance mean that the patient is unable to 
make the decision in question at the time it needs to be made? 
 
If the PI determines the patient is mentally able to understand the study and give their informed 
consent verbally, but the patient is not able to give the signature by him/herself because of 
physical impairment, the signature of an impartial witness will be accepted after the patient has 
given verbal informed consent. 
The adult lacking capacity will also be informed as best as possible about the study according 
to, and at a level appropriate for, their capacity of understanding (as determined by the PI). No 
assent will be obtained from the impaired patient as standard, but the information discussed 
with the impaired adult patient will be documented in the patient’s records. 
A copy of the ICF must be provided to the patient or the patient's legal representative. If 
applicable, it will be provided in a certified translation of the local language. The original 
signed ICF must remain in each patient’s study file and must be available for verification by 
study monitors at any time. 

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Due to COVID-19, reconsent for updated ICFs may be done remotely17. Approved updated 
patient information sheets and consent forms should be provided to trial participants by the 
investigator by e-mail, mail or courier before re-consent is obtained. The patient (or parent / 
legal representative) should be contacted by phone by the responsible site staff to discuss the 
updated ICF and answer all questions. After all questions have been answered and the patient 
(or parent/legal representative) has indicated their understanding of the ICF, oral consent 
should be obtained and documented. The patient (or parent/legal representative) will sign the 
ICF provided to them, and this will be returned to the site as soon as possible. A copy of the 
fully signed ICF will be provided to the patient (or parent/legal representative) as soon as 
possible.  
 
Both parties should sign and date the ICF and the wet-ink signed ICF should be filed in the 
investigator site file. The exact procedures by which remote ICF was obtained should be 
recorded in the patient source documents and / or on the applicable ICFs forms. 
 
11.3 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local regulatory 
requirements. The Sponsor must ensure that all ethical and regulatory requirements have been 
met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).  
In accordance with applicable regulatory body guidance’s issued in relation to COVID-19, 
changes to the protocol may need to be implemented without REC/IRB approval or before 
filing an amendment to the CTA/IND to minimize or eliminate immediate hazards or to 
protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) 
and to maintain the integrity of the clinical trial. 
Any guidance issued by the Sponsor to clinical trial sites describing deviations in protocol-
specific procedures which may be necessary due to COVID-19 should be submitted to the 
applicable CA/REA/IRB for reference at the time they are issued.  All changes will be 
reported afterwards in a substantial amendment (SA) protocol application. 
 
11.4 
Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product. 
 
 
17 Per EMA Guidance on the Management of Clinical Trials during the COVID-19 (CORONAVIRUS) 
Pandemic, Version 3, during the outbreak of COVID-19 “it should be avoided that trial participants visit trial 
sites for the sole purpose of obtaining re- consent.” 

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However, these documents should be retained for a longer period if required by the applicable 
regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
 
11.5 
Data Safety Monitoring Board 
The Data Safety Monitoring Board (DSMB), in conjunction with the study Medical Monitor 
and/or Sponsor, is responsible for the oversight of the safety. For this purpose, the DSMB will 
receive regular updates of safety.  
The DSMB will review all safety data on a regular basis. The exact content of review material 
and the frequency of review will be detailed in the DSMB charter.  
The DSMB will also be involved in risk-assessments of the impact of COVID-19, and 
reviewing any guidance issued by the Sponsor in regard to the global pandemic. They may 
give recommendations on the conduct of trial operations and protocol adjustments which may 
be required in light of COVID-19.   
11.6 
Premature Termination of the Study 
If Sponsor, an Investigator, or regulatory authorities discover conditions during the study 
that indicate that the study or related activities at a particular site should be terminated, this 
action may be taken after appropriate consultation between Sponsor and the Investigator. 
Conditions that may warrant study or site termination include but are not limited to: 
1. The incidence or severity of AEs in this or other studies indicates a potential health hazard 
to patients 
2. Patient recruitment is unsatisfactory 
3. Data recording is inaccurate or incomplete 
4. Investigator(s) do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
5. GCP is not being maintained or adequately followed 
6. Administrative reasons 
7. Reasons unrelated to the study. 
8. Complications related to pandemics such as COVID-19 
Study or site termination and follow-up will be performed in compliance with the conditions 
set forth in 21 Code of Federal Regulations (CFR) Section 3.1.2 and/or other national and local 
regulations, as applicable, and in compliance with the principles set forth in International 
Conference on Harmonization (ICH) Good Clinical Practices (GCPs) and ethical principles 
established by the Declaration of Helsinki. 

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11.7 
Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRFs and other documents submitted to IntraBio or affiliates by their patient number allocated 
in the trial, not by name. Documents not to be submitted to IntraBio or affiliates that identify 
the patient (e.g., the signed informed consent, patient identification list) must be maintained by 
the Investigator as part of the ISF in a secure and confidential manner.  
11.8 
Liability and Insurance 
In accordance with the relevant national regulations, the Sponsor will take out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is 
designed for the event that a fatality, physical injury, or damage to health occurs during the 
clinical study’s execution. 
11.9 
Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study for 
the purposes of national and international registration, publication and information for medical 
and pharmaceutical professionals. If necessary, the authorities will be notified of the 
investigator's name, address, qualifications and extent of involvement. 
It is understood that the Clinical Trial is part of the Multi-Center Clinical Trial and publication 
of results is expected. IntraBio will actively pursue publication of the results of the study in 
cooperation with the Principal Investigators (PIs), subject to the terms and conditions of the 
clinical trial agreement between IntraBio, the Investigator, and their respective clinical trial 
site. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. 

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Schneider L. S., Olin, J. T., Doody, R. S., Clark, C. M., Morris, J. C., Reisberg, B., et al. (1997). 
Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global 
Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc 
Disord., 11 Suppl 2, S22-32. 
Schniepp, R., Strupp, M., Wuehr, M., Jahn, K., Dieterich, M., Brandt, T., et al. (2016). 
Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia—a case series. 
Cerebellum Ataxias. 3, 8. 
Solmi, M., Pigato, G., Kane, J. M., Correll, C. U. (2018). Treatment of tardive dyskinesia with 
VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. 
Drug Des Devel Ther., 12: 1215-1238. 
Strupp, M., Teufel, J., Habs, M., Feuerecker, R., Muth, C., van de Warrenburg, B. P., et al. 
(2013). Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J 
Neurol., 260, 2556–2561. 
Study No. V00251 IV 101 (704045) (2008). Pharmacokinetic study of 250mg, 1 g, 4 g L-
acetylleucine and 500 mg Tanganil® single dose after intravenous administration in 24 
healthy volunteers, Mediscis.  
Study No. V00251 IV 201 (2012). Double-blind placebo controlled study of 1 g, 2 g and 4 g 
V0251 efficacy and safety in vestibular neuritis. 
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4 g and 8 g) and intravenous (1g, 2g, 4g) single increased doses in 18 healthy volunteers, 
Mediscis. 
Study No. V00251 ST 201 1A (2013). V0251 oral suspension efficacy and tolerance in 
vestibular neuritis. A randomised double-blind placebo controlled study. 
Subramony, S. H. (2007). SARA--a new clinical scale for the assessment and rating of ataxia. 
Nat Clin Pract Neurol., 3(3), 136–137. 
United Kingdom Medicines and Healthcare Products Regulatory Agency (UK MHRA) (2018). 
Scientific Advice Ref 1705/N-acetyl-L-leucine. Unpublished.  
United States Department of Health and Human Services (2018a). Meeting Minutes: PIND 
Application 134369 for N-Acetyl-L-Leucine (IB1001). Food and Drug Administration: 
Division of Gastroenterology and Inborn Errors. Unpublished.  
United States, Department of Health and Human Services (2018b). Meeting Request: Written 
Response PIND Application 138188 for N-Acetyl-L-Leucine (IB1001). Food and Drug 
Administration: Division of Neurology. Unpublished. 
Utz, J., Kim, S., King, K., Ziegler, R., Schema, L., Redtree, E., Whitley, C. (2017). Infantile 
gangliosidoses: Mapping a timeline of clinical changes. Mol. Genet. Metab., 121, 170–179. 
Vanier, M. (2010). Niemann-Pick disease type C. Orphanet J. Rare Dis., 5, 16. 
van Os, N. J. H., Roeleveld, N., Weemaes, C. M. R., Jongmans, M. C. J., Janssens, G. O., 
Taylor, A. M. R., et al. (2016). Health risks for ataxia-telangiectasia mutated heterozygotes: a 
systematic review, meta-analysis and evidence-based guideline. Clin. Genet. 90, 105–117. 
Wille, N., Badia, X., Bonsel, G., Burström, K., Cavrini, G., Devlin, N., et al. (2010). 
Development of the EQ-5D-Y: a child-friendly version of the EQ-5D. Qual Life Res., 19(6), 
875-886. 

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Wraith J.E., Baumgartner, M.R., Bembi, B., Covanis, A., Levade, T., Mengel, E., Pineda, M., 
Sedel, F., Topcu, M., Varnier, M.T., Widner, H., Wijburg, F.A., Patterson, M.C. (2009). 
Recommendation on the diagnosis and management of Niemann-Pick disease type C. Mol 
Genet Metab., 98, 152-165. 
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Validation of a Novel Scoring System for Changes in Skeletal Manifestations of 
Hypophosphatasia in Newborns, Infants, and Children: The Radiographic Global Impression 
of Change Scale. J Bone Miner Res., 33(5), 868-874. 
Yanjanin, N.M., Vélez, J.I., Gropman, A., King, K., Bianconi, S.E., Conley, S.K., Brewer, 
C.C., et al. (2010). Linear Clinical Progression, Independent of Age of Onset, in Niemann-Pick 
Disease, type C. Am J Med Genet B Neuropsychiatr Genet, 153B(1), 132–140.

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Name of Sponsor/Company: 
IntraBio Ltd. 
Protocol Number: 
IB1001-203 
Phase of Development: 
Phase II 
Title of the Protocol: 
Effects of N-Acetyl-L-Leucine on Ataxia-Telangiectasia: A multinational, multicenter, open-label, 
rater-blinded Phase II study. 
 
Short title: 
Short Title: A safety and efficacy study of N-Acetyl-L-Leucine on Ataxia-Telangiectasia  
Purpose: 
The primary purpose of the study is to evaluate the safety and efficacy of N-Acetyl-L-Leucine 
(IB1001) in the treatment of Ataxia-Telangiectasia (A-T) 
Study Rationale: 
The goal of this study is to demonstrate that N-Acetyl-L-Leucine is efficacious in improving 
symptoms, functioning, and quality of life against the defined endpoints in patients with Ataxia-
Telangiectasia (A-T) for the purpose of establishing the benefit/risk balance of investigational 
medicinal product in the proposed clinical setting. 
 
N-Acetyl-L-Leucine is the L-enantiomer of N-Acetyl-DL-Leucine, a modified amino acid that has 
been available in France since 1957 under the trade name Tanganil® (Pierre Fabre Laboratories) as 
a treatment for acute vertigo and is available as a solution for injection and as a tablet. N-Acetyl-L-
Leucine is not currently authorized anywhere in the world for the treatment of any condition.   
 
The sponsor’s (IntraBio Ltd.) development of N-Acetyl-Leucine for A-T began with the 
investigation of the commercially available racemic mixture, N-Acetyl-DL-Leucine (Tanganil®). 
Published case studies are available in the literature describing the effect of acute treatment with the 
racemate N-Acetyl-DL-Leucine in patients with inherited cerebellar ataxias [Strupp et al, 2013; 
Schniepp et al., 2016] as well as Niemann-Pick disease type C (NPC) [Bremova et al, 2015]. An 
additional case series is available in the literature describing the neuroprotective, disease modifying 
effect of long-term treatment with N-Acetyl-DL-Leucine for NPC [Cortina-Borja et al, 2018]. In all 
studies, the compound was well-tolerated with no discernible serious side effects. 
 
Recent in vitro and in vivo studies have demonstrated that the L-enantiomer is believed to mediate 
the therapeutic effect and have potential clinical benefits over the racemic mixture. IntraBio 
therefore intends to focus further development on N-Acetyl-L-Leucine without the presence of D-
enantiomer. The safety profiles of both N-Acetyl-DL-Leucine and N-Acetyl-L-Leucine have been 
characterized in both preclinical and clinical studies, and on the basis of compassionate use 
experience with N-Acetyl-DL-Leucine in Ataxia-Telangiectasia (as well as in patients with other 
Confidentiality Statement 
This clinical study protocol is the confidential information of IntraBio Ltd. and is 
intended solely for the guidance of the clinical investigation. This protocol may not be 
disclosed to parties not associated with the clinical investigation and may not be used for 
any purpose without the prior written consent of IntraBio Ltd. 

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lysosomal storage disorders, neurodegenerative and genetic diseases, and further indications 
[Michael Strupp, Personal Communication]. 
 
Based on these findings, IntraBio is conducting a Phase II study investigating the efficacy and safety 
of N-Acetyl-L-Leucine for the treatment of A-T. Patients will only be included in the study if they 
meet the inclusion and exclusion criteria described in the study protocol approved by the relevant 
ethics committees and the regulatory authorities and informed consent is obtained. To further 
minimize risks, patients will receive the best available clinical care to manage the underlying 
conditions with careful monitoring of adverse events that may arise during the course of the clinical 
study. 
 
The confidentiality of all patients will be protected by pseudonymization and in accordance with 
guidelines and local laws. 
Primary Objective: 
The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters’ 
Clinical Impression of Change in Severity (CI-CS) in the treatment of Ataxia-Telangiectasia (A-T) 
Secondary Objectives: 
o To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms of ataxia, 
functioning, and quality of life for patients with A-T. 
o To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in adults and 
children with A-T, including patients aged ≥13 years, and weight-tiered doses in 
children 6 - 12 years of age  
Exploratory Objectives: 
o To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with A-
T 
Primary Endpoint: 
The primary endpoint is defined as the Clinical Impression of Change in Severity (CI-CS) 
comparing end of treatment with N-Acetyl-L-Leucine (Visit 4) with baseline (Visit 2) minus the 
CI-CS comparing the end of washout (Visit 6) with the end of treatment with N-Acetyl-L-Leucine 
(Visit 4) based on the primary anchor test. 
.  
This primary endpoint will assess the efficacy of N-Acetyl-L-Leucine for the treatment of A-T, 
based on blinded raters’ CI-CS of patient’s change in performance over 6 weeks on either the 9-hole 
peg test of the dominant hand (9HPT-D) or the 8-meter walk test (8MWT).  
 
At Visit 1, the treating physician will evaluate each patient’s clinical symptoms and select either the 
9HPT-D or 8MWT as the primary anchor around which the CI-CS assessment will be based. The 
primary evaluation of the CI-CS will be performed by two independent raters whose assessments 
will be based on videos of the anchor test taken at each visit. The raters will be blinded to the 
treatment phases to reduce detection and performance biases and for each pair of visits will make 
an assessment based on a 7-point Likert scale, e.g., -3 = ‘significantly worse’, 0 = ‘no change’ to +3 
= ‘significantly improved’.   
 
Secondary Endpoints: 
There will be several secondary endpoints that closely relate to the primary endpoint: 
• 
The CI-CS for end of treatment with N-Acetyl-L-Leucine (Visit 4) versus baseline (Visit 2) 
and end of washout (Visit 6) versus end of treatment with N-Acetyl-L-Leucine (Visit 4) will 
each be summarized descriptively. 
• 
Improvement in the primary and non-primary anchor test measures will be evaluated based 
on the change in the blinded raters’ Clinical Impression of Severity (CI-S) between baseline 

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Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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(average for Visit 1 and Visit 2) and end of treatment with N-Acetyl-L-Leucine (average 
for Visit 3 and Visit 4) minus the change in CI-S between end of treatment with N-Acetyl-
L-Leucine (average for Visit 3 and Visit 4) and end of washout (average for Visit 5 and 
Visit 6). Statistical testing for the primary anchor test CI-S endpoint will be as for the 
primary endpoint. There will be no formal statistical testing of the non-primary test. 
• 
Sensitivity measurement of change in performance on either the 9HPT-D or the 8MWT on 
a 3-point scale. Using the CI-CS outcome for the primary anchor test based on the data for 
Visits 2 and Visit 4, any patient given a score of -1, -2, or -3 on the CI-CS will be classified 
as worsened (<0). Any patient classified as 0 on the CI-CS will be classified no change (0). 
Any patient given a score of +1, +2, +3 on the CI-CS will be classified as improved (>0). 
A similar classification will use the CI-CS comparing the end of treatment with N-Acetyl-
L-Leucine with end of washout based on the data for Visits 4 and Visit 6 and the difference 
between these scores calculated.  The descriptive table will be similar to the primary 
endpoint. No statistical analysis will be performed 
• 
An evaluation of the CI-CS for the test (9HPT-D or 8MWT) that was not selected as the 
primary anchor test (i.e., the non-primary anchor test) will also be undertaken. There will 
be no formal statistical testing of these endpoints, however.  
 
The following assessments will be based on the absolute changes from baseline (Visit 2) to the 
end of treatment with N-Acetyl-L-Leucine (Visit 4), as well as end of treatment with N-Acetyl-L-
Leucine (Visit 4) to the end of post-treatment washout (Visit 6)18. 
  
• 
Spinocerebellar Ataxia Functional Index (SCAFI)19 
• 
Scale for Assessment and Rating of Ataxia (SARA) score 
• 
Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y20 for children aged <18 years  
• 
Treating Physician Clinical Global Impression of Severity (CGI-S) 
• 
Treating Physician Clinical Global Impression of Change (CGI-C) 21  
• 
Caregiver Clinical Global Impression of Severity (CGI-S) 
• 
Caregiver Clinical Global Impression of Change (CGI-C)4  
• 
Patient Clinical Global Impression of Severity (CGI-S) if they are able 
• 
Patient Clinical Global Impression of Change (CGI-C)4 if they are able 
 
Safety Parameters: 
Adverse events (AEs), safety laboratory tests including biochemistry, hematology, urinalysis 
including pregnancy test, vital signs, 12-lead electrocardiogram (ECG), and concomitant 
medications. Blood samples may be collected or retained for research purposes about the disease A-
T. 
Note: in the Extension Phase, physical exams are also conducted. 
 
 
18 See the SAP for complete methods of dealing with missing data as well as how secondary endpoints will be 
investigated descriptively.  
19 Two subsets, the 9-hole peg test of the dominant hand (9HPT-D) and the 8-meter walk test (8MWT), will be 
videoed for every patient at every visit, except Visit 0. 
20 European Sites Only 
21 Based on the changes from baseline to the end of treatment with N-Acetyl-L-Leucine, as well as end of 
treatment with N-Acetyl-L-Leucine to the end of post-treatment washout. The two CI-S values at each of these 
periods (Visit 1 and Visit 2 for baseline, Visit 3 and Visit 4 for end of treatment and Visit 5 and Visit 6 for end of 
washout) will be averaged. 
 
 

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                                              IND NUMBER: 138188 
 
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Pharmacokinetics (PK): Sparse PK sampling will be carried out at Visits 1, 2, 3, 4, 5 and 6 (at 
the same times that blood is drawn for the safety blood laboratory tests) for possible future 
modeling purposes. This sampling is exploratory/descriptive. 
Lithium-Heparin plasma samples will be drawn and frozen at -70ºC or below and shipped on dry 
ice for analysis at 
 Note, for each PK blood draw, it is important 
that the day and exact time of the last dose of N-Acetyl-L-Leucine before the blood draw and the 
day and exact time of the blood draw are recorded. 
Urine samples will also be collected for concentrations of N-Acetyl-D-Leucine at Visit 1, Visit 2, 
Visit 5, and Visit 6. 
Urine samples for measurement of N-Acetyl-D-Leucine will be frozen at -70ºC or below and 
shipped on dry ice for analysis at 
  
The urine sample provided at Visit 1 will be analyzed after it is received by 
 and 
results should be made available before start of the treatment phase to demonstrate that levels of N-
Acetyl-D-Leucine are below the set threshold. 
The urine samples provided at Visit 2, Visit 5, and Visit 6 will be analyzed in batches and used for 
sensitivity analyses only. 
Study Design and Methodology:  
This is a multinational, multicenter, open-label, rater-blinded Phase II study. In the Parent Study, 
patients will be assessed during three study periods: a baseline period, treatment period, and a 
washout period.  
As it is not uncommon for symptoms and functioning to fluctuate over a week, to help account for 
intra-patient variability, patients will be assessed twice during each period. 
At the initial screening visit, patients will be classified as either “naïve” or “non-naïve” patients 
depending on their use of prohibited medications within the past 42 days. The schedule of events 
during the initial screening visit and throughout the baseline period (through Visit 1) will vary 
depending on patient’s classification as either “naïve” or “non-naïve”. 
After Visit 2, all visits will be the same for all patients regardless of whether they were considered 
to be “naïve” or “non-naïve” at the time of enrollment.  
Screening/Baseline Period 
Study Schema 1: “Naïve” Patients 
“Naïve” patients are defined as patients who, at the initial screening visit, confirm (or whose legal 
representatives confirm on behalf of the patient) that they have not used any prohibited medications 
within the past 42 days. For these patients, the initial screening visit will be treated as Visit 1 
(Baseline 1). 
A urine sample will be taken at Visit 1 to detect N-Acetyl-D-Leucine. Provided the patient’s levels 
of N-Acetyl-D-Leucine are below the permitted threshold, the initial screening visit will be 
confirmed as Visit 1 (Baseline 1). Visit 2 (Baseline 2/Start of treatment period) will take place 
14 days (+7 days) after Visit 1 (Figure 1). 

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                                              IND NUMBER: 138188 
 
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Figure 1: Study Schema for “Naïve” Patients  
 
Reclassifying “Naïve” Patients to “Non-naïve” Patients 
Visit 1 will not be confirmed for “naïve” patients whose urine sample unexpectedly detected levels 
of N-Acetyl-D-Leucine above the permitted threshold. Provided the treating physician believes the 
patient will indeed comply with the pre-treatment washout and complete study the protocol22, these 
patients will be given the option to undergo a minimum of 42 days washout before returning for a 
second screening visit. Provided the patient (or legal representative on behalf of the patient) consent, 
the patient will be reclassified as “non-naïve” and will return for a repeat Visit 1 after the study run-
in washout period.   
Study Schema 2: “Non-naïve” Patients 
“Non-naïve” patients are defined as patients who confirm (or whose legal representatives on 
behalf of the patient confirm) they have used, or are unable to confirm or deny if they have used, 
any prohibited medication within the past 42 days23.  
Provided the treating physician believes the patient will comply with the pre-treatment washout 
and complete the study protocol, the “non-naïve” patient will be given the opportunity to undergo 
a minimum of 42 days washout before returning for a second screening visit. Provided the patient 
(or their legal representatives on behalf of the patient) consent, the initial screening visit will be 
treated and confirmed as Visit 0 (Figure 2). 
Visit 0 will commence study run-in period where patients undergo a washout from prohibited 
medications. Patients are eligible to return for a second screening visit after a minimum of 42 days 
washout. For patients (or their legal representatives on behalf of the patient) who confirm they have 
not used any prohibited medications for a minimum of 42 days, the second screening visit will be 
treated as Visit 1 (Baseline 1)24.  
A urine sample will be taken at Visit 1 to assess the level of N-Acetyl-D-Leucine. Provided the level 
of N-Acetyl-D-Leucine is below the permitted threshold, the second screening visit will be 
 
 
22 If the treating physician has reason to believe the patient will not comply with the pre-treatment washout or the 
complete study protocol, the patient will be notified they are ineligible for the study.  
23 As described, “non-naïve” patients can also be defined as patients who were initially classified as “naïve,” but 
whose initial urine sample unexpectedly detected levels of N-Acetyl-D-Leucine above the permitted threshold. 
Provided they are eligible, patients will be reclassified as “non-naïve” and return for a second screening visit after 
a minimum of 42 days washout.  
24 At Visit 1, patients who confirm (or whose legal representatives confirm) they have used, or are unable to 
confirm or deny if they have used, any prohibited medication within the past 42 days are ineligible to continue in 
the study.   
 

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confirmed as Visit 1 (Baseline 1). Visit 2 (Baseline 2/ Start of treatment period) will take place 
14 days (+7 days) after Visit 1.  
 
Figure 2: Study Schema for Non-Naïve Patients  
 
Treatment Period:  
During the treatment period, all patients will receive N-Acetyl-L-Leucine for 42 days (+7 days). 
Visit 3 (Treatment 1) will occur at Day 28 (+7 days) of the treatment period and Visit 4 
(Treatment 2) will occur after the full 42 days (+7 days) of treatment. 
 
Washout Period:  
A 6-week washout period will be performed following treatment with N-Acetyl-L-Leucine. Visit 5 
(Washout 1) will occur on Day 28 (+7 days) of the washout period and Visit 6 (Washout 2) will 
occur after the full 42 days (+7 days) of washout. 
 
Remote Visits: 
For any (i) skipped in-person Visit 3/5; (ii) postponed in person Visit 4/6: based on the availability 
of the patient/ the study team, within approximately  +/- 3 days of the originally scheduled 
visit, the study team/ PI should contact the patient (and as applicable, their parents/caregiver/legal 
representative) via phone/Skype25 to collect information in order to monitor adverse or serious 
adverse events, and provide study oversight (hereafter referred to as “remote visits”).  
 
Extension Phase:  
Patients who have participated in the study will be offered the opportunity to participate in a planned 
Extension Phase (EP) if the safety and tolerability during the 42 day (+7 day) treatment are 
considered to be acceptable by the Investigator for each specific patient, and the Investigator 
determines further treatment with IB1001 to be in the patient’s interest. Provided the patient (or their 
legal representative on their behalf) subsequently consent to participate, the Extension Phase is 
planned to allow patients to have further access to IB1001 for two, one-year treatment periods 
(Extension Phase Treatment Period I, Visit 8 + Visit 9, and Extension Phase Treatment Period II, 
Visit 11 and 12). The two, one-year EP treatment periods are separated by a washout period of 
approximately 42 days (+14 days) (Visit 10). 
 
 
 
25 As feasible; Skype is used as a generic term for videoconferencing, telemedicine but other software’s may be used. No video 
recordings should be made of these remote visits.  

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COVID-19: 
This study is ongoing during the COVID-19 outbreak. Coronavirus (COVID-19) outbreaks have 
been recorded in all countries with study sites and subjects participating in IntraBio’s clinical trials 
and have significantly impacted the IB1001-203 clinical trial. 
 
The global pandemic has had a significant impact on the IB1001-203 clinical trial by impacting 
study subjects’ ability to attend study visits due to government-ordered lock downs, or the closure 
of state (domestic) and/or national borders. In addition, the issuance of site-specific policies 
limiting or halting the conduct of non-essential study visits, the conversion of study-sites into 
COVID-19 wards, and site staff not on duty or reassigned to other priorities at the hospitals have 
affected the feasibility of conducting study visits. Finally, considering A-T patients are already 
classified as a vulnerable patient population, patients may be self-isolating. 
 
Therefore, protocol deviations and changes to study visits have been /may be necessary in order to 
safeguard participants, their families, and study teams. These include: 
• 
Visit 3 and Visit 5 are “interim” visits of the treatment/washout phase (respectively), and 
the in-person visit may be skipped; 
• 
Visit 4 and Visit 6 are final visits of the treatment/washout phases and the in-person visit 
may be postponed, but cannot be skipped; 
• 
For any (i) skipped in-person Visit 3/5; (ii) postponed Visit 4/6: based on the availability 
of the patient/ the study team, within approximately +/- 3 days of the originally scheduled 
visit, a remote visit should be conducted; 
• 
If a visit is skipped or postponed, protocol-specific procedures may not take place at the 
designated timepoint in the schedule of events.  
 
Schedule of Events: 
An outline of the Parent Study design, defined by Visit, and per study schema, is shown below. 
For a detailed description of the study design and the tests, procedures and assessments performed 
at each visit, refer to the Schedule of Events in Appendix 3A for “naïve” patients and 3B for “non-
naïve” patients. 
“NAÏVE” PATIENTS: SCREENING PERIOD 
Screening Visit/Visit 1 (Baseline 1): Written informed consent will be obtained. All patients will 
be screened for inclusion and exclusion criteria. Only patients meeting all the inclusion and none of 
the exclusion criteria will be allocated to the trial. The Screening Visit will be treated as Visit 1: the 
first assessment of the baseline period.26  
• 
Informed consent/informed consent form (ICF) signature and patient information 
• 
Patient demographics27 
• 
Physical examination 
• 
Patient weight and height measurements  
• 
60-day drug history including documentation of prior therapies/medications, including 
prohibited medications, and concomitant medications/therapies for treatment of trial-
 
 
26 The Screening Visit will be confirmed as Visit 1 as soon as the patient’s eligibility is confirmed and the level of 
N-Acetyl-D-Leucine detected in their urine sample is confirmed to be below the permitted threshold. Visit 1 will 
not be confirmed for patients classified as “naïve” but whose urine sample unexpectedly detect levels of N-Acetyl-
D-Leucine above the permitted threshold. At the treating physician’s discretion, these patients will be given the 
option to undergo a minimum of 42 days washout before returning for a second screening visit. Should they agree, 
the patient will be reclassified and changed to “non-naïve”. 
27 Demographics for each patient will be collected according to local laws 

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                                              IND NUMBER: 138188 
 
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specific illness  
• 
Relevant medical history as well as medical history concerning the trial specific illness, 
including frequency of physiotherapy and speech therapy (documented in hours per week) 
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 28 
• 
Scale for Assessment and Rating of Ataxia (SARA)  
• 
Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• 
Check for remaining inclusion/exclusion criteria (including confirmation that prohibited 
medications have not been used for the past 42 days) 
• 
Patient classified as “naïve”  
• 
Vital signs 
• 
Cognitive assessment according to standard procedures of the clinical site to assist with the 
Clinical Impression of Change in Severity (CI-CS) Primary anchor test selection 
• 
Determine Clinical Impression of Change in Severity (CI-CS) Primary anchor test 
• 
Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients <18 years old  
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient (if able) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECG 
• 
Urinalysis (done at central lab) 
• 
Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• 
Blood draw for safety laboratory tests, including follicle stimulating hormone (FSH) for 
menopausal women (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
 
“NON-NAÏVE” PATIENTS: SCREENING PERIOD 
Screening Visit/Visit 0: Written informed consent will be obtained. All patients will be screened 
for inclusion and exclusion criteria. Patients who confirm (or whose legal representatives on behalf 
of the patient confirm) they have used, or are unable to confirm or deny if they have used, any 
prohibited medications within the past 42 days will, at the treating physician’s discretion, remain 
eligible for enrollment. The Screening Visit will be treated as Visit 0. 
• 
Informed consent/ ICF signature and patient information 
• 
Patient demographics  
• 
Physical examination 
• 
Patient weight and height measurements 
• 
60-day drug history including documentation of prior therapies/medications, including 
prohibited medications, and concomitant medications/therapies for treatment of trial-
specific illness  
• 
Relevant medical history as well as medical history concerning the trial specific illness, 
including frequency of physiotherapy and speech therapy (documented in hours per week) 
• 
Vital signs 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Spinocerebellar Ataxia Functional Index (SCAFI)  
• 
Scale for Assessment and Rating of Ataxia (SARA) 
 
 
28 The 9-hole peg test of the dominant hand (9HPT-D) and 8-meter walk test (8MWT) will be videotaped in a 
standardized manner at every visit, except Visit 0. At Visit 1, these videos are made before the CI-CS primary 
anchor test is determined.  

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                                              IND NUMBER: 138188 
 
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• 
Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• 
Check remaining inclusion/exclusion criteria  
• 
Patient classified as “non-naïve”  
• 
Documentation of adverse events  
 
Visit 1 (Baseline 1): Minimum of 42 days after Visit 0/washout from prohibited medication. All 
patients will be screened for inclusion and exclusion criteria.  Only patients meeting the inclusion 
and none of the exclusion criteria will be allocated to the trial. This second screening visit will be 
treated as Visit 1: the first assessment of the baseline period. 29 
• 
Check of inclusion/exclusion criteria (including confirmation that prohibited medications 
have not been used for the past 42 days) 
• 
Documentation of frequency of therapy (hours per week) 
• 
Documentation of concomitant medication and therapies  
• 
Physical examination 
• 
Vital signs  
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 30 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Cognitive assessment according to standard procedures of the clinical site to assist with the 
Clinical Impression of Change in Severity (CI-CS) primary anchor test selection 
• 
Determine Clinical Impression of Change in Severity (CI-CS) primary anchor test 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for patients aged <18 years  
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECG 
• 
Urinalysis (done at central Lab) 
• 
Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• 
Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• 
Blood draw for safety laboratory tests, including FSH for menopausal women (done at 
central lab) 
• 
Blood draw for sparse PK (done at PK Lab) 
• 
Documentation of adverse events  
 
FOR ALL PATIENTS (“NAÏVE” AND “NON-NAÏVE”) 
Visit 2 (Baseline 2): Day 14 (+7 days) after Visit 1 (Baseline 1). The final day/ second assessment 
of the baseline period. The start of the treatment period. 
• 
Reconfirm patient eligibility 
• 
Documentation of frequency of physiotherapy and speech therapy (hours per week) 
• 
Documentation of concomitant medication and therapies  
• 
Vital signs  
 
 
29 This screening visit will be confirmed as Visit 1 provided the patient’s eligibility is confirmed and the level of 
N-Acetyl-D-Leucine detected their urine sample is below the permitted threshold.  Non-naïve patients whose urine 
sample after Visit 1 unexpectedly detect levels of N-Acetyl-D-Leucine above the permitted threshold will be 
marked as non-compliant and withdrawn from the study. 
30 The 9-hole peg test of the dominant hand (9HPT-D) and 8-meter walk test (8MWT) will be videotaped in a 
standardized manner at every visit, except Visit 0. At Visit 1, these videos are made before the CI-CS primary 
anchor test is determined.  

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years 
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Urinalysis (done at central Lab) 
• 
Urine by dipstick: pregnancy test for women of childbearing potential done at site before 
first dose of study drug is taken) 
• 
Urine test for N-Acetyl-D-Leucine (test done at PK lab) 
• 
Blood test for safety laboratory tests (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
• 
Dispensing of trial drug + intake of study drug at site  
 
Visit 3 (Treatment 1) Day 28 (+7 days) of treatment period: First assessment of treatment period 
with N-Acetyl-L-Leucine 
• 
Return of trial drug and compliance check (if feasible) 
• 
Documentation of frequency of therapy (hours per week) 
• 
Documentation of concomitant medication  
• 
Vital signs 
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years 
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECG 
• 
Urinalysis (done at central Lab) 
• 
Blood test for safety laboratory tests (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
• 
Dispensing of study drug if needed 
 
Visit 4 (Treatment 2): Day 42 (+7 days) of treatment period: the final day/second assessment of 
treatment period with N-Acetyl-L-Leucine. The start of washout period. 
• 
Return of trial drug and compliance check31 
• 
Documentation of frequency of therapy (hours per week) 
• 
Documentation of concomitant medication  
• 
Physical examination 
• 
Vital signs 
 
 
31 Or after Visit 4 if IMP is returned via courier 

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                                              IND NUMBER: 138188 
 
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• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years  
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Clinical Global Impression of Change (CGI-C) by physician based on Visit 2 to Visit 4 
• 
Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 2 to Visit 4 
• 
Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 2 to Visit 
4 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Urinalysis (done at central lab) 
• 
Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• 
Blood draw for safety laboratory tests (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
 
Between Visit 4 – Visit 5: Wash-Out 
Visit 5 (Washout 1): Day 28 (+7 days) of wash-out period: First assessment of wash-out period.  
• 
Documentation of frequency of therapy (hours per week) 
• 
Documentation of concomitant medication  
• 
Vital signs 
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years 
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECG  
• 
Urinalysis (done at central Lab) 
• 
Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• 
Blood draw for safety laboratory tests (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
 
Visit 6 (Washout 2): Day 42 (+7 days) of washout period: the final day/second assessment of 
washout period. 
• 
Documentation of frequency of therapy (hours per week) 
• 
Documentation of concomitant medication  
• 
Physical examination 
• 
Vital signs 
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years 
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Clinical Global Impression of Change (CGI-C) by physician based on Visit 4 –to Visit 6 
• 
Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 4 to Visit 6 
• 
Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 4 to Visit 6 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Medication History: If the patient was classified as “naïve”, confirm if they have used N-
Acetyl-Leucine (L, DL, D) at any time prior to Visit 1 
• 
Urinalysis (done at central lab) 
• 
Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• 
Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• 
Blood draw for laboratory safety tests (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
• 
Investigator determines continued treatment with IB1001 in patient’s best interest (if 
applicable) 
• 
Informed consent/informed consent form (ICF) signature and patient information for 
Extension Phase (if applicable) 
• 
Check of inclusion/exclusion criteria for Extension Phase (if applicable) 
 
Early Termination Visit 
• 
Return of study drug and compliance check32 
• 
Documentation of frequency of therapy (hours per week) 
• 
Documentation of concomitant medication  
• 
Physical examination 
• 
Vital signs 
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years 
• 
Clinical Global Impression of Severity (CGI-S) by physician 
• 
Clinical Global Impression of Severity (CGI-S) by caregiver 
• 
Clinical Global Impression of Severity (CGI-S) by patient if able 
• 
Clinical Global Impression of Change (CGI-C) by physician based on Previous Visit to ET 
Visit Clinical Global Impression of Change (CGI-C) by caregiver based on Previous Visit 
to ET Visit Clinical Global Impression of Change (CGI-C) by patient if able based on 
Previous Visit to ET Visit 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Medication History: If the patient was classified as “naïve”, confirm if they have used N-
Acetyl-Leucine (L, DL, D) at any time prior to Visit 1 
• 
12-lead ECG   
• 
Urinalysis (done at central Lab) 
• 
Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• 
Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• 
Blood draw for safety laboratory tests (done at central lab) 
• 
Blood draw for sparse PK (done at PK lab) 
• 
Documentation of adverse events  
 
 
 
32 Or after ET if IMP is returned via courier 

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Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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Number of Patients: 
• 
To be enrolled: Approximately 39 patients  
 
• 
To be analyzed according to the modified Intention to Treat (mITT) analysis: 
Approximately 36 patients 
 
• 
To be analyzed according to the Per Protocol Analysis: Approximately 30 patients 
Number of Sites: 
Approximately 6 sites 
Number of Participating Countries: 
Approximately 4 countries: sites in the United Kingdom, Germany, US, or Spain. 
If necessary, additional countries may be included in the trial. 
 
Study Duration: 
The treatment and washout duration for the Parent Study for all patients, from the first day of dosing 
with the study drug (Visit 2) to the final follow-up visit after washout (Visit 6), is expected to be 
approximately 84 days.  
For “naïve” patients, there is a 14-day (+7 days) screening/ baseline period between Visit 1 and 
Visit 2. 
For “non-naïve” patients, there is a 42-day (+7 days) run-in period before Visit 1, and a 14-day (+7 
days) screening/ baseline period between Visit 1 and Visit 2.  
 
The total duration of the Parent Study may be impacted if Visit 4 and/or Visit 6 are postponed due 
to COVID-19. 
 
Study Population and Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible to participate in the study. 
1. Written informed consent signed by the patient and/or their legal representative/ parent/ 
impartial witness 
2. Male or female aged ≥6 years with a genetically confirmed diagnosis of A-T at the time of 
signing informed consent.   
3. Females of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, will be included if they are either sexually inactive (sexually abstinent33 for 
14 days prior to the first dose and confirm to continue through 28 days after the last dose) 
or using one of the following highly effective contraceptives (i.e. results in <1% failure rate 
when used consistently and correctly) 14 days prior to the first dose continuing through 
28 days after the last dose: 
 
 
33 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. In this trial, abstinence is 
only acceptable if in line with the patient’s preferred and usual lifestyle. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception.  
As well, female condom and male condom should not be used together. 
 

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                                              IND NUMBER: 138188 
 
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a) intrauterine device (IUD); 
b) surgical sterilization of the partner (vasectomy for 6 months minimum); 
c) combined (estrogen or progestogen containing) hormonal contraception associated with 
the inhibition of ovulation (either oral, intravaginal, or transdermal); 
d) progestogen only hormonal contraception associated with the inhibition of ovulation 
(either oral, injectable, or implantable); 
e) intrauterine hormone releasing system (IUS);  
f) bilateral tubal occlusion. 
4. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a) hysteroscopic sterilization; 
b) bilateral tubal ligation or bilateral salpingectomy; 
c) hysterectomy; 
d) bilateral oophorectomy; 
OR be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle 
stimulating hormone (FSH) serum levels consistent with postmenopausal status. FSH 
analysis for postmenopausal women will be done at screening. FSH levels should be in the 
postmenopausal range as determined by the central laboratory. 
5. Non-vasectomized male patient agrees to use a condom with spermicide or abstain from 
sexual intercourse during the study until 90 days beyond the last dose of study medication 
and the female partner agrees to comply with inclusion criteria 3 or 4. For a vasectomized 
male who has had his vasectomy 6 months or more prior to study start, it is required that 
they use a condom during sexual intercourse. A male who has been vasectomized less than 
6 months prior to study start must follow the same restrictions as a non-vasectomized male. 
6. If male, patient agrees not to donate sperm from the first dose until 90 days after their last 
dose. 
7. Patients must fall within: 
a) A SARA score of 5 ≤ X ≤ 33 points (out of 40)  
AND 
b) Either: 
i. 
Within the 2-7 range (0-8 range) of the Gait subtest of the SARA scale   
OR  
ii. 
Be able to perform the 9-Hole Peg Test with Dominant Hand (9HPT-D) 
(SCAFI subtest) in 20 ≤ X ≤150 seconds. 
8. Weight ≥15 kg at screening. 
9. Patients are willing to disclose their existing medications/therapies for (the symptoms) of 
A-T, 
including 
those 
on 
the 
prohibited 
medication 
list. 
Non-prohibited 
medications/therapies (e.g., concomitant speech therapy, and physiotherapy) are permitted 
provided: 
a) The Investigator does not believe the medication/therapy will interfere with the study 
protocol/results 

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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b) Patients have been on a stable dose/duration and type of therapy for at least 42 days 
before Visit 1 (Baseline 1)  
c) Patients are willing to maintain a stable dose/do not change their therapy throughout the 
duration of the study. 
10. An understanding of the implications of study participation, provided in the written patient 
information and informed consent by patients or their legal representative/parent, and 
demonstrates a willingness to comply with instructions and attend required study visits (for 
children this criterion will also be assessed in parents or appointed guardians).  
Exclusion Criteria: 
A patient will not be included in this study if one or more of the following criteria apply: 
1. Asymptomatic patients 
2. Patient has clinical features of A-T, but a completely negative result on a previous genetic 
test 
3. Patients who have any of the following: 
a) Chronic diarrhea; 
b) Unexplained visual loss; 
c) Malignancies; 
d) Insulin-dependent diabetes mellitus. 
e) Known history of hypersensitivity to Acetyl-Leucine (DL-, L-, D-) or derivatives. 
f) History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, 
sorbitol, 
cellulose, 
carboxymethylcellulose, 
xanthan 
gum, 
carrageenan, 
dimethiconne, methylparaben, and potassium sorbate). 
4. Simultaneous participation in another clinical study or participation in any clinical study 
involving administration of an investigational medicinal product (IMP; ‘study drug’) within 
42 days prior to Visit 1. 
5. Patients with a physical or psychiatric condition which, at the investigator’s discretion, may 
put the patient at risk, may confound the study results, or may interfere with the patient’s 
participation in the clinical study.  
6. Known clinically-significant (at the discretion of the investigator) laboratories in 
hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to: 
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x upper 
limit of normal (ULN); 
b. Total bilirubin >1.5x ULN, unless Gilbert’s syndrome is present in which case total 
bilirubin >2x ULN. 
7. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol. 
8. Current or planned pregnancy or women who are breastfeeding. 
9. Patients with severe vision or hearing impairment (that is not corrected by glasses or hearing 
aids) that, at the investigator’s discretion, interferes with their ability to perform study 
assessments. 
10. Patients who have been diagnosed with arthritis or other musculoskeletal disorders affecting 
joints, muscles, ligaments, and/or nerves that by themselves affects patient’s mobility and, 
at the investigator’s discretion, interferes with their ability to perform study assessments. 

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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11. Patients unwilling and/or not able to undergo a 6-week washout period from any of the 
following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited 
medication through Visit 6. 
a) Aminopyridines (including sustained-release form); 
b) N-Acetyl-DL-Leucine (e.g. Tanganil®); 
c) N-Acetyl-L-Leucine (prohibited if not provided as IMP); 
d) Riluzole; 
e) Gabapentin; 
f) Varenicline; 
g) Chlorzoxazone; 
h) Sulfasalazine; 
i) Rosuvastatin. 
 

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                                              IND NUMBER: 138188 
 
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IMP, Dose and Mode of Administration: 
N-Acetyl-L-Leucine is a powder for oral suspension, being investigated for the treatment of A-T. 
The study drug contains no excipients. 
The study drug is formulated as 1000 mg Powder for suspension in 40 mL Ora-Blend® and oral 
administration. The suspension vehicle Ora-Blend® contains the following excipients: purified 
water, sucrose, glycerin, sorbitol, flavoring, microcrystalline cellulose, carboxymethylcellulose 
sodium, xanthan gum, carrageenan, calcium sulfate, trisodium phosphate, citric acid and sodium 
phosphate as buffers, dimethicone antifoam emulsion, preserved with methylparaben and 
potassium sorbate.  
The 40mL of Ora-Blend® will be combined into the powder and must be shaken vigorously for 
2 minutes so that it fully mixes before being administered.  
During the treatment period of this study, the dosing of the study drug is as follows: 
o Adults and children aged ≥13 years will take 4 g per day: 2 g in the morning, 1 g in the 
afternoon, and 1 g in the evening. 
o Children aged 6-12 years weighing 15 to <25 kg will take 2 g per day: 1 g in the morning 
and 1 g in the evening. 
o Children aged 6-12 years weighing 25 to <35 kg will take 3 g per day: 1 g in the morning, 
1 g in the afternoon, and 1 g in the evening. 
o Children aged 6-12 years weighing ≥35 kg will take 4 per day: 2 g in the morning, 1 g in 
the afternoon and 1 g in the evening (as per adults). 
The study drug should be taken 30 minutes before, or at least two hours after a meal. 
Granules for Oral Suspension in  Sachet – Parent Study 
Patients enrolled under/ after protocol Version 5.1, 02-Sep-2020 may begin treatment with the 
commercial formulation, “Granules for oral suspension in Sachet”.  
 
Modifications to Scheduled Doses 
On visit days, patients should keep to their usual dosing schedule.  
If a patient misses a dose of study drug, the patient should wait and take the next dose according to 
the treatment schedule.  
Compliance will be assessed upon a review of the inventory of IB1001 bottles returned from 
patients.   
The patient’s total daily dose may be reduced by up to one-half of their assigned dose at the 
discretion of the investigator. 
In the event a patient turns 13 years old, or a patient aged 6-12 years old changes weight category 
over the course of the study, their daily dose will not change from the initial dosing regimen 
prescribed at Visit 2, the start of IMP.  
Study drug will be taken during the 42 days (+7 days) treatment period. After the 42 days (+7 days) 
treatment period, patients will enter a 42 day (+7 days) washout period, which includes efficacy and 
safety assessments.  

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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Concomitant Medications and Therapies 
At Visit 0/Visit 1, all medication taken in the last 60 days prior to date of informed consent must be 
recorded. The current amount (in hours per week) of therapy (e.g., physiotherapy, speech therapy) 
needs to be recorded at the time of informed consent.  
Table 1 lists therapies that are prohibited and must not have been used by the patient for at least 42 
days before Visit 1 (for both “naïve” and “non-naïve” patients). Medication not listed in this table 
will be permitted, at the discretion of the investigator, as long as there is no interference with the 
study objectives or patient’s safety. Doses of medications and therapies used for (the symptoms) A-
T should remain as constant as possible (at the investigator’s discretion) throughout the trial.  
 
Table 1: 
Prohibited Medications 
Prohibited medication 
Washout prior to treatment 
Aminopyridines (including sustained-release form) 
42 days 
N-Acetyl-DL-Leucine (e.g., Tanganil®) or N-Acetyl-L-
Leucine (if not provided as study drug during the study) 42 days 
Riluzole 
42 days 
Gabapentin 
42 days 
Varenicline 
42 days 
Chlorzoxazone  
42 days 
Sulfasalazine 
42 days 
Rosuvastatin 
42 days 
 
 

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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Statistical Methods:  
Populations for Analysis 
• 
The Safety Analysis Set (SAF) will consist of all patients who receive at least one dose of 
study drug (N-Acetyl-L-Leucine) 
• 
The intention-to-treat analysis set (ITT) will consist of all patients in the Safety Analysis 
Set with a video recording at either Visit 1 or Visit 2 (or both) 
• 
The modified intention-to-treat analysis set (mITT) will consist of all patients in the SAF 
with a video recording at either Visit 1 or Visit 2 (or both) and one video recording at either 
Visit 3 or Visit 4 (or both). 
• 
The Per Protocol Set (PPS) will consist of all patients with video recordings at baseline 
(Visit 1 or Visit 2), end of treatment (Visit 3 or Visit 4), and end of washout (Visit 5 or 
Visit 6) and without any major protocol deviations that could have influenced the validity 
of the data for the primary efficacy variable. 
 
Statistical analysis will be performed using SAS; the version used will be specified in the SAP. 
All variables will be summarized using descriptive statistics. The number of patients, mean, standard 
deviation (SD), minimum, median, and maximum will be calculated for continuous and score 
variables. Frequency tables will be generated for categorical data. 
A one-sided significance level of 5% will be used throughout for all endpoints as a guide for 
evidence for activity. Conclusions regarding treatment efficacy will not solely rely on detecting 
statistical significance with equal emphasis placed on the magnitude and clinical relevance of 
treatment differences as judged by the point estimates. 
No correction for multiple comparisons will be included.  
 
Primary Endpoint  
The primary endpoint for the study is based on blinded raters’ Clinical Impression of Change in 
Severity (CI-CS) comparing videos showing the patient’s change in performance over 6 weeks on 
a pre-defined anchor clinical symptom scale: either the 9 Hole Peg Test of the Dominant Hand 
(9HPT-D) or the 8 Meter Walk Test (8MWT). 
The comparison of the Visit 4 video with the Visit 2 video and the comparison of the Visit 6 video 
with the Visit 4 video will provide the scores that contribute to the primary endpoint. Each of these 
comparisons will score change on a 7-point Likert scale (+3=significantly improved to -3= 
significantly worse).  
During the pre-treatment period, the treating physician will evaluate each patient’s clinical 
symptoms and select, at Visit 1, either the 9HPT-D or 8MWT as the primary anchor around which 
the CI-CS assessment will be scored. A cognitive assessment should be performed at Visit 1 
according to standard procedures of the clinical site to assist with the selection of the anchoring 
functional test appropriate for each patient from both a cognitive and a motor perspective. 
The primary evaluation of the CI-CS will be performed by two independent raters whose 
assessments will be based on videos of the anchor test taken at each visit. These raters will be blinded 
to the treatment periods (baseline, treatment, or washout) to reduce detection and performance bias.  
The primary endpoint is defined as the CI-CS comparing end of treatment with N-Acetyl-L-Leucine 
(Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the 
end of treatment with N-Acetyl-L-Leucine (Visit 4) based on the primary anchor test.  
The CI-CS assessment will instruct the blinded rater to consider: ‘compared to the first video, how 
has the severity of their performance on the 9HPT-D or 8MWT changed (improved or worsened) in 
6-weeks as observed in the second video?’ 

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Each video pairing (CI-CS) will be read by the two independent raters, and the appropriate 
Likert scale score will be entered onto the eCRF. If there is a difference of one (1) point in the 
two primary blinded reviewers’ CI-CS scores for a specific video pairing, the two scores will 
be averaged. If there is difference greater than one (1) point between the two primary blinded 
reviewers’ CI-CS scores for a specific video pairing, an adjudication read will be triggered. In 
such cases, a third blinded reviewer will review the scores given from each of the two primary 
independent reviewers and determine which score is more accurate, that of reviewer A or 
reviewer B (adjudication by consensus). The adjudicator's decision will be the final score for 
that video assessment.  
The statistical analysis of this endpoint will utilize a single sample t-test comparing the mean value 
of the primary endpoint with zero. This endpoint allows the effect N-Acetyl-L-Leucine to be 
measured both in terms of improvement during treatment followed by any deterioration once 
treatment is removed. 
Secondary Endpoints 
Supportive secondary endpoints will be evaluated that directly supplement the analysis of the 
primary endpoint as follows: 
 
• 
The CI-CS for end of treatment with N-Acetyl-L-Leucine (Visit 4) versus baseline (Visit 2) 
and end of washout (Visit 6) versus end of treatment with N-Acetyl-L-Leucine (Visit 4) will 
each be summarized descriptively. 
• 
Improvement in the primary and non-primary anchor test measure will be evaluated based 
on the change in the blinded raters’ Clinical Impression of Severity (CI-S) between baseline 
(average for Visit 1 and Visit 2) and end of treatment with N-Acetyl-L-Leucine (average 
for Visit 3 and Visit 4) minus the change in CI-S between end of treatment with N-Acetyl-
L-Leucine (average for Visit 3 and Visit 4) and end of washout (average for Visit 5 and 
Visit 6). The statistical analysis for the primary anchor test CI-S endpoint will be as for the 
analysis of the primary endpoint. There will be no formal statistical testing of the non-
primary anchor test for the CI-S endpoint. 
• 
Sensitivity measurement of change in performance on either the 9HPT-D or the 8MWT on 
a 3-point scale. Using the CI-CS outcome for the primary anchor test based on the data for 
Visits 2 and Visit 4, any patient given a score of -1, -2, or -3 on the CI-CS will be classified 
as worsened (<0). Any patient classified as 0 on the CI-CS will be classified no change (0). 
Any patient given a score of +1, +2, +3 on the CI-CS will be classified as improved (>0). 
A similar classification will use the CI-CS comparing the end of treatment with N-Acetyl-
L-Leucine with end of washout based on the data for Visits 4 and Visit 6 and the difference 
between these scores calculated. The statistical analysis of this endpoint will be based on a 
single sample Wilcoxon signed-rank test. 
• 
An evaluation of the CI-CS for the test (9HPT-D or 8MWT) that was not selected as the 
primary anchor test will also be undertaken. This will enable the separate analysis of CI-CS 
for both the 9HPT-D and the 8MWT.  
Each individual video (CI-S) will also be read by the two independent raters. For the CI-S, if there 
is one (1) point or more in the two blinded reviewers scores, the two scores will still be averaged.  
Additional secondary endpoints will investigate other measures of symptoms and quality of life. 
Descriptive statistics will be provided for these measures at each visit and also changes from 
baseline (Visit 2) to the end of treatment with N-Acetyl-L-Leucine (Visit 4), as well as end of 
treatment with N-Acetyl-L-Leucine (Visit 4) to the end of post-treatment washout (Visit 6) for the 
following measures: 
 

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• 
Spinocerebellar Ataxia Functional Index (SCAFI)34 
• 
Scale for Assessment and Rating of Ataxia (SARA) score 
• 
Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y35 for children aged <18 years 
(visual analogue scale; descriptive system) 
• 
Treating Physician Clinical Global Impression of Severity (CGI-S) at every visit  
• 
Treating Physician Clinical Global Impression of Change (CGI-C) comparing end of 
treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment 
(Visit 4) 
• 
Caregiver Clinical Global Impression of Severity (CGI-S) at every visit  
• 
Caregiver Clinical Global Impression of Change (CGI-C) comparing end of treatment 
(Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4) 
• 
Patient Clinical Global Impression Scales Impression of Severity (CGI-S) at every visit if 
they are able 
• 
Patient Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) 
to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4) if they are 
able 
 
The SARA total score, the SCAFI total score, the individual SCAFI subtests: 9 Hole Peg Test with 
the Dominant Hand (9HPT-D), 8 Meter Walk Test (8MWT), and PATA test, will be evaluated 
statistically based on a single sample t-test or a single sample Wilcoxon Signed Rank test. 
 
The individual SCAFI subtest: 9 Hole Peg Test with Nondominant hand (9HPT-ND) will be 
evaluated descriptively. 
 
All CGI-S measures and the caregiver and patient CGI-C measures will be summarised 
descriptively. The CGI-C measures will be analysed as for the CI-CS primary endpoint. 
 
The measures of the two indices (-5L and -Y) of the EQ-5D descriptive system and measures of the 
two indices (-5L and -Y) of the EQ-5D visual analogue scale (VAS) will be evaluated descriptively 
 
Exploratory Endpoints 
Sparse PK sampling will be collected to characterize the pharmacokinetics of N-Acetyl-L-Leucine 
in patients with A-T.  
 
Determination of Sample Size 
It is postulated that N-Acetyl-L-Leucine will show effectiveness in 30% of patients and this 
success rate is viewed as being clinically important. Assuming that this group of patients will have 
scores that are evenly distributed across the values 1 and 2 for the primary endpoint and further 
that the remaining 70% of patients will have scores that are evenly distributed between the values -
1, 0, and 1. The resulting mean score is 0.45 and the standard deviation (SD) for the primary 
endpoint under these assumptions is then 1.02. With 30 patients reporting on the primary endpoint, 
the study will have 76% power to detect a treatment benefit in a 5% one- sided one-sample t-test. 
 
Significance Level and Multiplicity 
A one-sided significance level of 5% will be used throughout for all endpoints as a guide for 
evidence for activity. Conclusions regarding treatment efficacy will not solely rely on detecting 
statistical significance with equal emphasis placed on the magnitude and clinical relevance of 
treatment differences as judged by the point estimates. 
 
 
34The 9-hole Peg Test of the Dominant Hand (9HPT-D) and the 8-meter Walk Test (8MWT), will be videoed for 
every patient at every visit, except Visit 0. 
35 European sites only 

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                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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No correction for multiple comparisons will be included.  
Missing Data 
The primary endpoint will utilise assessments based on single video recordings at the end baseline 
period (Visit 2), end of the treatment period (Visit 4), and end of the washout period (Visit 6). If the 
Visit 2 video is missing, the Visit 1 video will be used in its place. Similarly, if the Visit 4 and Visit 
6 videos are missing, Visit 3 and Visit 5 videos will respectively be used in their place.  
Analyses based on the mITT analysis set will utilise a last observation carried forward (LOCF) 
approach for missing videos at Visit 5 and Visit 6. For the primary endpoint CI-CS this implies that 
the CI-CS value for Visit 2 to Visit 4 will be assigned the value 0 if both videos at Visit 5 and Visit 
6 are not available. 
Additional methods to deal with missing data will be detailed in the Statistical Analysis Plan 
(SAP). Any changes from the SAP will be described and justified in the Clinical Study Report. 
  
Subgroup Evaluation 
For each of the primary and additional secondary endpoints there will be separate analyses within 
key subgroups. These subgroups will be detailed in the SAP. 
 
Meta-Analysis 
Separate trials will be conducted for NPC, GM2-gangliosidosis (Tay-Sachs and Sandhoff disease), 
and A-T. There will however be a series of meta-analyses that will bring together the data from the 
studies for the primary and secondary endpoints. Further details will be provided in a Meta-
Analysis Statistical Analysis Plan (MASAP). 
 
Sparse PK sampling is exploratory/descriptive.  
 
COVID-19  
This study is conducted during the COVID-19 outbreak. Data capture decisions have been taken 
due to national, local, or site-specific restrictions imposed due to COVID-19, with the primary 
need to prioritize the safety of clinical study teams and patients, and to maintain the integrity of 
the study/data collection. 
 
The complete impact of COVID-19 on the proposed statistical analyses is unknown. The statistical 
analysis plan already contains policies for handling missing data, however, specific items/changes 
related to COVID-19 are detailed in a separate document to the SAP (Addendum 1), which will be 
maintained throughout the study continuation and adjusted as needed based on the duration and 
extent of the impact of the COVID-19 situation.  
 
Relevant safety related alerts/Withdrawal Criteria: 
The Data Safety Monitoring Board (DSMB), in conjunction with the study Medical Monitor and/or 
Sponsor, is responsible for the oversight of safety. For this purpose, the DSMB will receive regular 
updates of safety.  
The DSMB will review all safety data on a regular basis. The exact content of review material and 
the frequency of review will be detailed in the DSMB charter.  
The DSMB will also be involved in risk-assessments of the impact of COVID-19, and reviewing 
any guidance issued by the Sponsor in regard to the global pandemic.  The DSMB may be asked 
to give recommendations on the conduct of trial operations and protocol adjustments which may 
be required in light of COVID-19.   
Patient Withdrawal 

IntraBio Ltd. 
Study Code: IB1001-203 
                    EUDRACT NUMBER: 2018-004407-39 
                                              IND NUMBER: 138188 
 
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13.3 Appendix 3: Schedule of Events 
 

 
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Period 
Baseline Period 
Treatment Period 
Wash-Out Period 
Early Term. 
Duration of the whole period 
1 Day 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening/Bsl 1 
Baseline 2 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -14 
Day 1, Start IMP 
Day 28 
Day 42 
Day 70 
Day 84 
XX 
Visit Window allowed 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+ 7days  
na 
Appendix 3A – Schedule of Events for “Naïve” Patients 
Patient information and informed consent 
process  
X 
 
 
 
 
X19 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
X19 
 
Patient weight and height measurements 
X 
 
 
 
 
 
 
Confirmation prohibited medications have 
not been used in the past 42 days 
X 
X3,4 
 
 
 
 
 
Classify patient as “Naïve” or “Non-naïve” 
X 
 
 
 
 
 
 
Patient demographics (in accordance with 
local regulations) 
X 
 
 
 
 
 
 
Relevant medical history 
X 
 
 
 
 
 
 
60-Day drug history 
X 
 
 
 
 
 
 
Documentation of therapy 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram (ECG)5 
X 
 
X 
 
X 
 
X 
Urine test for N-Acetyl-D-Leucine6 
X7 
X 
 
 
X 
X 
X 
Blood safety laboratory tests8 
X 
X 
X 
X 
X 
X 
X 
Follicle stimulating hormone serum 8, 9 
X 
 
 
 
 
 
 
Urinalysis 8 
X 
X 
X 
X 
X 
X 
X 
Urine by dipstick for pregnancy test10 
X 
X 
 
X 
 
X 
X 

 
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Period 
Baseline Period 
Treatment Period 
Wash-Out Period 
Early Term. 
Duration of the whole period 
1 Day 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening/Bsl 1 
Baseline 2 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -14 
Day 1, Start IMP 
Day 28 
Day 42 
Day 70 
Day 84 
XX 
Visit Window allowed 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+ 7days  
na 
 
Blood sample for sparse PK 6 
X 
X 
X 
X 
X 
X 
X 
Quality of Life EQ-5D-5L for patients aged 
≥18; EQ-5D-Y11 for children aged <18 years 
X 
X 
X 
X 
X 
X 
X 
Scale for Ataxia Rating (SARA) 
X 
X 
X 
X 
X 
X 
X 
Scale for Spinocerebellar Ataxia Functional 
Index (SCAFI)12  
X 
X 
X 
X 
X 
X 
X 
Cognitive assessment according to standard 
procedures of the clinical site 
X 
 
 
 
 
 
 
Determination of CI-CS Primary Anchor 
Test (9HPT-D or 8MWT) 
X 
 
 
 
 
 
 
Clinical Global Impression of Severity 
(CGI-S) by Physician 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression of Severity 
(CGI-S) by Caregiver 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression of Severity 
(CGI-S) by Patient13 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression of Change  
(CGI-C) by Physician 
 
 
 
X 
 
X 
X 
Clinical Global Impression of Change  
(CGI-C) by Caregiver 
 
 
 
X 
 
X 
X 
Clinical Global Impression of Change 
(CGI-C) by Patient13 
 
 
 
X 
 
X 
X 
Medication History: Confirm if N-acetyl-
leucine ever used for “naïve” patients  
 
 
 
 
 
X 
X 
Columbia-Suicide Severity Rating Scale 
X 
X 
X 
X 
X 
X 
X 

 
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Period 
Baseline Period 
Treatment Period 
Wash-Out Period 
Early Term. 
Duration of the whole period 
1 Day 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening/Bsl 1 
Baseline 2 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -14 
Day 1, Start IMP 
Day 28 
Day 42 
Day 70 
Day 84 
XX 
Visit Window allowed 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+ 7days  
na 
 
1 If the patient’s eligibility is confirmed and their urine screen for N-Acetyl-D-Leucine is below the permitted threshold. The next visit, Visit 2, should be planned 14 days (+7 days) from Visit 1.  
2 All assessments must be done pre-dose 
3 At Visit 2, confirm no prohibited medications since Visit 1  
4 If the patient (or caregiver) states the patient has been using prohibited medication at Visit 2, they will be classified as non-compliant and withdrawn from the study 
5 If feasible, repeat assessments performed at treating physician’s discretion if clinically significant results at Visit 3 
6 To be analyzed at PK lab 
7 If the patient’s urine sample unexpectedly detects levels of N-Acetyl-D-Leucine above the permitted threshold, they will (provided eligible) switch to “non-naïve” 
8 To be analyzed at the central lab 
9 Only for post-menopausal women of non-child bearing potential with amenorrhea for at least 1 year prior to the first dose (and have not undergone sterilization procedures at least 6 months prior to the first dose) 
10 Only for women of childbearing potential; done at site  
11 If a patient turns 18 during the study, the EQ-5DY should be used for the remainder of the study 
12 Two subtests, the 9-hole Peg Test of the Dominant Hand (9HPT-D) and 8-meter Walk Test (8MWT) will be videoed in a standardized format at every visit (except Visits 0). 
13 If the patient is able to provide the CGI-S/C 
14 Any concomitant medication needs to be recorded, used or not used for (symptoms of) A-T since the last 60 days prior to date of informed consent, up to End of Study / ET 
15 If needed 
16 Patient should not have used any of the prohibited concomitant medication 42 days prior to first dose of study drug, and have had a urine screen for N-Acetyl-D-Leucine below the permitted threshold prior to first dose 
of study drug. 
17 If feasible 
18 Or after the Visit if IMP is returned via courier 
19 If Investigator determines continued treatment with IB1001 in patient’s best interest, and patient would like to participate in the optional Extension Phase, task performed for continuation into the Extension Phase 
General note: due to COVID-19, deviations from the schedule of visits and assessments may be necessary, i.e. visits may be skipped, postponed, or performed remotely. See Section 3.1.2 for 
details
Documentation of concomitant medication14 
X 
X 
X 
X 
X 
X 
X 
Documentation of AEs 
X 
X 
X 
X 
X 
X 
X 
Dispensing of study drug 
 
X 
X15 
 
 
 
 
Intake of study drug at site 
 
X16 
 
 
 
 
 
Return of study drug 
 
 
X 
X 
 
 
X 
Study drug compliance check 
 
 
X17 
X18 
 
 
X18 

 
 
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13.4 Appendix 4: Rationale for the Clinical Impression of Change in Severity 
(CI-CS) Appendix 4: Rationale for the Clinical Impression of Change in 
Severity (CI-CS) 
Detailed rational for the development, administration, and scoring of the primary 
Clinical Impression of Change in Severity (CI-CS) endpoint is located in the 
supplementary document “Clinical Impression of Change in Severity. Administration 
and Scoring Manual” 
]. 
 

 
 
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13.5 Appendix 5: Protocol Amendment History 
 
The Protocol Amendment Summary of Changes is located in the supplementary 
document, “IB1001-203 Protocol Summary of Changes Version 1.2, 03-Mar-2021”. 
An overview of the Protocol Version history is located directly before the Table of 
Contents (TOC). 

 
 
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13.6 Appendix 6: Extension Phase 
 
 

 
 
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1 
Introduction – Extension Phase 
This Extension Phase study schema allows patients who have completed Visit 6 of the 
Parent Study of IB1001-203 to, at the discretion of the Principal Investigator (PI), 
continue treatment with N-Acetyl-L-Leucine (IB1001) if the PI determines it is in their 
best interest. The design of the Extension Phase is presented in Section 3.1.236. 
 
The Extension Phase will be conducted at clinical sites that participated in the Parent 
Study, and in countries that have regulatory and ethics/institutional review board 
approval for the Extension Phase.  
 
The Extension Phase will assess patients after one-year of treatment with IB1001, 
followed by a 42-day (+14 day) washout. After the 42-day Extension Phase washout 
(Visit 10), at the discretion of the Principal Investigator (PI), patients will be able to 
continue treatment with N-Acetyl-L-Leucine (IB1001) for an additional 1-year if the PI 
determines it is in their best interest. 
 
The Extension Phase will collect information on the long-term safety, tolerability, 
pharmacokinetics (PK), and efficacy of IB1001 as a treatment for A-T for the purpose 
of further assessing the risk/ benefit balance of the investigational medicinal product in 
the proposed clinical setting.  
 
1.1 
Risk/Benefit Considerations 
A-T is a rare, serious, and life-threatening disorder that predominantly affects the 
pediatric population [Gatti et al, 2001]. There are no approved therapies for A-T, and 
therefore a strong need exists for the development of an effective therapy to treat this 
disease.  
 
The active ingredient in IB1001 is N-Acetyl-L-Leucine, an acetylated derivate of a 
ubiquitously present amino acid occurring in human food. N-Acetyl-L-Leucine is also 
an endogenously generated metabolite of L-Leucine.  
 
Appropriate patient selection is one factor in considering the balance of risks of adverse 
events (AEs) against potential clinical benefit. Patients will only be considered for the 
Extension Phase, if they have completed the Parent Study and the PI determined 
continued treatment with N-Acetyl-L-Leucine to be in the patient’s best interest.  
 
Based upon the very good safety profile of N-Acetyl-L-Leucine (and N-Acetyl-DL-
Leucine) observed in animals at dose levels up to the limit dose (
) 
as well as knowledge of safe use of N-Acetyl-DL-Leucine in children as young as 
9 months of age [Picone, 2018], inclusion of children aged 6 years and over who took 
part in the Parent Study is judged to be safe. Women of childbearing potential and 
partners of women of childbearing potential will continue to be required to adhere to 
strict precautions to prevent pregnancy. Women who are pregnant, breast-feeding, or 
planning to become pregnant will be excluded from the study. In addition, a negative 
pregnancy test will be a prerequisite for the inclusion of women of childbearing 
 
 
36 Sections referenced in Appendix 6 refer to the Appendix 6 Sections, unless otherwise indicated by 
“..of the Parent Study”  

 
 
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The investigator will monitor the degree of stress to patients and the risk threshold 
throughout the trial. Patients will be instructed to report any AEs that they experience 
to the Investigator and the Investigator will ask about the occurrence of AEs at each 
visit. As described in Section 11.6 of the Parent Study, if the Investigator (or the 
Sponsor or Medical Monitor) becomes aware of conditions or events that suggest a 
possible hazard to patients if the study continues, the clinical study may be terminated 
after appropriate consultation between the involved parties. 
 
In addition, as described in Section 11.5 of the Parent Study, the Data Safety Monitoring 
Board (DSMB), in conjunction with the study Medical Monitor and/or Sponsor, will 
monitor the level of risk on a regular basis throughout the study. The DSMB is a 
multidisciplinary group consisting of clinicians with pediatric experience and a 
biostatistician. The DSMB has been set up to safeguard the interests of study 
participants by providing an independent review of patient safety data to monitor that 
no undue harm is occurring to patients due to their participation. The DSMB may 
recommend changes in the conduct of the studies to IntraBio, if needed, to ensure the 
safety of patients in the study and the proper conduct of the studies. The DSMB may 
also recommend suspending recruitment or terminate the study early because of undue 
safety risks to patients or any issues concerning the rights of patients. For this purpose, 
the DSMB will receive regular updates of safety and review all safety data on a regular 
basis.  
 
Based upon the nature of the drug, the available non-clinical and clinical data for N-
Acetyl-L-Leucine and N-Acetyl-DL-Leucine, the current lack of effective treatments 
for A-T, and in the context of a marketed racemate, this clinical trial is concluded to 
pose acceptable levels of risk and burden on participants. 
 
Extension Phase Treatment Period II  
Protocol Amendment 6.0 introduces an additional year of dosing upon completion of 
the extension-phase washout Visit 10. Extension Phase Treatment Period II will provide 
additional information on long-term safety and tolerability of IB1001 while allowing 
patients to have further access to IB1001 for an additional one-year period. Based on 
the nature of the drug and previous non-clinical and clinical findings (as detailed in 
Section 1 of the Parent Study) and the safety profile observed in this ongoing study (and 
in other ongoing IB1001 clinical trials) to date, the risk of allowing patients who have 
completed the first year of extension-phase dosing, and who agree to continue in the 
study, is considered acceptable.  
 
 

 
 
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2 
STUDY OBJECTIVES – EXTENSION PHASE 
All endpoints in the extension phase are considered secondary to those in the Parent 
Study. 
 
2.1 
Primary Objective 
The primary endpoint in this Extension Phase is success measured on the Scale for the 
Assessment and Rating of Ataxia (SARA) from the Extension Phase baseline (Visit 7) 
to the end of treatment in the Extension Phase (Visit 9). 
2.2 
Secondary Objectives 
The secondary objective is to: 
o To evaluate the long-term safety and tolerability of N-Acetyl-L-Leucine at 
4 g/day in patients aged ≥13 years, and weight-tiered doses in patients 6 to 
12 years of age, with A-T  
o To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in 
patients with A-T. 
2.3 
Exploratory Objectives 
The exploratory objectives are: 
• To assess the clinical efficacy of long-term treatment with N-Acetyl-L-Leucine 
on symptoms, functioning, and quality of life for patients with A-T 
• To assess the effects of a 42-day (+14 days) washout from N-Acetyl-L-Leucine 
after one-year treatment on symptoms, functioning, and quality of life for 
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3 
OVERALL DESIGN AND PLAN OF THE EXTENSION PHASE 
3.1 
Overview 
3.1.1 Trial Design/Patient Population 
This Extension Phase will enroll patients who have completed Visit 6 of the parent 
study phase of IB1001-203. Patients will be offered the opportunity to participate in 
this Extension Phase if the safety and tolerability during the 42-day (+7 days) treatment 
period of the parent study are considered to be acceptable by their Principal Investigator 
(PI) and the PI determines further treatment with IB1001 to be in the patient’s best 
interest.  
Recruitment into the Extension Phase will continue until all patients who participated 
in the parent study, and who are willing and eligible to participate in the Extension 
Phase, are enrolled.  
Section 4 contains more detailed information on the eligibility criteria for the Extension 
Phase.  
3.1.2 Study Design 
Patients will be assessed approximately 6 times over a 116-week period: at the start of 
the Extension Phase, after 6 months of treatment, 1 year of treatment, and after a 42-
day (+14 day) post-extension-phase treatment washout, after 6 months of resuming 
treatment, and 1 year of resuming treatment. 
Section 7 contains detailed information on the study assessments and procedures that 
will be conducted at each study phase and visit.  
3.1.2.1 Baseline Visit of the Extension Phase 
Preferably, the first visit of the Extension Phase (Visit 7 Part A and Part B; Baseline 
Visit) should be conducted 1 day (+6 days) after Visit 6, the end of the parent study.  
 
The assessments comprising Visit 7 may be conducted over a two-day period (“Part A” 
and “Part B”)37. If Visit 7, Part B is scheduled 1 day (+6 days) after Visit 6 (Washout 2 
of the parent study), the assessments conducted at Visit 6 will count as Visit 7, Part A 
(i.e. the assessments do not need to be repeated). 
 
If Visit 7B cannot be scheduled 1 day (+6 days) after Visit 6, the assessments included 
in Visit 7, Part A and Visit 7, Part B may be performed over two consecutive days, i.e. 
Visit 7B occurs +1 day after Visit 7A. 
 
At Visit 7, Part B, after all efficacy assessments have been performed, the patient will 
take the first Extension-Phase dose of N-Acetyl-L-Leucine on site.  
 
3.1.2.2 Extension Phase Treatment Period 
From Visit 7B onward, all patients will receive treatment with N-Acetyl-L-Leucine for 
365 days (+/-14 days).  
 
 
37 If Visit 7 is conducted within +7 days of Visit 6, the assessments performed at “Part A” do not need 
to be duplicated and Visit 7 will be conducted over one day only.  

 
 
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Visit 8 will occur at Day 180 (+/-14 days). 
Visit 9, Part A will occur at Day 365 (+/-14 days). 
Visit 9, Part B should occur on the day after Visit 9, Part A 
3.1.2.3 Extension Phase Washout Period 
After Visit 9, all patients will enter a 42-day (+14 days) washout phase.  
Visit 10 will occur at Day 407 (+ 14 days) 
3.1.2.4 Extension Phase Treatment Period II 
From Visit 10 onward, all patients will receive treatment with N-Acetyl-L-Leucine 
for 365 days (+/-14 days). 
Visit 11 will occur at Day 587 (+/-14 days). 
Visit 12 will occur at Day 767 (+/-14 days). 
3.1.3 Centers 
The trial will be conducted in clinical trial centers that participated in parent study and 
continue to meet the requirements for performing the planned trial-related 
investigations. The Extension Phase will only be conducted in countries/study centers 
where regulatory and Independent Ethics Committee/Institutional Review Board 
approval has been granted for the Extension Phase. 
3.1.4 Study Duration 
The treatment and washout duration for all patients, from the first day of dosing with 
the study drug during the Extension Phase (Visit 7) to the final follow-up visit 
(Visit 12), is expected to be approximately 767 days.  
3.2 
Discussion of Study Design 
3.2.1 Choice of the Primary Endpoint 
The primary endpoint in this Extension Phase is success measured on the Scale for the 
Assessment and Rating of Ataxia (SARA) from the Extension Phase baseline (Visit 7) 
to the end of treatment in the Extension Phase (Visit 9).  
 
3.2.2 Choice of the Secondary Endpoints  
Full PK sampling will be conducted during the Extension Phase.  
 
3.2.3 Choice of the Exploratory Endpoints  
All endpoints in the Extension Phase are considered secondary to those in the Parent 
Study. The exploratory endpoints are defined in Section 8.5.2 
 
3.2.4 Dose/ Duration of Treatment 
The purpose of the Extension Phase is to give patients who participated in the Parent 
Study, and whose investigators believe may benefit from continued treatment with 
IB1001, the opportunity to further access N-Acetyl-L-Leucine once the parent study 
has been completed. During the Extension Phase, long-term safety and efficacy data 

 
 
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will be recorded. In order to be eligible for the Extension Phase, the investigator must 
also be of the opinion that this is in the patient’s best interest.  
 
As discussed in Section 1.1, on the basis of the chemical nature of N-Acetyl-L-Leucine, 
available non-clinical and clinical evidence, and post marketing experience with the 
racemate (including compassionate use in A-T), it is considered justifiable from a safety 
point-of-view to dose for an additional year. This will provide patients continued access 
to drug while other patients complete the Parent Study and the results from the 
symptomatic study with a 6-week treatment period are generated (including the blinded 
rater review) and analyzed.  
 
3.3 
End of Study Definition 
A patient is considered to have completed the Extension Phase if he/she has completed 
all routine visits of the Extension Phase including the last visit (Visit 12). 
The end of the study (Parent Study + Extension Phase) is defined as the date of the last 
visit of the last patient in Study IB1001-203 globally. 

 
 
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4 
STUDY POPULATION – EXTENSION PHASE 
The study population comprises patients with A-T who have completed Visit 6 of the 
parent study of IB1001-203. To be eligible, patients must satisfy the following entry 
criteria:   
4.1 
Inclusion Criteria 
1. Completed Visit 6 of the IB1001-203 Parent Study  
2. The Principal Investigator determines further treatment with IB1001 to be in 
patient’s best interest  
3. Written informed consent signed by the patient and/or their legal 
representative/parent/ impartial witness for participation in the Extension 
Phase  
4. Patients are willing to continue to remain without the following prohibited 
medication from Visit 6 throughout the duration the Extension Phase: 
a) Aminopyridines (including sustained-release form); 
b) N-Acetyl-DL-Leucine (e.g. Tanganil®); 
c) N-Acetyl-L-Leucine (prohibited if not provided as investigational 
medicinal product [IMP]); 
d) Riluzole; 
e) Gabapentin; 
f) Varenicline; 
g) Chlorzoxazone; 
h) Sulfasalazine; 
i) Rosuvastatin. 
 
4.2 
Patient Withdrawal  
Patients may withdraw from the study at any time at their own request, without stating 
the reason(s) for withdrawal. The policies/procedures for patient withdrawal are defined 
in Parent Study Section 4.3. 
 
4.3 
Patient Identification  
Patients will be defined by their unique, seven-digit identification number assigned at 
screening of the Parent Study (see Section 4.4 of the Parent Study).  

 
 
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See Section 5.1.1 and Section 5.1.2 for instructions regarding preparation before 
administration for the powder for oral suspension and the granules for oral suspension, 
respectively.  
The study drug should be taken 30 minutes before, or at least two hours after a meal. 
During the treatment period of this Extension Phase, the dosing of the study drug is as 
follows: 
• Patients aged ≥13 years will take 4 g per day: 2 g in the morning, 1 g in the 
afternoon, and 1 g in the evening. 
• Patients aged 6-12 years weighing 15 to <25 kg will take 2 g per day: 1 g in the 
morning and 1 g in the evening. 
• Patients aged 6-12 years weighing 25 to <35 kg will take 3 g per day: 1 g in the 
morning, 1 g in the afternoon, and 1 g in the evening. 
• Patients aged 6-12 years weighing ≥35 kg will take 4 g per day: 2 g in the 
morning, 1 g in the afternoon, and 1 g in the evening (as per patients aged ≥13). 
Study drug will be taken during the two 365-day (+/- 14 days) Extension Phase 
treatment periods. The patient’s dose for the extension treatment phase will be 
determined based on their age and weight at Visit 7. In the event a patient turns 13 years 
old or a patient aged 6-12 years old changes weight categories between Visit 7 and 
Visit 8 of the Extension Phase, their daily dose will be adjusted accordingly at Visit 8. 
In the event a patient turns 13 years old or a patient aged 6-12 years old changes weight 
categories between Visit 8 and Visit 10, or Visit 10 and Visit 11 of the Extension 
Phase, their daily dose will be adjusted accordingly at Visit 10 or Visit 11. 
 
5.3 
Modification of Dose Schedule and Transition to Sachet Formulation 
5.3.1 Modification of Dose  
On visit days, patients should keep to their usual dosing schedule, except for Visit 9B, 
which is a PK day. 
If a patient misses a dose of study drug, the patient should wait and take the next dose 
according to the treatment schedule.  
Compliance will be assessed upon a review of the inventory of IB1001 bottles/sachets 
returned by patients.   
The patient’s total daily dose may be reduced by up to one-half of their assigned dose 
at the discretion of the investigator. 
At Visit 8, Visit 10, or Visit 11, the patient’s daily dose may be modified if a patient 
aged 6-12 years turned 13 or if a patient aged 6-12 years changed weight category since 
the previous (see Section 5.2).  
During the Extension Phase treatment period I, study drug will be taken for 
approximately 365-day (+/- 14 days). After the Extension Phase treatment period I, 
patients will enter a 42-day (+14 days) extension phase washout period, which includes 
efficacy and safety assessments. During the Extension Phase treatment period II 
(starting at the end of the extension phase washout), study drug will then be taken for 
an additional 365 days (+/- 14 days). 

 
 
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Table 5.1 lists medications that are prohibited. Medication not listed in this table may 
be permitted, at the discretion of the investigator, as long as there is no interference 
with the study objectives or patient safety. Doses of medications and therapies used for 
(the symptoms of) A-T should remain as constant as possible (at the investigator’s 
discretion) throughout the trial. Table 5.1: Prohibited Medications 
Aminopyridines (including sustained-release form) 
N-Acetyl-DL-Leucine (e.g. Tanganil®) or N-Acetyl-L-Leucine (if not provided as 
study drug during the study) 
Riluzole 
Gabapentin 
Varenicline 
Chlorzoxazone  
Sulfasalazine 
Rosuvastatin 
 
Any medication the patient takes other than the study drug is considered a concomitant 
medication. All concomitant medications must be recorded in the electronic case report 
form (eCRF). The following information must be recorded in the eCRF for each 
concomitant medication: generic name, route of administration, start date, stop date, 
dosage, and indication. Any changes in the dosage or regimen of a concomitant 
medication must be recorded in the eCRF.  
A patient found using a new concomitant medication, or a patient who changes their 
previous regimen/dose, may continue with the study/study drug if the Investigator does 
not believe the medication/therapy will interfere with the patient’s safety.  
Note: Drug interactions with substrates of transporters MDR1, BCRP, or BSEP cannot 
be excluded as N-Acetyl-L-Leucine is an inhibitor of these transporters in vitro. 
Sulfasalazine and rosuvastatin are included under prohibited medications, whereas 
substrates of MDR1 and BSEP and other substrates of BCRP may be used at the 
discretion of the investigator. 
 
5.9 
Treatment of Overdose 
No specific information on overdose of N-Acetyl-L-Leucine (IB1001) exists for 
humans. Based on the pharmacology, it is not expected that overdose would produce a 
clinically relevant reaction. The patient should be appropriately monitored.  

 
 
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6 
PARAMETERS AND METHODS OF ASSESSMENT – EXTENSION 
PHASE 
All analyses of the extension phase are considered secondary to ones of the parent 
study. For the most part, the same clinical outcome assessments used during the Parent 
Study (described in Section 6 of the Parent Study) will be used during the Extension 
Phase. These outcome assessments will be used in the Extension Phase to continue to 
assess the long-term effects of IB1001. The section below describes how existing 
efficacy parameters have been updated for use in the Extension Phase, as well as 
additional efficacy parameters that have been added. Assessments in the Extension 
Phase will be performed at the times indicated in the Extension Phase schedule of 
events (see Table 6.1).  
 
6.1 
Updated Efficacy Parameters 
6.1.1 Measurement of Global Impression 
The clinical global impression of severity (CGI-S) and change (CGI-C) will continue 
to be measured, with the questions for the physicians, caregivers, and patients modified 
to accommodate the Extension Phase visits.  
 
Physician, Caregivers, and Patients (if able) will be asked to assess the CGI-S at each 
visit (Visit 7, Visit 8, Visit 9, Visit 10, Visit 11, Visit 12, and at the Extension Phase 
Early Termination visit, if applicable). The question is identical to that described in the 
Parent Study Section 6.1.4. 
 
Physician, Caregivers, and Patients (if able) will be asked to assess the CGI-C at Visit 
8, Visit 9, Visit 10, Visit 11, and Visit 12 and the Extension Phase Early Termination 
Visit (if applicable).   
The Clinical Global Impression of Change (CGI-C) - clinician asks the clinician 
one question: 
“Compared to the patient's condition at:  
(i) Visit 7 (extension phase baseline) versus (ii) Visit 8 (interim extension phase 
treatment visit) OR versus Visit 9 (end of extension phase treatment); 
OR 
(i) Visit 9 (end of extension phase treatment) versus (ii) Visit 10 (end of extension phase 
washout); 
OR 
(i) Visit 10 (end of extension phase washout) versus (ii) Visit 11 (interim extension 
phase treatment visit) OR versus Visit 12 (end of extension phase treatment period II); 
OR 
(i) Early Termination Visit versus (ii) the previous visit, 
this patient’s condition is: 1=very much improved since the initiation of treatment; 
2=much improved; 3=minimally improved; 4=no change from baseline (the initiation 
of treatment); 5=minimally worse; 6= much worse; 7=very much worse.” 
 

 
 
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The Clinical Global Impression of Change (CGI-C) - caregiver asks the caregiver 
one question: 
“Compared to the patient's condition at:  
(i) Visit 7 (extension phase baseline) versus (ii) Visit 8 (interim extension phase 
treatment visit) OR versus Visit 9 (end of extension phase treatment); 
OR 
(i) Visit 9 (end of extension phase treatment) versus (ii) Visit 10 (end of extension phase 
washout); 
OR 
(i) Visit 10 (end of extension phase washout) versus (ii) Visit 11 (interim extension 
phase treatment visit) OR versus Visit 12 (end of extension phase treatment period II); 
OR 
(i) Early Termination Visit versus (ii) the previous visit, 
how much has he/she changed: 1=very much improved; 2=much improved; 
3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very 
much worse.” 
 
The Clinical Global Impression of Change (CGI-C) - patient asks the patient (if 
able) one question: 
“Compared to your condition at:  
(i) Visit 7 (extension phase baseline) versus (ii) Visit 8 (interim extension phase 
treatment visit) OR versus Visit 9 (end of extension phase treatment); 
OR 
(i) Visit 9 (end of extension phase treatment) versus (ii) Visit 10 (end of extension phase 
washout); 
OR 
(i) Visit 10 (end of extension phase washout) versus (ii) Visit 11 (interim extension 
phase treatment visit) OR versus Visit 12 (end of extension phase treatment period II); 
OR 
(i) Early Termination Visit versus (ii) the previous visit, 
how much have you changed? 1=very much improved; 2=much improved; 
3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very 
much worse.” 
6.1.2 Clinical Impression of Change in Severity 
Videos of the primary and non-primary anchor tests are collected throughout the 
extension phase for the Clinical Impression of Change in Severity (CI-CS). These 
videos may be analyzed in order to inform the development and validation of the CI-
CS endpoint.  
 

 
 
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6.2 
Exploratory Endpoints for the Washout Phase 
Exploratory endpoints are defined in Section Error! Reference source not found..  
 
6.3 
Safety Parameters 
The Investigator is responsible for monitoring the safety of patients who have been 
enrolled in this study and for accurately documenting and reporting information as 
described in this section.  
6.3.1 Adverse Events 
See Section 6.2.1 of the Parent Study.   
6.3.2 Serious Adverse Events 
See Section 6.2.2 of the Parent Study.  
6.3.3 Pregnancy  
The policies for pregnancy are identical to the Parent Study (see Section 6.2.3 of the 
Parent Study) except that at all visits of the Extension Phase (Visits 7 through Visit 10 
and the Extension Phase Early Termination Visit [if applicable]), females of 
childbearing potential will have a urine dipstick pregnancy test (analyzed on site).  
6.3.4 Vital Signs 
Vital signs will be measured and recorded at the time points designated on the 
Extension Phase schedule of events (see Table 6.1), in accordance with the procedures 
and policies described in Section 6.2.4 of the Parent Study. 
6.3.5 Electrocardiograms (ECGs) 
During the Extension Phase, one 12-lead ECG will be performed at the time point 
designated on the Extension Phase schedule of events (Table 6.1), following the 
procedures and policies provided in Section 6.2.5 of the Parent Study.  
In addition, ECGs may be performed at other visits at the discretion of the Investigator.  
6.3.6 Physical Examinations 
A complete physical examination that is limited to the following body systems: general 
appearance (including skin), head and neck, eyes and ears, nose and throat, pulmonary, 
cardiovascular, gastrointestinal, muscular skeletal, lymphatic, neurological, will be 
performed at the time points designated on the Extension Phase schedule of events 
(Table 6.1). 
 
If a new, significant abnormal or worsened abnormal pre-existing condition is detected, 
the condition needs to be recorded as an AE.  
 
Weight will be measured at the time points designated on the Extension Phase schedule 
of events (Table 6.1). 
6.3.7 Medical History 
While providing informed consent for participation Extension Phase, patients (or their 
legal representative on their behalf) will be asked if they agree to provide relevant 
medical history, including outcomes of functional assessments such as the SARA 
conducted prior to their enrollment and participation in the Parent Study. Provided the 

 
 
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patient 
(or 
legal 
representative 
on 
their 
behalf) 
consents, 
the 
available retrospective data may be used to conduct additional analyses which assess 
the slope of disease progression before enrollment in the trial and after the initiation of 
treatment with IB1001.  
 
6.4 
Laboratory Parameters 
6.4.1 Safety Laboratory Assessments 
Samples will be collected and analyzed by standard laboratory procedures at the time 
points designated on the schedule of events – Extension Phase (see Table 6.1), in 
accordance with the procedures and policies described in Section 6.3.1 of the Parent 
Study.  
The total amount of blood taken per patient during the study (Parent Study + Extension 
Phase) is provided in Section 6.4.5.  
6.4.2 Measurement of N-Acetyl-L-Leucine Concentration in Blood on FULL PK 
days 
Blood samples for the quantification of N-Acetyl-L-Leucine in plasma will be obtained 
according to the Extension Phase schedule of events (Table 6.1). 
At Visit 7B, the first sample will be taken before first dosing of N-Acetyl-L-Leucine in 
the Extension Phase; subsequent samples will be taken at 30 minutes (+/- 5 minutes), 
60 minutes (+/- 5 minutes), 90 minutes (+/- 10 minutes), 120 minutes (+/- 10 minutes), 
150 (+/- 15 minutes), 180 minutes (+/- 15 minutes), 240 minutes (+/- 15 minutes), and 
360 minutes (+/- 15 minutes) after the first extension phase IMP dose is taken. 
At Visit 9B, the first sample will be taken directly before last IMP intake of the 
treatment period; subsequent samples will be taken at 30 minutes (+/- 5 minutes), 
60 minutes (+/- 5 minutes), 90 minutes (+/- 10 minutes), 120 minutes (+/- 10 minutes), 
150 minutes (+/- 15 minutes), 180 minutes (+/- 15 minutes), 240 minutes (+/- 15 
minutes), and 360 minutes (+/- 15 minutes) after the last extension phase IMP dose is 
taken.  
At Visit 7B and Visit 9B, it is important that the day and exact time of the dose of N-
Acetyl-L-Leucine that is taken after the first pre-dose PK blood draw and before the 
subsequent first post-dose blood draw at 30 minutes (+/- 5 minutes) is recorded.  
At Visit 7B and Visit 9B, for each PK blood draw, it is important that the day and exact 
time of each blood draw is recorded. 
On Visit 7B and Visit 9B, when full PK sampling is conducted, the drug should be 
taken in accordance with the protocol (that is, taken 30 minutes before or at least two 
hours after a meal). In addition, on Visit 7B and Visit 9B, the days PK sampling is 
conducted, all meal times should be recorded until the last PK draw has been made. For 
Visit 7B, the next dose of N-Acetyl-L-Leucine should be taken after the last PK draw 
has been made at the earliest. Note, for Visit 9B, no further doses will be given after 
the PK draws until the end of Visit 10 (Visit 9B marks the end of the Extension Phase 
treatment period I0. Shipment instructions for N-Acetyl-L-Leucine PK blood samples 
will be provided in the laboratory manual.  
The total amount of blood taken per patient during the Extension Phase (that is, in 
addition to the Parent Study) is provided in Section 6.4.55. 

 
 
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6.4.3 Measurement of N-Acetyl-D-Leucine Concentration in Urine 
Urine tests for N-Acetyl-D-Leucine will be done pre-dose at Visit 7A41 and pre-dose at 
Visit 10. Data will be analyzed in batches and used for sensitivity analyses only.  
6.4.4 Additional Laboratory Samples for Research Purposes 
Retained samples from the Parent Study or Extension Phase may be used for research 
purposes to provide more information on the disease A-T. 
 
Blood samples will be obtained for possible research purposes to provide more 
information on the disease A-T according to the Extension Phase schedule of events 
(Table 6.1).   
 
6.4.5 Total Blood Volume 
The total amount of blood taken per subject during the Extension Phase will be 
approximately 119 mL (35 mL for safety analysis, 72 mL for the PK analysis, and 12 
mL for research purposes). If a safety laboratory analysis is performed at Visit 7, Part 
A, an additional 7 mL will be taken, and the total amount of blood taken per subject 
during the Extension Phase will be approximately 126 mL. The total of blood taken 
during the total study, Parent study + Extension phase will be approximately 192 mL 
(66mL from the Parent study + 126mL from the Extension Phase). 
 
 
 
41 If Visit 7 is scheduled within +7 days of Visit 6, the urine test for N-Acetyl-D-Leucine taken at Visit 6 may be 
used as the pre-dose urine test. 

 
 
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7 
STUDY CONDUCT – EXTENSION PHASE 
7.1 
Observations by Visit 
7.1.1 Visit 7: Extension Phase Baseline Visit 
Visit 7: The assessments comprising Visit 7 may be conducted over a two-day period 
(“Part A” and “Part B”)42. If Visit 7, Part B is scheduled 1 day (+6 days) after Visit 6 
(Washout 2), the assessments defined as Part A will use the results obtained at Visit 6. 
At Visit 6 of the Parent Study, the PI should determine continued treatment with IB1001 
to be in the patient’s best interest, and, provided the patient/caregiver would like to 
continue participation in the Extension Phase, the PI should obtain informed 
consent/informed consent form (ICF) signature and patient information (see Section 
7.1.6 of the Parent Study). 
 
Visit 7, Part A: Part A of the Extension Phase baseline assessment. 
If Visit 7, Part B is scheduled 1 day (+6 days) after Visit 6, the results obtained for 
assessments at Visit 6 can be carried over to Visit 7, Part A (i.e. assessments performed 
at Visit 6 don’t need to be repeated). If Visit 7, Part B cannot be scheduled within 1 day 
(+6 days) after Visit 6, Visit 7 Part A assessments may be carried out and Visit 7 
conducted over 2 days.  
 
• Addendum to the informed consent/informed consent form (ICF) signature and 
patient information for Extension Phase (if applicable) 
• Check of inclusion/exclusion criteria for Extension Phase (if applicable) 
• Vital signs 
• Physical Exam 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of 
Clinical Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 
8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients 
aged <18 years  
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Columbia Suicide Severity Rating Scale (C-SSR) 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at 
site) 
• Urine test for N-Acetyl-D-Leucine 
• Blood draw for laboratory safety tests (done at central lab) 
• Blood draw for research purposes 
 
 
42 If Visit 7 is conducted within +7 days of Visit 6, the assessments performed at “Visit 7 Part A” do 
not need to be duplicated.  

 
 
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• Documentation of adverse events 
 
 
Visit 7, Part B:  Part B of the Extension Phase baseline assessment. Scheduled either 1 
day (+6 days) after Visit 6, or +1 Day after Visit 7, Part A. Start of IMP during the 
Extension Phase.  
• Weight 
• Pre-dose blood draw for PK (taken directly before the first dose of N-Acetyl-L-
Leucine in the Extension Phase) (done at PK lab) 
• Dispensing of study drug + intake of study drug at site  
• Blood draws for PK taken at the defined post-dose timepoints (done at PK lab) 
• Documentation of adverse events  
 
7.1.2 Visit 8: Day 180 (+/- 14 days: First assessment of the Extension Phase 
treatment period I 
• Return of trial drug and compliance check 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Physical Exam 
• Weight 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on previous visit 
• Clinical Global Impression of Change (CGI-C) by caregiver based on previous visit 
• Clinical Global Impression of Change (CGI-C) by patient if able based on previous 
visit 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Blood draw for safety laboratory tests (done at central lab) 
• Documentation of adverse events  
• Dispensing of additional study drug  
7.1.3 Visit 9:  Day 365 (+/- 14 days): Final assessments of the Extension Phase 
treatment period I 
The assessments comprising Visit 9 may be conducted over a two-day period (“Part 
A” and “Part B”). 

 
 
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7.1.3.1 Visit 9, Part A:  Day 365 (+/- 14 days) of the treatment period 
• Spinocerebellar Ataxia Functional Index (SCAFI) + including Video-Recording of 
Clinical Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 
8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on Visit 7 
• Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 7 
• Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 7 
• 12-lead ECG 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Documentation of adverse events  
 
7.1.3.2 Visit 9, Part B 
The final treatment visit in the Extension Phase treatment Period I.  +1 Day after Visit 
9, Part A.  
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Physical Exam 
• Weight 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for research purposes 
• Pre-dose blood draw for PK (taken directly before the last dose of N-Acetyl-L-
Leucine in the Extension Phase) (done at PK lab) 
• Last intake of study drug at site  
• Blood draws for PK taken at the defined post-dose timepoints (done at PK lab) 
• Return of trial drug and compliance check 
• Documentation of adverse events  
 
7.1.4 Visit 10: Washout Visit  
The final day of the Extension Phase Washout / First date of Extension Phase 
Treatment Period II 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Physical Exam 
• Weight 

 
 
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• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on previous visit 
• Clinical Global Impression of Change (CGI-C) by caregiver based on previous visit 
• Clinical Global Impression of Change (CGI-C) by patient if able based on previous 
visit 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for safety laboratory tests (done at central lab) 
• Documentation of adverse events  
• Addendum to the informed consent/informed consent form (ICF) signature and 
patient information for Extension Phase treatment period II (if applicable) 
• Dispensing of study drug + intake of study drug at site.  
 
7.1.5 Visit 11: Day 587 (+/- 14 days): Interim Extension Phase visit treatment 
period II 
• Return of trial drug and compliance check 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Physical examination 
• Weight 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on Visit 10 
• Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 10 
• Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 10 
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Blood draw for safety laboratory tests (done at central lab) 
• Documentation of adverse events  
• Dispensing of additional study drug.  

 
 
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7.1.6 Visit 12 Day 767: Final assessments of the Extension Phase treatment 
period II with N-Acetyl-L-Leucine 
• Return of trial drug and compliance check 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Physical examination 
• Weight 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on Visit 10 
• Clinical Global Impression of Change (CGI-C) by caregiver based on Visit 10 
• Clinical Global Impression of Change (CGI-C) by patient if able based on Visit 10  
• Urinalysis (done at central lab) 
• Urine by dipstick: pregnancy test for women of childbearing potential (done at site) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for research purposes 
 
7.1.7 Extension Phase Early Termination (ET) 
• Return of trial drug and compliance check 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
• Physical Exam 
• Weight 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 
• Scale for Assessment and Rating of Ataxia (SARA) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged 
<18 years 
• Clinical Global Impression of Severity (CGI-S) by physician 
• Clinical Global Impression of Severity (CGI-S) by caregiver 
• Clinical Global Impression of Severity (CGI-S) by patient if able 
• Clinical Global Impression of Change (CGI-C) by physician based on previous visit 
• Clinical Global Impression of Change (CGI-C) by caregiver based on previous visit 
• Clinical Global Impression of Change (CGI-C) by patient if able based on previous 
visit 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• 12-lead ECG 

 
 
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• Urinalysis (done at central lab) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
• Blood draw for safety laboratory tests (done at central lab) 
• Blood draw for research purposes 
• Documentation of adverse events  
 

 
 
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8 
STATISTICAL METHODS – EXTENSION PHASE 
8.1 
General Analysis Plan 
8.1.1 Disposition of Patients 
The number of patients enrolled, plus the numbers contained within the Extension 
Phase Safety Analysis Set (SAFe) modified intention-to-treat analysis set (mITTe). The 
number of patients discontinuing treatment, together with the primary reason for 
discontinuation will be presented. 
 
Protocol Deviations 
Protocol deviations include but are not limited to: 
• Violation of key inclusion /exclusion criteria  
• Use of Prohibited Medications 
Further detail will be provided in the Statistical Analysis Plan (SAP).  
8.1.2 Analysis Populations 
• The Safety Analysis Set Extension Phase (SAFe) will consist of all patients who 
receive at least one dose of study drug (N-Acetyl-L-Leucine) in the Extension 
Phase  
• The modified intention-to-treat analysis set Extension Phase (mITTe) will 
consist of all patients in the SAF with a SARA score at Visit 7 of the Extension 
Phase and either at Visit 8 or Visit 9 (or both) 
8.2 
General Considerations 
Statistical analysis will be performed using SAS; the version used will be specified in 
the SAP. 
All variables will be summarized using descriptive statistics. The number of patients, 
mean, standard deviation (SD), minimum, median, and maximum will be calculated for 
continuous and score variables. Frequency tables will be generated for categorical data. 
90% confidence intervals, together with a one-sided significance level of 0.05 where 
appropriate, will be used for all endpoints as a guide for evidence for activity. 
Conclusions regarding treatment efficacy will not solely rely on detecting statistical 
significance with equal emphasis placed on the magnitude and clinical relevance of 
treatment differences as judged by the point estimates and confidence intervals. 
No correction for multiple comparisons will be included.  
8.3 
Demographics, Baseline Characteristics and Concomitant Medications 
Demographic data and patient characteristics at baseline will be summarized 
descriptively. 
Frequency and percentage of prior and concomitant medication use will be summarized 
by World Health Organization (WHO) Drug dictionary coded terms - Anatomic 
Therapeutic Chemical (ATC) classification and preferred term. 
8.4 
Treatment Compliance 
Summary statistics for the number of N-Acetyl-L-Leucine doses taken, based on bottles 
or sachets of Study Drug dispensed and return bottle or sachet counts, will be 
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data will be summarized descriptively together with the proportion of patients who take 
at least 80% of the prescribed medication. 
8.5 
Efficacy Analyses 
The primary analyses of efficacy will be based on the mITTe.  
For each of the primary endpoint there will be separate analyses within key subgroups. 
The subgroups to be considered will be defined by: 
• Naïve versus non-naïve as determined at screening 
• Age (pediatric versus adult) 
• Age/weight/dosing group  
• Disease severity based on SARA below/ above the median SARA score at 
Visit 1 
• Gender (male versus female) 
• Region (US versus Europe) 
• Primary Anchor Test (9HPT-D or 8MWT)   
• Individual components of SARA scale: Gait Subtest 
• Composite of SARA Subtests 1-4 (Gait, Stance, Sitting, Speech)  
• Intra-patient variability between SARA score at Visit 1 (Baseline 1) versus 
Visit 2 (Baseline 2) (below/above median). 
Additional subgroups can be added at the time of analysis on an exploratory basis. 
Separate Extension Phases are planned to be conducted with N-Acetyl-L-Leucine for 
NPC, GM2-gangliosidosis, and ataxia-telangiectasia. There may be meta-analyses that 
will bring together the data from the studies for the primary and selected secondary 
endpoints. Further details will be provided in a meta-analysis statistical analysis plan 
(MASAP). 
8.5.1 Primary Efficacy Endpoint 
The primary endpoint is based on the SARA score with success defined as no change 
or a decrease in the mDRS score from Visit 7 to Visit 9.  
 
It is postulated that under standard of care, 90% of patients would worsen (higher score) 
in terms of their performance on the SARA scale over a 12-month period, while 
conversely only 10% would show similar performance or some improvement. 
Statistical evaluation of the primary binary endpoint (success/failure on  SARA scale) 
will compare the proportion of success with 10% in a one-sided Fishers Exact test at 
the one-sided 5% significance level. 
 
8.5.2 Exploratory Efficacy Endpoints 
 
Additional exploratory endpoints will investigate other measures of symptoms and 
quality of life. Descriptive statistics will be provided for these measures at each visit 
and also changes from Extension Phase baseline (Visit 7) to the end of Extension Phase 
treatment period I with N-Acetyl-L-Leucine (Visit 9) for the following measures: 

 
 
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Spinocerebellar Ataxia Functional Index (SCAFI)43 score 
• Scale for Assessment and Rating of Ataxia (SARA) score 
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y44 for patients aged 
<18 years 
• Treating Physician Clinical Global Impression of Severity (CGI-S)  
• Treating Physician Clinical Global Impression of Change (CGI-C) comparing 
end of treatment (Visit 9) to Extension Phase baseline (Visit 7) 
• Caregiver Clinical Global Impression of Severity (CGI-S)  
• Caregiver Clinical Global Impression of Change (CGI-C) comparing end of 
treatment (Visit 9) to Extension Phase baseline (Visit 7) 
• Patient Clinical Global Impression Scales Impression of Severity (CGI-S) if 
they are able 
• Patient Clinical Global Impression of Change (CGI-C) comparing end of 
treatment (Visit 9) to Extension Phase baseline (Visit 7) if they are able 
 
Exploratory endpoints in the Extension Phase may also be based on changes over the 
following time periods: 
 
• The beginning of the Extension Phase (Visit 7) to the end of the Extension Phase 
washout period (Visit 10) 
• The end of the Extension Phase treatment period I (Visit 9) to the end of the 
Extension Phase washout period (Visit 10). 
• The end of Extension Phase period I washout (Visit 10) to the end of Extension 
Phase treatment period II (Visit 12) 
• The beginning of the Parent study (Visit 1) to the end of the Extension Phase 
treatment period II (Visit 12) 
 
Videos of the primary and non-primary anchor tests are collected throughout the 
extension phase for the CI-CS. These videos may be analyzed in order to inform the 
development and validation of the CI-CS. 
 
While providing informed consent for participation Extension Phase, patients (or their 
legal representative on their behalf) will be asked if they agree to provide relevant 
medical history, including outcomes of previous functional assessments such as the 
SARA scale conducted prior to their enrollment and participation in the Parent Study. 
Provided the patient (or legal representative on their behalf) consents, the 
available retrospective data may be used to conduct additional analyses which assess 
the slope of disease progression before enrollment in the trial and after the initiation of 
treatment with IB1001.  
 
All exploratory endpoints relating to the washout phase, or Extension Phase treatment 
period II, will be evaluated based on descriptive statistics. 
 
 
 
43The 9 Hole Peg Test of the Dominant Hand (9HPT-D) and the 8 Meter Walk Test (8MWT) will be videoed for 
every patient at every visit except Visit 0 of the parent study. 
44 European Sites Only 

 
 
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8.6 
Missing Data 
Analyses based on the mITT analysis set will utilize a last observation carried forward 
(LOCF) approach for a missing score at Visit 9.  
For the primary SARA endpoint, this implies that the score of Visit 8 willbe used 
instead. Other endpoints will not be imputed, and missing data will be reported as is. 
No sensitivity analyses will be applied.  
 
For all other endpoints there will be no imputation for missing data and data will be 
reported and evaluated as observed.  
8.7 
Blinding 
This study is not blinded. Videos of the primary and non-primary anchor tests collected 
throughout the extension phase for the CI-CS may be analyzed in order to inform the 
development and validation of the CI-CS. Further details regarding this blinding 
process will be detailed in the SAP. 
8.8 
Safety Analyses 
The SAFe will be the basis for all analyses of safety and tolerability.  
8.9 
Determination of Sample Size 
Sample size is determined by the number of patients that move into this Extension 
Phase from the parent study. The expectation is that between 60% and 70% of patients 
will rollover into the extension period. With 20 out of 32 patients (62.5%) rolling over, 
the study will have 80% power to detect an improvement in the success rate to 31% 
compared to the null hypothesis value of 10%. 

 
 
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9 
DATA HANDLING AND RECORD KEEPING – EXTENSION PHASE 
See Section 9 of Parent Study.  

 
 
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10 QUALITY CONTROL AND QUALITY ASSURANCE – EXTENSION 
PHASE 
See Section 10 of the Parent Study.  

 
 
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11 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS – EXTENSION 
PHASE 
See Section 11 of the Parent Study.  

 
 
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Table 6.1: 
Schedule of Events for the Extension Phase

 
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Period in the Extension Phase (EP) 
EP Baseline Period 
EP Treatment Period I 
EP Wash-Out Period 
EP Treatment Period II 
EP Early Term. 
Duration of the whole period 
1 Day 
1 Day 
1 Year 
6 Weeks 
1 Year 
1 Day 
Visit number 
Visit 7Ai 
Visit 7B 
Visit 8 
Visit 9A 
Visit 9B 
Visit 10  
Visit 11 
Visit 12 / EOS 
ET 
Name of the Visit 
EP Screening/Bsl 
EP Baseline  
EP Treatment 1 
EP Treatment 2 
EP Treatment 2 
EP Washout 1 
EP Treatment 3 
EP Treatment 4 
EP ET 
Timeline (Days) 
Day -1 
Day 1, Start IMP 
Day 180 
Day 365 
Day 366  
Day 407 
Day 587 
Day 767 
XX 
Visit Window allowed 
na 
+6 dayii 
+/- 14 days 
+/- 14 days 
na 
+14 days 
+/- 14 days 
+/- 14 days 
na 
 
 
Patient information and informed 
consent process  
X 
 
 
 
 
X 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
Patient Weight  
 
X 
X 
 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
X 
 
X 
X 
X 
X 
X 
Documentation of concomitant 
medication 
X 
 
X 
 
X 
X 
X 
X 
X 
Documentation of frequency of 
therapy (hours per week) 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
X 
12-lead electrocardiogram (ECG) 
 
 
 
X 
 
 
 
 
X 
Blood safety laboratory testsiii 
X 
 
X 
 
X 
X 
X 
X 
X 
Blood samples for research purposes 
X 
 
 
 
X 
 
 
X 
X 
PK Blood Samplingiv 
 
X 
 
 
X 
 
 
 
 
Urinalysis 
X 
 
X 
X 
 
X 
X 
X 
X 
Urine by dipstick for pregnancy testv  
X 
 
X 
X 
 
X 
X 
X 
X 
Urine test for N-Acetyl-D-Leucine 
X 
 
 
 
 
X 
 
 
X 
Quality of Life EQ-5D-5L for 
patients aged ≥18; EQ-5D-Y for 
children aged <18 yearsvi 
X 
 
X 
X 
 
X 
X 
X 
X 
Scale for Ataxia Rating (SARA) 
X 
 
X 
X 
 
X 
X 
X 
X 

 
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Period in the Extension Phase (EP) 
EP Baseline Period 
EP Treatment Period I 
EP Wash-Out Period 
EP Treatment Period II 
EP Early Term. 
Duration of the whole period 
1 Day 
1 Day 
1 Year 
6 Weeks 
1 Year 
1 Day 
Visit number 
Visit 7Ai 
Visit 7B 
Visit 8 
Visit 9A 
Visit 9B 
Visit 10  
Visit 11 
Visit 12 / EOS 
ET 
Name of the Visit 
EP Screening/Bsl 
EP Baseline  
EP Treatment 1 
EP Treatment 2 
EP Treatment 2 
EP Washout 1 
EP Treatment 3 
EP Treatment 4 
EP ET 
Timeline (Days) 
Day -1 
Day 1, Start IMP 
Day 180 
Day 365 
Day 366  
Day 407 
Day 587 
Day 767 
XX 
Visit Window allowed 
na 
+6 dayii 
+/- 14 days 
+/- 14 days 
na 
+14 days 
+/- 14 days 
+/- 14 days 
na 
 
Abbreviations: EP = Extension Phase; na = not applicable   
i Visit 7A may be taken from Visit 6, provided Visit 7B is scheduled within 1 day (+6 days) of Visit 6 
ii if Visit 7B cannot be scheduled 1 day (+6 days) after Visit 6 (Visit 7A), Visit 7A and Visit 7B should be conducted over a two-day period on two consecutive days, i e  Visit 7B occurs +1 day after Visit 7A 
iii Analyzed at central lab 
iv Analyzed at PK lab 
v Only for women of childbearing potential; done at site 
vi If a patient turns 18 over the course of the study, they should continue to use the EQ-5D-Y 
vii If Visit 7A is based on Visit 6 assessments, the video recordings from Visit 6 should be used  
viii Or after visit if IMP is returned via courier 
ix If applicable 
Scale for Spinocerebellar Ataxia 
Functional Index (SCAFI) 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Video-Recording Primary Anchor 
Tests (8MWT + 9HPT-D) 
Xvii 
 
X 
X 
 
X 
X 
X 
X 
Columbia Suicide Severity Rating 
Scale (CSSR-S) 
X 
 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Severity (CGI-S) by Physician 
X 
 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Severity (CGI-S) by Caregiver 
X 
 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Severity (CGI-S) by Patient 
X 
 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Change (CGI-C) by Physician 
 
 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Change  
(CGI-C) by Caregiver 
 
 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Change 
(CGI-C) by Patient 
 
 
X 
X 
 
X 
X 
X 
X 
Documentation of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing of study drug 
 
X 
X 
 
 
X 
X 
 
 
Intake of study drug at site 
 
X 
 
 
X 
X 
 
 
 
Return of study drugviii 
 
 
X 
 
X 
 
X 
X 
X 
Study drug compliance check 
 
 
X 
 
X 
 
X 
X 
X