Conditions: GM2 Gangliosidosis Tay-Sachs Disease Sandhoff Disease
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This is a multinational, multicenter, open-label, rater-blinded prospective Phase II study which will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).

There are two phases to this study: the Parent Study, and the Extension Phase.

The Parent Study evaluates the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the symptomatic treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).

The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the neuroprotective, disease-modifying treatment of GM2 Gangliosidosis. The Extension Phase was considered exploratory.

Detailed description:
In the Parent Study, Patients will be assessed during three study phases: a baseline period, a 6-week treatment period, and a 6-week post-treatment washout period. If within 6 weeks prior to the initial screening visit, a patient has received any of the prohibited medications defined in the eligibility criteria (irrespective of the preceding treatment duration) a wash-out study-run-in of 6 weeks is required prior to the first baseline assessment. All patients will receive the study drug during the treatment period. For each individual patient, the Parent Study lasts for approximately 3.5 - 4 months during which there are 6 visits to the study site.

This Extension Phase allows patients who have completed the Parent Study to, at the discretion of the Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001). Patients will receive treatment with IB1001 for two one-year treatment periods, separated by a 6-week washout. All patients will receive the study drug during these two one-year treatment periods. For each individual patient, the Extension Phase lasts for approximately 25.5 months, during which there are 6 visits to the study site.

Arms:
arm 1: Parent Study: 6-weeks treatment with IB1001 administered orally. Extension Phase: 1-year treatment with IB1001 administered orally.

Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day).

Patients 6-12 years old will receive weight-tiered doses:

* 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 adults) arm 2: After the Parent Study 6-week treatment period, and Extension Phase one-year treatment period, patients will enter a 6-week post-treatment washout period.

Interventions: intervention 1: IB1001
Intervention descriptions: intervention 1: IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered.

Protocol document:
SAP_002.pdf: 
 
 
 
 
 
Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease):  
A multinational, multicenter, open-label, rater-blinded Phase II study 
 
 
 
 
NCT Number: NCT03759665 
 
 
Version and date of SAP: Final SAP 4.0, 08 Mar 2023 


 
 
Protocol ID: Version 7.0 (30-Nov-2022) /  
Clinical Study Reference: IB1001-202 
 
Updated final SAP 4.0, 08 Mar 2023 
Confidential 
 
Page 1 of 66 
  
STATISTICAL ANALYSIS PLAN 
 
 
 
 
(Short) study title:  
Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-
Sachs and Sandhoff Disease): A multinational, multicenter, open-
label, rater-blinded Phase II study.  
 
Name of the sponsor:  
IntraBio Ltd.  
 
Protocol identification:  
IB1001-202, version 7.0 (30Nov2022) 
Version and date of SAP:  Final SAP 4.0, 08 Mar 2023 
 
 
 
 
 
                                          
 
 
 
 
 
Confidentiality statement 
This document is confidential. The information within this document may not be reproduced or otherwise 
disseminated without approval of IntraBio Ltd. 






 
 
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TABLE OF CONTENTS 
Version history ........................................................................................................................... 2 
Approval page ............................................................................................................................ 3 
Table of contents ........................................................................................................................ 4 
List of Abbreviations ................................................................................................................. 8 
1 
General ........................................................................................................................... 10 
2 
Study Information ........................................................................................................... 10 
2.1 
Study Objectives ................................................................................................. 10 
2.1.1 
Parent study ................................................................................................. 10 
2.1.2 
Extension phase ........................................................................................... 10 
2.2 
Design of the Study ............................................................................................ 11 
2.2.1 
Parent study ................................................................................................. 11 
2.2.2 
Extension phase ........................................................................................... 12 
2.3 
Study medication ................................................................................................ 13 
2.3.1 
Parent study ................................................................................................. 13 
2.3.2 
Extension phase ........................................................................................... 13 
2.4 
Sample size ......................................................................................................... 14 
2.4.1 
Parent study ................................................................................................. 14 
2.4.2 
Extension phase ........................................................................................... 14 
2.5 
Study flow chart .................................................................................................. 15 
2.5.1 
Parent study ................................................................................................. 15 
2.5.2 
Extension phase ........................................................................................... 24 
3 
Subjects for Analysis ...................................................................................................... 26 
3.1 
Parent study: Analysis populations ..................................................................... 26 
3.1.1 
Intention-to-Treat (ITT) population ............................................................ 26 
3.1.2 
Modified Intention-to-Treat (mITT) population.......................................... 26 
3.1.3 
Per Protocol Set (PPS) ................................................................................. 26 
3.1.4 
Safety Analysis Set (SAF) ........................................................................... 26 
3.2 
Extension phase: Analysis populations .............................................................. 26 
3.2.1 
Modified Intention-to-Treat Extension phase (mITTe) population ............. 26 
3.2.2 
Safety Analysis Set Extension phase (SAFe) .............................................. 26 
3.3 
Protocol deviations ............................................................................................. 26 
3.4 
Blinded Data Review Meeting ........................................................................... 27 
4 
Study endpoints .............................................................................................................. 27 
4.1 
Parent study ........................................................................................................ 27 


 
 
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4.1.1 
Primary endpoint ......................................................................................... 27 
4.1.2 
Key secondary efficacy endpoints ............................................................... 27 
4.1.3 
Additional secondary efficacy endpoints .................................................... 28 
4.1.4 
Exploratory endpoints ................................................................................. 28 
4.1.5 
Safety endpoints .......................................................................................... 29 
4.2 
Extension phase .................................................................................................. 29 
4.2.1 
Primary endpoint ......................................................................................... 29 
4.2.2 
Secondary efficacy endpoints ...................................................................... 29 
4.2.3 
Exploratory Endpoints ................................................................................. 29 
4.2.4 
Additional exploratory endpoints ................................................................ 30 
4.2.5 
Safety endpoints .......................................................................................... 30 
5 
Parent study: Statistical Analysis ................................................................................... 31 
5.1 
General considerations ....................................................................................... 31 
5.2 
Adjudication of endpoint data ............................................................................ 31 
5.3 
Missing data ........................................................................................................ 32 
5.4 
Interim analysis ................................................................................................... 33 
5.5 
Baseline characteristics ....................................................................................... 34 
5.5.1 
Inclusion/exclusion criteria.......................................................................... 34 
5.5.2 
Demographics .............................................................................................. 34 
5.5.3 
Baseline characteristics................................................................................ 34 
5.5.4 
Disposition ................................................................................................... 34 
5.5.5 
Medical history ............................................................................................ 35 
5.5.6 
Pregnancy data ............................................................................................. 35 
5.5.7 
Other screening data .................................................................................... 35 
5.6 
Statistical analysis efficacy endpoints ................................................................ 35 
5.6.1 
Primary endpoint ......................................................................................... 36 
5.6.2 
Key secondary endpoints ............................................................................. 37 
5.6.3 
Additional secondary endpoints .................................................................. 37 
5.6.4 
Other additional statistical analyses ............................................................ 39 
5.7 
Safety and tolerability evaluation ....................................................................... 39 
5.7.1 
Adverse events ............................................................................................. 39 
5.7.2 
Clinical laboratory ....................................................................................... 41 
5.7.3 
Vital Signs ................................................................................................... 41 
5.7.4 
Electrocardiography (ECG) ......................................................................... 42 
5.7.5 
Prior and concomitant medication/therapies ............................................... 42 


 
 
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5.8 
Scheduled visits, dosing, and treatment compliance .......................................... 42 
5.8.1 
Visit dates .................................................................................................... 42 
5.8.2 
Dosing and treatment compliance ............................................................... 42 
6 
Extension phase: Statistical Analysis ............................................................................. 42 
6.1 
General considerations ....................................................................................... 42 
6.2 
Adjudication of endpoint data ............................................................................ 43 
6.3 
Missing data ........................................................................................................ 44 
6.4 
Interim analysis ................................................................................................... 44 
6.5 
Baseline characteristics ....................................................................................... 44 
6.5.1 
Inclusion/exclusion criteria.......................................................................... 44 
6.5.2 
Demographics .............................................................................................. 44 
6.5.3 
Baseline characteristics................................................................................ 44 
6.5.4 
Disposition ................................................................................................... 45 
6.5.5 
Medical history ............................................................................................ 45 
6.5.6 
Pregnancy data ............................................................................................. 45 
6.5.7 
Other screening data .................................................................................... 45 
6.6 
Statistical analysis efficacy endpoints ................................................................ 45 
6.6.1 
Primary endpoint Extension phase .............................................................. 46 
6.6.2 
Key secondary endpoints Extension phase .................................................. 46 
6.6.3 
Exploratory Endpoints ................................................................................. 46 
6.6.4 
Additional exploratory endpoints ................................................................ 48 
6.6.5 
Other additional statistical analyses ............................................................ 48 
6.7 
Safety and tolerability evaluation ....................................................................... 48 
6.8 
Scheduled visits, dosing, and treatment compliance .......................................... 48 
7 
Changes to protocol and other relevant remarks ............................................................ 48 
8 
COVID-19 details ........................................................................................................... 50 
9 
Data receipt ..................................................................................................................... 50 
10 
Technical details ............................................................................................................. 50 
10.1 
Programming conventions .................................................................................. 50 
10.2 
Coding ................................................................................................................ 53 
10.3 
Analysis software ............................................................................................... 54 
10.4 
Presentation of tables, listings, graphs ................................................................ 54 
11 
Tables, listings, graphs – parent study............................................................................ 54 
11.1 
General ................................................................................................................ 54 
11.2 
In-text tables and graphs ..................................................................................... 54 


 
 
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11.3 
End-of-text tables and graphs ............................................................................. 55 
11.4 
Listings ............................................................................................................... 60 
12 
Tables, listings, graphs – Extension phaCse .................................................................. 62 
12.1 
General ................................................................................................................ 62 
12.2 
In-text tables and graphs ..................................................................................... 62 
12.3 
End-of-text tables and graphs ............................................................................. 62 
12.4 
Listings ............................................................................................................... 64 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
_avg 
Average 
_recipr 
Reciprocal 
8MWT 
8-Meter Walking Test 
9HPT-D 
9 Hole Peg Test of the Dominant Hand 
9HPT-ND 
9 Hole Peg Test of the Non-Dominant Hand 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Transaminase 
ATC 
Anatomic Therapeutic Chemical 
BDRM 
Blinded Data Review Meeting 
BL 
Baseline 
CFB 
Change from Baseline 
CGI-C 
Clinical Global Impression of Change 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CI 
Confidence Interval 
CI-CS 
Clinical Impression of Change in Severity 
CI-S 
Clinical Impression of Severity 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice  
ICC 
Intraclass Correlation Coefficient 
ICH 
International Council on Harmonisation 
LoA 
Limits of Agreement 
LOCF 
Last Observation Carried Forward 
M(C)AR 
Missing (Completely) at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mDRS 
Modified Disability Rating Scale 
mITT 
Modified Intention-to-Treat  


 
 
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PI 
Principal Investigator 
PK 
Pharmacokinetics 
PM 
Project Manager 
PPS 
Per Protocol Set 
PT 
Preferred Term 
RBC 
Red Blood Cell Count 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SARA 
Scale for the Assessment and Rating of Ataxia 
SCAFI 
Spinocerebellar Ataxia Functional Index 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
 
 
 


 
 
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1 
GENERAL 
This Statistical Analysis Plan (SAP) describes in detail the methods and presentation of the 
data analyses which will be conducted by 
 for study IB1001-202. This plan is 
written in agreement with protocol version 7.0, dated 30 November 2023 and annotated Case 
Report Form (CRF), version 3.4, dated 11 June 2021, and the relevant Good Clinical Practice 
International Council on Harmonisation (GCP-ICH) guidelines. Furthermore, sponsor 
requirements for reporting will be considered. Additional changes or updates of those 
documents or requirements may result in a new version of the reporting/statistical analysis 
plan. This plan is to be finalized preferably prior to enrolment of the first patient in the study, 
but at least before first programming/data analysis. 
 
2 
STUDY INFORMATION 
2.1 
Study Objectives 
2.1.1 Parent study 
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 GM2 
Gangliosidosis. 
 
Secondary Objectives 
The secondary objectives are: 
• To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms of ataxia, 
functioning, and quality of life for patients with GM2 Gangliosidosis. 
• To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in patients with 
GM2 Gangliosidosis, including patients aged ≥18 years in the United States and 
patients aged ≥13 years in Europe, and weight-tiered doses in patients 6 to 12 years of 
age in Europe. 
 
Exploratory Objectives 
The exploratory objective is: 
• To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with 
GM2 Gangliosidosis. 
2.1.2 Extension phase 
Primary Objective 
The primary objective in the Extension Phase is to evaluate the efficacy of N-Acetyl-L-
Leucine based on the Modified Disability Rating Scale (mDRS). 
Secondary Objectives 
The secondary objectives are: 


 
 
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• 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 
GM2 Gangliosidosis 
• To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with 
GM2 Gangliosidosis. 
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 GM2 Gangliosidosis 
• To evaluate the effects of a 42-day (+14 days) washout from N-Acetyl-L-Leucine after 
one-year treatment based on blinded raters’ Clinical Impression of Change in Severity 
(CI-CS) 
• 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 patients with GM2 
Gangliosidosis. 
• 
To evaluate the long-term clinical efficacy, safety and tolerability of N-Acetyl-L-
leucine for patients with GM2 Gangliosidosis  
2.2 
Design of the Study 
2.2.1 Parent study 
This is a multinational, multicenter, open-label, rater-blinded Phase II study investigating the 
efficacy and safety of N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis. 
Approximately 39 male and female patients aged ≥6 years in Europe or ≥18 years in the 
United States with a confirmed diagnosis of GM2 Gangliosidosis are planned to be enrolled. 
 
The visit schedule differs between “naïve” (patients not previously exposed to prohibited 
medications within the 6 weeks (42 days) before the initial screening visit) and “non-naïve” 
patients: see figures 1 and 2 below. 
 
 
Figure 1: Study Scheme for Naïve Patients 
 
Figure 2: Study Scheme for Non-naïve Patients 


 
 
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2.2.2 Extension phase 
The (full) Extension phase is considered the study period starting with the Extension phase 
baseline (Visit 7) until Visit 12. In some instances, however, it may be beneficial to make the 
following split:  
• Extension phase I is considered the study period starting with the Extension phase 
Visit 7 until Visit 10.  
• Extension phase II is considered the study period starting with the Extension phase 
Visit 10 until Visit 12. 
 
The Extension phase will enroll patients who have completed Visit 6 of the Parent study 
phase of IB1001-202.  
 
During the Extension phase, patients will be assessed 6 times over a 25,5-month period. 
 
Baseline Visit of the Extension Phase  
Visit 7 (Part A and B) is the baseline of the extension phase. The assessments (Part A and 
Part B) comprising Visit 7 may be conducted over a two-day period 
(“Part A” and “Part B”). If Visit 7B is scheduled 1 day (+6 days) after Visit 6 
(Washout 2 of the Parent study), the assessments conducted at Visit 6 should count as 
Visit 7A (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 7A and Visit 7B should be performed over two consecutive days, i.e. Visit 7B occurs 
+1 day after Visit 7A. 
 
In general Visit 7A will be the same as Visit 6 in the Parent phase, or within one week 
following Visit 6. But a non-seamless transition of several weeks or months is possible. The 
same subject numbers will be used throughout the Parent and the Extension phase. 
 
Extension Phase Treatment Period I 
From Visit 7B onward, all patients will receive treatment with N-Acetyl-L-Leucine for 365 
days (+/-14 days).  
Visit 8 will occur at approximately Day 180 (+/-14 days). 
Visit 9 (Part A and B) will occur at approximately Day 365 (+/-14 days). 
The assessments comprising Visit 9 may be conducted over a two-day period (“Part A” and 
“Part B”). 
 


 
 
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Extension Phase Washout Period 
After Visit 9B, all patients will enter a 42-day (+14 days) washout phase.  
Visit 10 will occur at Day 407 (+ 14 days).   
 
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). 
 
 
2.3 
Study medication 
2.3.1 Parent study 
All patients are to receive N-Acetyl-L-leucine (IB1001) in this single-arm study. The study 
drug will be taken during a 6-week (42 days + 7 days) treatment period. The patient’s dose 
for the Parent phase will be determined based on their age and weight at Visit 1. During the 
treatment phase of this study, the dosing of the study drug is as follows: 
 
• Patients aged ≥13 years in Europe and aged ≥18 years in the United States 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) 
2.3.2 Extension phase 
All patients are to receive N-Acetyl-L-leucine (IB1001) during the Extension phase. The study 
drug will be taken for two 365-day (+/- 14 days) treatment periods (Extension phases I and II). 
The patient’s dose for the Extension phase I will be determined based on their age and weight 
at Visit 7, following the same tiered doses as for the Parent study (see Section 2.3.1). The 
patient’s dose for the Extension phase II will be determined based on their age and weight at 
Visit 10, following the same tiered doses as for the Parent study (see Section 2.3.1). 
In the event a patient turns 13 years old or a patient aged 6-12 years old changes weight 
categories between Visit 7 and 8 or Visit 10 and 11 of the Extension Phase, their daily dose 
will be adjusted accordingly at Visit 8 or Visit 11 (respectively). 


 
 
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2.4 
Sample size 
2.4.1 Parent study 
Under the original protocol, it was 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 for the primary endpoint is 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. 
 
Recruitment will continue until approximately 30 patients complete dosing. The following 
numbers of patients are foreseen: 
 
• To be enrolled: Approximately 39 patients  
• To be analyzed according to the modified Intention to Treat analysis (mITT): 
Approximately 36 patients 
• To be analyzed according to the Per Protocol Set (PPS): Approximately 30 patients 
 
2.4.2 Extension phase 
The 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%. 
 
Patients who completed Visit 10 of the Extension phase and are willing to continue for an 
additional year will continue in the Extension Phase until Visit 12. 


 
 
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2.5 
Study flow chart 
2.5.1 Parent study 
Schedule of Events for “Naïve” Patients 
 
 
 
 


 
 
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Schedule of Events for “Non-naïve” Patients 
 
 
 


 
 
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2.5.2 Extension phase 
 
 
 
 


 
 
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3 
SUBJECTS FOR ANALYSIS 
3.1 
Parent study: Analysis populations  
3.1.1 Intention-to-Treat (ITT) population 
The ITT population will consist of all patients who receive at least one dose of study drug (N-
Acetyl-L-Leucine) and with one video recording at either Visit 1 or Visit 2 (or both). 
3.1.2 Modified Intention-to-Treat (mITT) population 
The mITT population will consist of all patients who receive at least one dose of study drug (N-
Acetyl-L-Leucine) and with one video recording at either Visit 1 or Visit 2 (or both) and one 
video recording at either Visit 3 or Visit 4 (or both). 
3.1.3 Per Protocol Set (PPS) 
The PPS will consist of all patients with at least one video recording at baseline (either Visit 1 or 
Visit 2), end of treatment (either Visit 3 or Visit 4), and end of washout (either Visit 5 or Visit 6) 
and without any major protocol deviations that can influence the validity of the data for the 
primary efficacy variable.  
3.1.4 Safety Analysis Set (SAF) 
The Safety Analysis Set (SAF) will consist of all patients who receive at least one dose of study 
drug (N-Acetyl-L-Leucine). 
 
3.2 
Extension phase: Analysis populations 
The Extension phase will only include patients who completed Visit 6 of the Parent study and 
fulfill the inclusion criteria of Extension phase. Patients who completed Visit 10 of the Extension 
phase and are willing to continue for an additional year will continue in the Extension Phase 
until Visit 12. 
3.2.1 Modified Intention-to-Treat Extension phase (mITTe) population 
The mITTe population will consist of all patients who receive at least one dose of study drug (N-
Acetyl-L-Leucine) in Extension phase and with a mDRS score at Visit 7 and at either Visit 8 or 
Visit 9 (or both). This analysis population will be used for efficacy analyses throughout the 
Extension phase until Visit 12. 
3.2.2 Safety Analysis Set Extension phase (SAFe) 
The SAFe will consist of all patients who receive at least one dose of study drug (N-Acetyl-L-
Leucine) in the Extension phase. This analysis population will be used for all safety analyses 
throughout the Extension phase until Visit 12. Only reported data will be used in the analysis. 
3.3 
Protocol deviations 
Major protocol deviators will be identified to the extent possible by individuals responsible for 
data collection/compliance, and its analysis and interpretation. Any subjects or data values 
excluded from the PPS/PPSe analysis will be identified, along with their reason for exclusion. 


 
 
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3.4 
Blinded Data Review Meeting 
There will be a BDRM meeting held for the Parent study. No BDRM will be necessary for the 
Extension phase since no Per Protocol analysis population will be defined then. 
 
The patients will be classified during the BDRM to the analysis populations based upon the 
protocol deviations. Invitees to this meeting are the Sponsor’s Medical Expert, the Sponsor’s 
representative, the Sponsor’s Project Manager (PM), the Medical Monitor, the Sponsor 
statistician, and the 
 statistician, but more roles can be invited if considered necessary. 
Input to this meeting will be supplied by the involved Data Management provider or the 
responsible PM at least one week in advance of the meeting: a blinded list of all protocol 
deviations (including missing and likely erroneous data), with specific detailing and description 
regarding the deviation, preferably in Excel. 
 
Possible compliance issues and unforeseen or reclassification of categories for missingness of 
the primary endpoint data will be part of the discussions held at the meeting.  
 
Where possible, this meeting will be held in a blinded manner, that is blind to study outcome 
data (also for open studies). The goal of this meeting is to reach consensus on minor and major 
protocol deviations. In case of a major deviation impacting the primary or secondary endpoints, 
the specific patient will be excluded from the PPS population, either completely or from a 
specific time point onwards. The meeting must be held prior to database lock.  
 
The decisions taken during this meeting and the reasons for those decisions will be documented 
by the PM (or a delegate as agreed) and sent for review to all parties involved as soon as possible 
after the meeting, but before database lock. If all parties involved agree, then the document is 
finalized, signed and stored in the TMF before database lock. 
 
4 
STUDY ENDPOINTS  
4.1 
Parent study 
4.1.1 Primary endpoint 
The primary efficacy endpoint is based on the blinded raters’ Clinical Impression of Change in 
Severity (CI-CS) score on either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 
Meter Walk Test (8MWT). The primary endpoint is defined as the CI-CS comparing the end of 
treatment (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout 
(Visit 6) with the end of treatment (Visit 4). 
4.1.2 Key secondary efficacy endpoints  
Supportive secondary endpoints that directly supplement the analysis of the primary endpoint 
will be evaluated as follows: 
 
• 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. 
• Difference in the blinded rater’s Clinical Impression of Severity (CI-S) values from 
baseline (average of Visit 1 and Visit 2) to end of treatment (average of Visit 3 and Visit 
4) and from end of treatment (average of Visit 3 and Visit 4) to end of washout (average 
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• Measurement of change in performance of the CI-CS score of either the 9HPT-D or the 
8MWT reclassified to a 3-point scale.  
• An evaluation of the CI-CS for the test (9HPT-D or 8MWT) that was not selected as the 
primary anchor test. 
4.1.3 Additional secondary efficacy endpoints 
For all additional secondary endpoints, the change from Visit 2 to Visit 4 and the change from 
Visit 4 to Visit 6 will be evaluated. 
Measurement of Ataxia and Functioning 
• Spinocerebellar Ataxia Functional Index (SCAFI). 
The SCAFI is composed of the 8MWT, the 9HPT, and the PATA rate, a measure of 
speech performance. 
• Scale for Assessment and Rating of Ataxia (SARA) score. 
SARA has 8 items that are related to gait, stance, sitting, speech, finger-chase test, nose-
finger test, fast alternating movements and heel-shin test. 
 
Measurement of Health-related Quality of Life 
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for children aged 6-17 years 
(two parts: the EQ visual analogue scale (EQ-VAS) and the EQ descriptive system). 
 
Measurement of Overall Neurological status 
• Modified Disability Rating Scale (mDRS) 
The scores of the six components (ambulation, language, manipulation, swallowing, 
seizures, and ocular movement) of this scale add up to a composite value. 
 
Measurement of Global Impression 
• Clinical Global Impression of Severity by the treating physician (CGI-S-physician) at 
every visit. 
• Clinical Global Impression of Change by the treating physician (CGI-C-physician) 
comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to 
end of treatment (Visit 4). 
• Clinical Global Impression of Severity by the caregiver (CGI-S-caregiver) at every visit. 
• Clinical Global Impression of Change by the caregiver (CGI-C-caregiver) comparing 
Visit 4 to Visit 2 and Visit 6 to Visit 4. 
• Clinical Global Impression of Severity by the patient (CGI-S-patient) at every visit if they 
are able. 
• Clinical Global Impression of Change by the patient (CGI-C-patient) comparing Visit 4 
to Visit 2 and Visit 6 to Visit 4 if they are able. 
 
The CGI-S scales are on a 7-point scale ranging from ‘normal, not ill at all’ to ‘among the 
most ill patients’. The CGI-C scales are also on a 7-point scale ranging from ‘very much 
improved’ to ‘very much worse’. 
 
4.1.4 Exploratory endpoints  
Sparse PK sampling will be collected for biochemical analysis so to characterize the 
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(Note that analysis and reporting of pharmacokinetics is outside the scope of this analysis plan. 
PK data handling, analysis and reporting will be done by an external company that specializes in 
PK analysis and reporting. The PK report will be added to Appendix 16.1 of the CSR as a 
separate document.) 
4.1.5 Safety endpoints 
The safety parameters to be evaluated are: 
• Adverse Events 
• Laboratory safety measurements: haematology, clinical chemistry, urinalysis 
• Vital signs 
• Electrocardiography (ECG) 
4.2 
Extension phase  
With respect to the Parent study, all endpoints for the Extension phases are considered secondary 
to the endpoints of the Parent study phase.  
4.2.1 Primary endpoint  
The primary endpoint in the Extension phase is “success” based on the mDRS score, with 
success defined as no change or improvement (decrease) in the mDRS score from Visit 7 to Visit 
9.   
4.2.2 Secondary efficacy endpoints  
Supportive secondary endpoints for the Extension phase that directly supplement the analysis of 
the primary endpoint for the Extension phase will be evaluated as follows: 
 
• Full PK sampling at Visit 7 and Visit 9 to characterize the pharmacokinetics of N-Acetyl-
L-Leucine in patients with GM2 Gangliosidosis.  
(Note that analysis and reporting of pharmacokinetics is outside the scope of this analysis 
plan. PK data handling, analysis and reporting will be done by an external company that 
specializes in PK analysis and reporting. The PK report will be added to Appendix 16.1 
of the CSR as a separate document.)  
4.2.3 Exploratory Endpoints 
Exploratory endpoints will investigate other measures of symptoms and quality of life from Visit 
7 to Visit 9 for the following measures: 
Measurement of Ataxia and Functioning 
• Spinocerebellar Ataxia Functional Index (SCAFI). 
The SCAFI is composed of the 8MWT, the 9HPT, and the PATA rate, a measure of 
speech performance. 
• Scale for Assessment and Rating of Ataxia (SARA) score. 
SARA has 8 items that are related to gait, stance, sitting, speech, finger-chase test, nose-
finger test, fast alternating movements and heel-shin test. 
 
Measurement of Health-related Quality of Life 
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for children aged 6-17 years 
(two parts: the EQ visual analogue scale (EQ-VAS) and the EQ descriptive system). 
 


 
 
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Measurement of Global Impression 
• Clinical Global Impression of Severity by the treating physician (CGI-S-physician).  
• Clinical Global Impression of Change by the treating physician (CGI-C-physician). 
• Clinical Global Impression of Severity by the caregiver (CGI-S-caregiver). 
• Clinical Global Impression of Change by the caregiver (CGI-C-caregiver). 
• Clinical Global Impression of Severity by the patient (CGI-S-patient) if they are able. 
• Clinical Global Impression of Change by the patient (CGI-C-patient) if they are able. 
 
The CGI-S scales are on a 7-point scale ranging from ‘normal, not ill at all’ to ‘among the 
most ill patients’. The CGI-C scales are also on a 7-point scale ranging from ‘very much 
improved’ to ‘very much worse’. 
 
 
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.  
4.2.4 Additional exploratory endpoints  
For all additional exploratory endpoints, the change from Visit 7 to Visit 10, Visit 9 to Visit 10 
and Visit 10 to Visit 12 may also be evaluated. In addition, the change from Visit 1 to Visit 12 
may also be investigated. 
• SCAFI 
• 9-HPT of dominant hand 
• 8MWT 
• SARA 
• Health-related Quality of Life (EQ-5D-5L/Y) 
• CGI-S by physician 
• CGI-S by caregiver 
• CGI-S by patient if able 
• CGI-C by physician 
• CGI-C by caregiver 
• CGI-C by patient if able 
• mDRS 
4.2.5 Safety endpoints 
The safety parameters to be evaluated are: 
• Adverse Events 
• Laboratory safety measurements: haematology, clinical chemistry, urinalysis 
• Vital signs 
• ECGs 
• Physical Examination 
 


 
 
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5 
PARENT STUDY: STATISTICAL ANALYSIS  
5.1 
General considerations 
The Parent study is considered the study period between screening (Visit 0 or Visit 1) through 
Visit 6. 
 
Raw data (in listings) will be presented in the same precision as received. Appropriate rounding 
will be performed for the following summary statistics, where applicable: mean, standard 
deviation (SD) and two-sided 90% confidence limits will be presented with at least one more 
decimal than the original data; minimum and maximum values will be presented with the same 
precision as the original data. In frequency tables, percentages will be presented with 1 decimal 
unless otherwise stated.  
 
P-values will be presented with 3 decimals, and those smaller than 0.001 will be replaced by 
<0.001. One-sided p-values smaller than 0.05 will be considered statistically significant for the 
primary endpoint and indicative for other endpoints. No adjustment for multiple comparisons 
will be applied. Conclusions regarding treatment efficacy will not solely rely on detecting 
statistical significance but equal emphasis will be placed on the magnitude and clinical relevance 
of treatment differences as judged by the point estimates. All evaluations other than the primary 
endpoint will be considered exploratory in nature. 
 
Descriptive statistics presented in general summary tables will be the number of non-missing 
observations (n), mean, SD, minimum, median and maximum for quantitative data. For 
categorical data, frequency counts and percentages will be determined. 
 
In general, baseline is defined as the value measured prior to first study treatment administration 
(at Visit 2), unless otherwise specified. In case no value at Visit 2 is available, the value 
measured at Visit 1 will be used. A footnote may be added to those tables/listings presenting 
baseline value, with an explanation how this value was assessed.  
 
If available in the database, data for screening failures will not be presented in summary tables, 
except for disposition, medical history and end-of-study displays. Data for screening failures will 
be listed as available. 
 
A treatment emergent adverse event (TEAE) is defined as an adverse event that appears during 
or after study treatment and was absent before.  
5.2 
Adjudication of endpoint data 
Each individual video (CI-S) or video pairing (CI-CS) will be read by two independent 
reviewers. For the CI-S assessments of the primary and non-primary anchor test, the independent 
raters will be given 6 videos of the patient’s performance taken at Visit 1 to Visit 6. For the CI-
CS assessments of the primary and non-primary anchor test, the raters will be given three pairs 
of videos and asked to score the CI-CS for each video pair. The video pairs will be labeled Video 
A to Video B, Video B to Video C, and Video C to Video A1. The videos will be presented in a 
random order, and the independent raters will be blinded to the timepoint corresponding to each 
video. The appropriate Likert scale score will be provided to each of the videos and pairs of 
videos. 
 
 (2019). Video Review Charter. IntraBio Ltd. Internal Document. 


 
 
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For the CI-CS assessment, pairs of videos will be evaluated with the Likert scale defined as: 
• Significantly Improved (Score = +3) 
• Much Improved (Score = +2) 
• Minimally Improved (Score = +1) 
• No Observable Change (Score = 0) 
• Minimally Worse (Score = -1) 
• Much Worse (Score = -2) 
• Significantly Worse (Score = -3) 
 
If there is a scoring difference between the two blinded raters for a CI-CS assessment, the 
following rules will apply: 
• If the difference between the blinded raters is 1, the two scores will be averaged, and the 
unrounded average value will be used for further analysis.  
• If there is a scoring difference of >1 between the two blinded raters for a CI-CS 
assessment, then a third blinded rater will review the scores and will determine which 
score is more accurate (adjudication by consensus). The adjudicator's decision will be the 
final score for that video assessment and used for further analysis. 
For the CI-S assessment, individual videos will be evaluated with the Likert scale defined as: 
• Normal, not at all ill (Score = +3) 
• Borderline ill (Score = +2) 
• Mildly ill (Score = +1) 
• Moderately ill (Score = 0) 
• Markedly ill (Score = -1) 
• Severely ill (Score = -2) 
• Among the most extremely ill patients (Score = -3) 
 
If there is any scoring difference between the two blinded raters for a CI-S assessment, the two  
scores will be averaged, and the unrounded average value will be used for further  
analysis.  
 
Note that in averaging situations for the CI-CS and CI-S assessments, the scores may not fit  
the Likert scales as mentioned above. In case of average scoring present in the database,  
presentations will be on score only, without the additional description. 
5.3 
Missing data 
Patients that withdraw from the study are replaced at the discretion of the sponsor. Data from 
withdrawal patients will be included in the analysis until their last assessment. 
 
For handling missing data of the statistical analyses applied to the primary and key secondary 
endpoints, refer to the respective analysis sections.  
 
For other endpoints being presented with descriptive statistics only, such as baseline/screening 
data, safety presentations, additional secondary endpoints and (additional) exploratory endpoints, 
no imputation will be performed, unless otherwise specified (in the respective analysis section or 
in Section 10.1). All these analyses will be performed on data available at the visit considered. In 
summary tables, the number of patients without missing data will be presented (per visit, if 


 
 
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applicable) unless otherwise specified. In calculations of percentages, subjects with missing data 
will not be considered in numerator or denominator unless otherwise specified.  
 
Using the most conservative approach, missing/incomplete information related to AEs will be 
handled as listed below, to indicate an AE as being treatment emergent or presented having a 
certain intensity/causality. Note that the imputed dates or intensity/causality will not appear in 
data listings, but only in descriptive statistics tables (where applicable). 
 
• In case of (partially) missing onset dates, the AE will be handled as follows: 
o If full start date is available, and on or after first dosing date, the AE is considered 
treatment emergent. 
o In case full stop date is available and prior to first dosing date, the AE is 
considered prior. 
o If the day part of the start date is missing: 
 The AE is considered treatment emergent if the month and year of the start 
date are the same or after the month and the year of the first dosing date. 
o If the day and month part of the start date are missing: 
 The AE is considered treatment emergent if the year of the start date is the 
same or after the year of the first dosing date. 
o In case the start date is completely missing:  
 If stop date is fully available and on or after the first dosing date, the AE is 
considered treatment emergent. 
 If the stop date is partially missing, but the month and year (or year alone 
in case of missing month) are after the month and year (or year alone) of 
the first dosing date, the AE is considered treatment emergent. 
o In case full start date and full stop date are missing, the AE is considered 
treatment emergent. 
 
• In case intensity is missing for a certain TEAE, this will be regarded as severe.  
• In case causality is missing for a certain TEAE, this will be regarded as related.  
• In case seriousness is missing for a certain AE, this is discussed and addressed prior to 
database lock and unblinding in agreement with the sponsor and data management 
provider.  
 
Regarding prior/concomitant medication, a similar approach will be followed for partially 
missing dates, as will be done for AEs as described above. If a comedication is started and 
stopped prior to the first date of study treatment (i.e. first dosing date), this is considered prior. 
 
Based on the BDRM, certain values can be decided to be excluded from analyses. These values 
will be listed, but not included in descriptive statistics, plots or statistical analyses. This may be 
outlier data that are a result of unambiguous measurement errors.  
5.4 
Interim analysis 
Per-patient data listings and summary tables/plots will be provided for the several DSMB 
meetings and as specified in the DSMB Charter. 
 
There will be an analysis of the primary, secondary, and exploratory endpoints relating to the 
Parent phase once Visit 6 has been completed, and an interim CSR will be written.  


 
 
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5.5 
Baseline characteristics 
5.5.1 Inclusion/exclusion criteria 
An individual patient listing of the deviations from inclusion and exclusion criteria will be 
presented. 
 
5.5.2 Demographics 
Demographic data at baseline will be summarized for all patients and by the 4 age/weight/dosing 
groups in tabulations.  
 
Appropriate descriptive statistics for age, height, weight, BMI, ethnic group and sex will be 
given. The summary will be created for each analysis population separately. Additionally, 
demographic data will be listed.  
 
5.5.3 Baseline characteristics 
The following relevant patient baseline characteristics will be listed and summarized overall 
(frequency and percentage) and are considered key subgroups. The subgroups differentiated on a 
median value will use the median value as determined for the specific analysis population. 
• Naïve versus non-naïve as determined at screening 
• Age (paediatric versus adult) 
• Gender (male versus female) 
• Age/weight/dosing group  
• Region (US versus EU) 
• Selected Primary Anchor Test (9HPT-D or 8MWT)  
• Tay-Sachs versus Sandhoff Patients 
• SARA Subtest Gait: classification based on below (≤)/above the median value at Visit 1. 
• Composite of SARA Subtests 1- 4 (Gait, Stance, Sitting, Speech): classification based on 
below (≤)/above the median value at Visit 1. 
• Intra-Patient variability between SARA score at Visit 1 (Baseline 1) vs Visit 2 (Baseline 
2): classification based on below (≤)/above the median value of the difference between 
the two visits. 
• Intra-Patient variability between CI-S score (for primary anchor only) Visit 1 (Baseline 
1) vs Visit 2 (Baseline 2): classification based on below (≤)/above the median value of 
the difference between the two visits. 
• Age of diagnosis:  Infantile (<2 years), Juvenile (2 to <15 years), Adolescent/Late Onset 
(≥ 15 years) 
• Disease severity: classification based on below (≤)/ above the median SARA score at 
Visit 1. 
 
5.5.4 Disposition 
A summary table will be created, stating the number of patients per site, including site number, 
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To present disposition, a summary of all included, randomised, treated and completed patients 
will be created. Number/percentage screened will be included as well (if available in the 
database). Additionally, in the same summary, the number/percentage of patients in the SAF, 
mITT and PPS will be presented. Furthermore, the frequency and percentage per reason for non-
completion will be added. 
 
Additionally, a listing displaying all disposition information (including reasons for withdrawal 
and reasons for exclusion from the analysis population, if available electronically) on a per 
patient level will be created. This listing will include follow-up time for each patient, calculated 
from date of first dose until end of study for the Parent phase. 
 
5.5.5 Medical history 
Medical history will be tabulated per System Organ Class (SOC) and Preferred term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology list and 
presented as number/percentage of patients in each SOC and PT for the SAF. SOC and PT will 
be presented in descending order of frequency of occurrence based on SOC and PT. These data 
will also be listed on a per patient level. 
 
GM2 Gangliosidosis specific history will be summarized as appropriate, presenting confirmed 
diagnosis (yes/no) and time since diagnosis. For calculation of time since diagnosis, see Section 
10.1.  
 
GM2 Gangliosidosis specific history data as collected will also be listed on a per patient level. 
5.5.6 Pregnancy data 
Pregnancy test result data will be listed for females of childbearing potential only, on a per visit 
basis. 
5.5.7 Other screening data 
Other data collected at screening and/or baseline only, if available, will be listed. These 
screening/baseline data will be presented using all subjects included in the study, if applicable.  
5.6 
Statistical analysis efficacy endpoints 
The primary analysis population is the mITT for the primary and all secondary endpoints. 
Analyses of these endpoints based on the PPS will also be undertaken to provide supplementary 
information on efficacy. The ITT population will be used only for baseline summary tables. 
 
Analyses of the primary endpoint based on the mITT population will utilise a last observation 
carried forward (LOCF) approach for missing/unreadable 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 are unavailable. 
 
Also for the key secondary endpoint, Change in Severity Score based on Averaged Clinical 
Impression of Severity (CI-S), it is assumed that if both videos are missing/unreadable for the 
baseline (Videos from Visit 1 or 2), treatment (Videos from Visit 3 or 4), or washout (Videos 
from Visit 5 or 6) period, the change from one period to another will be assigned the value 0 
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A sensitivity analysis for missing data will be performed for the statistical analyses to compare 
patient’s outcome on the primary outcome measure and their compliance throughout the study. 
The robustness of the primary analyses in the mITT analysis set will be assessed as follows:  
• If either video for Visit 3 or Visit 4 is available but both videos for Visit 5 and Visit 6 are 
not available, then the value -1 (worsening) will be used instead of 0 for the CI-CS for 
Visit 4 to Visit 6 unless the missingness is due to a technical reason (MCAR, e.g. due to 
machine failure).  
 
For each of the primary and secondary endpoints there will be separate descriptive statistical 
displays within the key subgroups as listed in Section 5.5.3 without any statistical analysis. For 
the subgroup presentations, only the mITT population will be used. Spaghetti plots will not be 
created for the subgroup analyses; these will be presented in forest plots (one for each endpoint, 
excluding the SARA -, SAFI - and mDRS subscores and excluding the EQ-5D-5L/Y), presenting 
the mean or (pseudo-)median with a 90% two-sided CI, using a stem at mean or median 
difference of 0, where applicable. Upon discretion of the programmer, the forest plots may be 
presented as two plots: one for Visit 4 versus Visit 2 and one for Visit 6 versus Visit 4.  
Considering the number of subgroups, the forest plots may become unclear and indecipherable. 
When that occurs, a split will be made into two forest plots for the endpoints: one for the first 7 
subgroups, and one for the remaining. 
All individual primary and secondary endpoint data will be listed as well. 
 
5.6.1 Primary endpoint 
The primary efficacy endpoint is based on the blinded raters’ Clinical Impression of Change in 
Severity (CI-CS) score over 6 weeks determined by comparing videos showing the patient’s 
performance 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).  
 
For each patient, there will be two CI-CS scores. These two scores indicate the level of change in 
severity observed in Visit 4 (end of treatment) compared to Visit 2 (baseline) and the level of 
change in severity observed in Visit 6 (end of washout) compared to Visit 4 (end of treatment). 
Both CI-CS scores are measured on a 7-point Likert-point scale (-3 = significantly worse to +3 = 
significantly improved, see Section 5.2 for the precise definition) and the primary endpoint is 
defined as the difference between both CI-CS scores.  
 
The primary endpoint will be summarized using descriptive statistics, including a frequency 
table, and frequency percentages will be presented graphically using a bar chart.  
The primary statistical analysis will be performed using a one-sample t-test comparing the CI-CS 
difference score to zero. Statistical output will present the number of patients included in the 
analysis, both CI-CS scores, the mean of the difference, the corresponding two-sided 90% 
confidence interval, and a one-sided p-value. 
 
The assumption of normality will be visually checked and if the assumption does not hold, a 
Wilcoxon signed-rank test will be performed instead of the t-test using the difference score. 
Statistical output will then present the number of patients included in the analysis, both CI-CS 
scores, the (pseudo-) median of the difference using the Hodges-Lehmann estimator, the 
corresponding two-sided 90% confidence interval, and a one-sided p-value. 
 


 
 
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5.6.2 Key secondary endpoints 
All key secondary endpoints will be presented using the mITT and PPS populations. 
 
Clinical Impression of Change in Severity 
The CI-CS scores on the pre-defined anchor test for Visit 4 versus Visit 2, and the CI-CS score 
on the pre-defined anchor test for Visit 6 versus Visit 4 will be evaluated separately. These key 
secondary endpoints will be summarized using descriptive statistics and frequency tables, and 
percentages will be shown graphically using a bar chart. No sensitivity analysis will be applied. 
 
Change in severity score based on Averaged Clinical Impression of Severity (CI-S) 
CI-S scores are measured on a 7-point Likert-point scale (-3 = among the most extremely ill 
patients to +3 = normal, not at all ill; see Section 5.2 for the precise definition) and the primary 
endpoint is defined as the difference between both CI-CS scores.  
Improvement in the pre-defined anchor test measure will be evaluated based on the change in the 
blinded raters’ CI-S scores between the baseline period (average for Visit 1 and Visit 2) and end 
of treatment period (average for Visit 3 and Visit 4) minus the change in CI-S between end of 
treatment period (average for Visit 3 and Visit 4) and end of washout period (average for Visit 5 
and Visit 6). Note that if a CI-S score is missing at one visit for a period, but available at the 
other visit in the same period, that one value will be used instead of the average. If both videos in 
a period are missing, then we cannot determine the average and the period will be assigned a 
value of 0 (stable). The presentations and statistical analyses will be similar to the primary 
endpoint, excluding the sensitivity analysis which is only to be used for the primary endpoint. 
Data received for non-anchor CI-S scores will only be listed. 
 
Clinical Impression of Change in Severity reclassified on a 3-point scale 
Using the CI-CS outcome on the pre-defined anchor test based on the data for Visits 2 and Visit 
4, any patient given a score <0 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 >0 on the 
CI-CS will be classified as improved (+1). Similarly, the CI-CS comparing Visit 4 and Visit 6 
will be reclassified and the differences between these two scores on a 3-point scale will be 
calculated. 
The descriptive table and graphical presentations will be similar to the primary endpoint. No 
statistical analysis will be performed, and no sensitivity analysis will be applied. 
 
Clinical Impression of Change in Severity (CI-CS) score non-primary anchor test  
Descriptive statistics and frequency tables of the CI-CS scores for the test (9HPT-D or 8MWT) 
that was not selected as the primary anchor test will be presented for Visit 4 versus Visit 2, and 
separately, for Visit 6 versus Visit 4. No plots will be created, and no sensitivity analysis will be 
applied. 
 
5.6.3 Additional secondary endpoints 
All additional secondary endpoints will be presented using the mITT and PPS populations, and 
all individual data will be listed as well. No sensitivity analysis will be applied. 
 
Measurement of Ataxia and Functioning 
• SARA total score 
• SCAFI total score 
o 9HPT-D 


 
 
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o 9HPT-ND 
o 8MWT 
o PATA test 
 
Descriptive statistics will be used to summarize the endpoints above at each visit.  
 
The subscores of the SARA score (gait, stance, sitting, speech disturbance, finger chase, nose-
finger test, fast alternating hand movements, heel-shin slide) will also be summarized for each 
visit using descriptive statistics. Stacked bar charts will be provided per visit, based on the 
subscores of the total SARA score.  
 
Spaghetti plots of individual patient SARA total scores and the SCAFI total scores versus time 
will be made as well as a mean or median display versus time, depending upon the distribution, 
and corresponding two-sided 90% CI at each visit. 
 
The average SCAFI subscores (8MW_avg, 9HPT-D_avg, 9HPT-ND_avg and PATA_avg) as 
determined according to Section 10.1, following the scoring manual, will also be summarized 
with descriptive statistics. 
 
The changes in SARA total score, SCAFI total score, the SCAFI subscores (8MW_avg, 9HPT-
D_avg, and PATA_avg) between Visit 2 and Visit 4, as well as the changes between Visit 4 and 
Visit 6 will be analysed using a one-sample t-test or a Wilcoxon Signed Rank test depending on 
the distribution of the data. The SCAFI subscore 9HPT-ND_avg will only be descriptively 
summarized in tabular format. 
 
Measurement of Health-related Quality of Life 
The results of EQ-5D-5L as well as the EQ-5D-Y will be combined into a 5-digit number 
presenting the health status of the subject. Frequency tables will be presented per visit for the 5 
domains, as well as for the 5-digit number of the EQ-5D-5L and the EQ-5D-Y separately.  
In addition, EQ-5D-5L and EQ-5D-Y domain percentages will be presented in separate bar 
charts per visit, with all visits combined into one plot (if possible). 
 
The EQ-VAS score will be summarized by visit using descriptive statistics for patients aged < 
and ≥18 years combined. Spaghetti plots of individual patient EQ-VAS scores versus time will 
be made as well as a mean or median display versus time, depending upon the distribution, and 
corresponding two-sided 90% CI at each visit. 
 
Measurement of Overall Neurological Status 
The mDRS composite score and individual components (ambulation, language, manipulation, 
swallowing, seizures, and ocular movement) will be summarized using descriptive statistics at 
each visit. As graphical display, a stacked bar chart of the 6 mDRS subscores at each visit will be 
created. Spaghetti plots of individual patient mDRS composite scores versus time will be made 
as well as a mean or median display versus time, depending upon the distribution, and 
corresponding two-sided 90% CI at each visit. 
 
Furthermore, changes in the mDRS composite score between Visit 2 and Visit 4 as well as 
between Visit 4 and Visit 6 will be descriptively presented in a summary table.  
 
Measurement of Global Impression 


 
 
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The three CGI-S scores (scored by treating physician, caregiver, and patient) will be summarized 
using descriptive statistics and frequency tables for each visit. 
Bar charts will be presented for the three CGI-S scores, spaghetti plots of individual CGI-S 
scores versus time will be made as well as a mean or median display versus time, depending 
upon the distribution, and corresponding two-sided 90% CI at each visit. 
 
Descriptive statistics and frequency tables will also be used to summarize the three CGI-C scores 
(treating physician, caregiver and patient) between Visit 2 and Visit 4, and between Visit 4 and 
Visit 6, and corresponding bar charts will be created. 
 
The CGI-C scores for Visit 4 versus Visit 2, and for Visit 6 versus Visit 4 will be evaluated using 
descriptive statistics. Similarly, the CGI-C from Visit 2 to Visit 4 minus the CGI-C from Visit 4 
to Visit 6 will be presented descriptively. In addition, the CGI-C measures for treating physician 
will be analyzed similar to the primary endpoint: the CGI-C from Visit 2 to Visit 4 minus the 
CGI-C from Visit 4 to Visit 6 will be compared to a difference of zero using a one-sample t-test 
or Wilcoxon signed-rank test. 
 
Note that CGI-C is referred to as CGI-I in the eCRF. 
 
It is important to realize that the CGI-S and CGI-C scores per visit for each patient as provided 
by the caregiver may be based on varying caregivers and hence additional variation is 
introduced. No correction for this variation can be done and a footnote will be added to the table 
to describe this situation. 
 
5.6.4 Other additional statistical analyses 
The following analysis will provide an estimate of intra-patient variability and provides 
information on the stability of the outcome evaluation. Note that, considering the high degree of 
variability within and between these patients, this is only a simple approach as results may be 
influenced by e.g. rater variability, disease progression or treatment effect. 
 
The analysis will be done for the mITT population only, and only for the CI-S outcome of the 
videos. No sensitivity analysis will be applied, and no separate analysis will be performed for 
subgroups. 
 
The Intraclass Correlation Coefficient (ICC) will be used as an index of reliability to measure 
agreement between pairs of observations for Visit 1 and 2, Visit 3 and 4, and Visit 5 and 6 
respectively, presenting the proportion of the total variance in the observations that is due to the 
differences between pairs. The ICC takes on values between 0 (meaning no agreement) to 1 
(perfect agreement), with and ICC >0.80 representing high reliability. No imputation for missing 
visits will be done, and the ICC can only be determined for subjects having data for both visits in 
the pairs. The ICC value and the corresponding 95% confidence interval will be presented in a 
tabular format, and for additional clarity the number of available pairs will be added as well. 
5.7 
Safety and tolerability evaluation 
5.7.1 Adverse events 
A treatment emergent adverse event (TEAE) is defined as an adverse event that appears during 
or after study treatment and was absent before. 
 


 
 
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An AE overview table will be created displaying the number and percentage of subjects 
experiencing a treatment-emergent adverse event (TEAE) and the number of TEAEs for: any 
TEAE, any mild/moderate/severe TEAE, any related/unrelated TEAE, any serious AE, and any 
TEAE leading to study discontinuation. 
 
Furthermore, all TEAEs will be tabulated by System Organ Class (SOC) and Preferred Terms 
(PTs) within each SOC according to the MedDRA terminology list, using frequency counts 
(number of subjects with at least one event, and number of events) and percentage of subjects 
with the event.  
 
TEAEs will also be tabulated by severity (mild/moderate/severe) and by relationship to study 
medication (related/unrelated). Similar tables will be created for TEAEs leading to premature 
discontinuation, SAEs and deaths, if applicable. These summary tables will be presented by 
decreasing frequency of occurrence based on SOC and PT. 
 
In addition, similar TEAE tables (overall, by severity and by relationship, premature 
discontinuation, SAEs, and deaths) by SOC and PT will be presented per treatment cycle, and 
frequencies and percentages will be determined for the active treatment cycle and the washout 
cycle. The treatment cycle is the period between start of first treatment at Visit 2 and 24 hours 
after last dose at Visit 4. The washout cycle starts 24 hours after last dose at Visit 4 until and 
including Visit 6. 
  
The summary tables will be accompanied by individual subject listings of all AEs including 
information on AE number, actual AE description, date/time of start and end of AE (or ongoing), 
PT (MedDRA), SOC (MedDRA), severity, relationship, pre-dose (yes/no), seriousness, action 
taken, outcome and other information collected in the CRF for adverse events. Pre-dose AEs are 
not considered to be treatment-emergent, except in case of worsening during/after study 
treatment (to be collected as separate AE in the database). AEs starting prior to administration of 
the study drug will only be listed. In this listing, a clear distinction will be made between prior 
and treatment emergent events. 
 
To address the study delays due to Covid-19 in reference to AE occurrences, AE incidence rates 
will also be determined per study cycle (treatment cycle and washout cycle). Incidence rate of 
adverse events is defined as the number of adverse event cases per patient-year(s). The 
calculation of the incidence rate is the number of cases (i.e. patient with an AE) divided by the 
sum of the follow-up time of all patient at risk (which will be all subjects receiving treatment). 
This calculation is accomplished as follows: 
- 
Denominator: ∑pi × ti, where pi = patient i and ti= treatment duration of 
patient i in years (total # days divided by 365.25), where treatment duration is 
determined based on first and last (dose) date. 
- 
Numerator: the total number of cases (note: a single patient can be counted 
more than once if the AE occurs on separate occasions) 
- 
Incidence rate=numerator/denominator 
 
The use of this measure implies the assumption that the incidence rate is constant over different 
periods of time. Since the calculation is done per cycle, the denominator (patient-years) is also 
determined per cycle, based on the patients available within that cycle. 
 




 
 
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5.7.4 Electrocardiography (ECG) 
ECG outcome results (corrected QT interval and normal/abnormal result) will be presented 
descriptively per protocol visit. If applicable, ECG measurements collected as 
additional/unscheduled assessments (i.e. apart from those per protocol) will only be listed and 
will not be used in summary statistics. The SAF population is used for the presentations. 
5.7.5 Prior and concomitant medication/therapies 
The use of prior and concomitant medication/therapies will be listed for all subjects: included 
will be the preferred term, World Health Organization (WHO) coding information and the 
Anatomic Therapeutic Chemical (ATC) class code), dose, route of administration, start and stop 
date, frequency and reason for administration, as well as information if given for an AE. 
Differentiation will be made between prior and concomitant medication/therapies, by creating 
two separate listings. A frequency table per ATC class code and WHO drug code will be created 
if considered relevant, separately for prior and concomitant medication/therapies. The SAF 
population is used for the presentation. 
5.8 
Scheduled visits, dosing, and treatment compliance 
5.8.1 Visit dates  
A listing with actual visit dates (and times, if applicable) per patient will be presented.  
 
5.8.2 Dosing and treatment compliance 
Relevant dosing information (first dosing date, last dosing date), scheduled and actual dosing 
dates/times and treatment compliance information will be determined and listed for each patient. 
Summary statistics for the number of N-Acetyl-L-Leucine doses taken, based on bottles of 
dispensed and returned unused bottle counts, will be calculated for Visit 3 and Visit 4 if this 
information is collected on a per-visit basis. Compliance is defined as 100% * (total number of 
IB1001 bottles and/or sachets dispensed – total number of IB1001 unused bottles and/or sachets 
returned), divided by the number of bottles and/or sachets which should have been used. Note that 
the number of bottles the patients should have used depends on the dosage they should take (see 
Section 2.3 for reference) and the duration of the treatment period. Considering the fact that the 
patient’s total daily dose may be reduced by up to half of their assigned dose at the discretion of 
the investigator, the actual dose will be used to determine the correct compliance calculation, if 
collected in the eCRF. The proportion of patients who take at least 80% of the prescribed 
medication will also be shown. Total dosing period is defined as the duration (in days) between 
first dose date and last dose date.  
 
6 
EXTENSION PHASE: STATISTICAL ANALYSIS  
6.1 
General considerations 
The Extension phase is considered the study period starting with the Extension phase baseline 
(Visit 7) until Visit 12. In principle, data presentations will be created for the full Extension 
phase. Only where applicable and relevant, a separation will be made as follows:  
• Extension phase I:  Extension phase Visit 7 until Visit 10.  
• Extension phase II: Extension phase Visit 10 until Visit 12. 
 


 
 
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All evaluations will be exploratory in nature, and all endpoints for the complete Extension phase 
are considered secondary to the endpoints of the Parent study. Statistical analysis will only be 
applied for some of the endpoints as defined for Extension phase I, no statistical analyses will be 
done for the endpoints in Extension phase II. 
Summary presentations and listings will be presented and only reported data will be presented 
(i.e. no imputation or LOCF will be done) for data collected during Extension phase II. If not 
otherwise defined, data will we presented as missing where applicable. 
Raw data (in listings) will be presented in the same precision as received. Appropriate rounding 
will be performed for the following summary statistics, where applicable: mean, standard 
deviation (SD) and two-sided 90% confidence limits will be presented with at least one more 
decimal than the original data; minimum and maximum values will be presented with the same 
precision as the original data. In frequency tables, percentages will be presented with 1 decimal 
unless otherwise stated.  
 
P-values will be presented with 3 decimals, and those smaller than 0.001 will be replaced by 
<0.001. One-sided p-values smaller than 0.05 will be considered statistically significant for the 
primary endpoint and indicative for other endpoints. No adjustment for multiple comparisons 
will be applied. Conclusions regarding treatment efficacy will not solely rely on detecting 
statistical significance but equal emphasis will be placed on the magnitude and clinical relevance 
of treatment differences as judged by the point estimates.  
 
Descriptive statistics presented in general summary tables will be the number of non-missing 
observations (n), mean, SD, minimum, median and maximum for quantitative data. For 
categorical data, frequency counts and percentages will be determined. 
 
For the full Extension phase, the measurement at Visit 7 is considered the baseline. In case of 
missing Visit 7A data for safety measurements (e.g. for safety lab), and Visit 7B has occurred 
within 1 (+6) days of Visit 6, the Visit 6 data from the Parent study should be used instead (data 
are not being re-entered in the database): see also Section 2.2.2 for clarification.  
 
No screen failures will be present in the data. 
 
For the full Extension phase, a treatment emergent adverse event (TEAE) is defined as an 
adverse event that appears during or after the start of study treatment in the Extension phase at 
Visit 7B and was absent before. As a consequence, adverse events occurring during the washout 
phase between V9 and V10 will also be considered treatment emergent. 
6.2 
Adjudication of endpoint data 
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 but will not be reported in the CSR (and hence not listed or tabulated). Data 
received will be included as-is in the CDISC files. In case of analysis, the following process 
applies: For the CI-CS assessments of both the primary and non-primary anchor tests, after a 
patient completes Visit 10 of the Extension phase, the independent raters will be given 3 video 
pairs of from Visit 7 to Visit 9, Visit 9 to Visit 10, and Visit 7 to Visit 10. After a patient 
completes Visit 12 of the Extension phase, the independent raters will be given a video pair from 
Visit 10 to Visit 12 (the raters may also assess additional video pairs, i.e. Visit 1 to Visit 12, on 
an exploratory basis). After a patient completes Visit 12 of the Extension phase, the independent 


 
 
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raters will be given a video pair from Visit 10 to Visit 12 (the raters may also assess additional 
video pairs, i.e. Visit 1 to Visit 12, on an exploratory basis). The videos will be presented in a 
random order, and the independent raters will be blinded to the timepoint corresponding to each 
video. The appropriate Likert scale score will be provided to each of the videos and pairs of 
videos. For further details regarding scoring and adjudication, which will be similar to that of the 
Parent study, see Section 5.2. 
6.3 
Missing data 
Data from withdrawal patients will be included in the analysis until their last assessment. 
 
For handling missing data in Extension phase, similar approaches as described in Section 5.3 
will be followed, with the alteration that “first dose date” is the first dosing during Extension 
phase I or II, respectively. For AE and concomitant medication this indicates that events started 
during the Parent study and continuing during Extension phase will be considered prior for the 
Extension phase.  
6.4 
Interim analysis 
Per patient data listings and summary tables/plots will be provided for several DSMB meetings 
as specified in the DSMB Charter created for the Parent study. 
 
The final CSR will be written upon the completion of the full Extension phase, and no interim 
analysis is performed during the Extension phase. 
6.5 
Baseline characteristics 
6.5.1 Inclusion/exclusion criteria 
An individual patient listing of the deviations from inclusion criteria will be presented. No 
exclusion criteria are collected for the Extension phase, and no separate inclusion is done for 
Extension phase II. 
 
6.5.2 Demographics 
Demographic data at baseline will be summarized for all patients and by the 4 age/weight/dosing  
groups (using Visit 7 information) in tabulations, even if there is a change in dose between Visit 
7 and 8, or between Visit 8 and 10, or Visit 10 and 11 (see Section 2.3.2).  
Appropriate descriptive statistics for age, height, weight, BMI, ethnic group and sex will be 
given. The summary will be created for each analysis population separately. Additionally, 
demographic data will be listed.  
 
6.5.3 Baseline characteristics 
The following relevant patient baseline characteristics will be listed and summarized overall 
(frequency and percentage) and are considered key subgroups, and will only be used for 
presentations of the primary endpoint in Extension phase I analyses: 
• Naïve versus non-naïve, as determined at screening during the Parent study phase 
• Age (paediatric versus adult) at Visit 7 
• Gender (male versus female) 


 
 
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• Age/weight/dosing group as applicable at Visit 7 
• Selected Primary Anchor Test (9HPT-D or 8MWT) as defined during the Parent study 
phase 
• Tay-Sachs versus Sandhoff Patients  
• Composite of SARA Subtests 1- 4 (Gait, Stance, Sitting, Speech): classification based on 
below(≤)/above the median value at Visit 7 
• Age of diagnosis: Infantile (<2 years), Juvenile (2 to <15 years), Adolescent/Late Onset 
(≥ 15 years) 
• Disease severity: classification based on below (≤)/ above the median SARA total score 
at Visit 1. 
 
6.5.4 Disposition 
A summary table will be created, stating the number of patients per site, including site number, 
location/country, and investigator. 
 
To present disposition, a summary of all included, treated, and completed patients will be created 
for the Extension phase I and II separately, and for the full Extension phase . Additionally, in the 
same summary, the number/percentage of patients in the SAFe and mITTe will be presented. 
Furthermore, the frequency and percentage per reason for non-completion will be added.  
 
A listing displaying all disposition information (including reasons for withdrawal and reasons for 
exclusion from the analysis population, if available electronically) on a per patient level will be 
created. This listing will include follow-up time for each patient, calculated from date of first 
dose during the Extension phase until end of Extension phase or withdrawal date. 
 
6.5.5 Medical history 
Note that only for patients not having a seamless transition from the Parent study to the 
Extension phase, additional medical history data may be collected during the intermediate time. 
Medical history will be tabulated per System Organ Class (SOC) and Preferred term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology list and 
presented as number/percentage of patients in each SOC and PT for the SAFe. SOC and PT will 
be presented in descending order of frequency of occurrence based on SOC and PT. These data 
will also be listed on a per patient level.  
6.5.6 Pregnancy data 
Pregnancy test result data will be listed for females of childbearing potential only, on a per visit 
basis. 
6.5.7 Other screening data 
Other data collected at screening and/or baseline only, if available, will be listed. These 
screening/baseline data will be presented using all subjects included in the Extension phase, if 
applicable.  
6.6 
Statistical analysis efficacy endpoints 
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Analyses of the primary endpoint based on the mITTe population will utilise a last observation 
carried forward (LOCF) approach for missing mDRS at Visit 9. For the primary mDRS endpoint 
this implies that the measurement of Visit 8 will be used instead. Other endpoints will not be 
imputed, and missing data will be reported as is. No sensitivity analyses will be applied.  
 
For the primary endpoint for the Extension phase there will be separate descriptive statistical 
displays within the key subgroups as listed in Section 6.5.3, without any statistical analysis. For 
the subgroup presentations, only the mITTe population will be used. No plots will be created. All 
individual primary endpoint data will be listed as well. 
 
All efficacy endpoints for Extension phase Visit 10 to Visit 12 are considered exploratory, and 
therefore described under section 6.6.4. 
 
6.6.1 Primary endpoint Extension phase 
The primary efficacy endpoint is based on the Modified Disability Rating Scale (mDRS). The 
mDRS measures neurological status via clinical signs and symptoms in 6 domains (ambulation, 
language, manipulation, swallowing, seizures, and ocular movement). A higher mDRS score 
indicates a clinical worsening, while a lower mDRS score indicates a clinical improvement. A 0-
point change in the mDRS score represents a stabilization of disease progression, which is also 
considered a significant clinical improvement. 
 
The mDRS composite score and individual domains, including change values, will be 
summarized using descriptive statistics at each visit for Extension phase. 
 
The primary endpoint in this Extension Phase is success measured on the mDRS score from the 
Extension Phase baseline (Visit 7) to the end of treatment in the Extension Phase (Visit 9).  
Success is defined as no change or a decrease in mDRS score from Visit 7 to Visit 9.  
The primary endpoint will be summarized using a frequency table. The primary statistical 
analysis of comparing the proportion success with the null proportion of 0.10 will be done using 
a one-sided Fisher’s Exact Test, expecting an increase in the success rate. The statistical result 
(one-sided p-value and exact 90% confidence interval2) will be added to the frequency table. 
This analysis is considered to be exploratory.  
 
In addition, a spaghetti plot presenting the total mDRS scores of each patient through time will 
be created. 
 
6.6.2 Key secondary endpoints Extension phase  
As PK is handled by an external company, there are no analyses for secondary endpoints to add 
here. 
 
6.6.3 Exploratory Endpoints 
All exploratory endpoints for the Extension phase will be presented using the mITTe population, 
and all individual data will be listed as well. For all exploratory endpoints, the change from Visit 
 
2 The exact CI and the p-value using the Fisher’s Exact test can contradict each other, especially in small sample sizes. Therefore, the exact CI 
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7 to Visit 9 will be evaluated. No statistical analysis other than descriptive statistics will be done. 
No plots will be created. 
Measurement of Ataxia and Functioning 
• SARA total score 
• SCAFI total score 
o 9HPT-D 
o 9HPT-ND 
o 8MWT 
o PATA test 
 
Descriptive statistics will be used to summarize the endpoints above at each visit.  
 
The subscores of the SARA score (gait, stance, sitting, speech disturbance, finger chase, nose-
finger test, fast alternating hand movements, heel-shin slide) will not be summarized separately, 
and only listed. 
 
The average SCAFI subscores (8MW_avg, 9HPT-D_avg, 9HPT-ND_avg and PATA_avg) as 
determined according to Section 10.1, following the scoring manual, will also be summarized 
with descriptive statistics. 
 
The changes in SARA total score, SCAFI total score, and the SCAFI subscores (8MW_avg, 
9HPT-D_avg, 9HPT-ND_avg and PATA_avg) between Visit 7 and Visit 9, and Visit 10 and 
Visit 12, will be descriptively summarized in tabular format as well. 
 
Measurement of Health-related Quality of Life 
The results of EQ-5D-5L as well as the EQ-5D-Y will be combined into a 5-digit number 
presenting the health status of the subject. Frequency tables will be presented per visit for the 5 
domains, as well as for the 5-digit number of the EQ-5D-5L and the EQ-5D-Y separately.  
 
Note that if a patient turns 18 before Visit 7, this patient can have results on EQ-5D-Y in the 
Parent Study, and results on EQ-5D-5L in the Extension phase Visit 7 to 10. For this reason, 
separate QoL presentations will be created for Extension phase I, using Visit 7 measurements as 
baselines. The EQ-VAS score will be summarized by visit using descriptive statistics in a 
combined manner for patients aged < and ≥18 years (using Visit 7 age values).  
 
Measurement of Global Impression 
The three CGI-S scores (scored by treating physician, caregiver, and patient) will be summarized 
using descriptive statistics and frequency tables for each visit.  
 
Descriptive statistics and frequency tables will also be used to summarize the three CGI-C scores 
(treating physician, caregiver, and patient) between Visit 7 and Visit 9. 
 
Note that CGI-C is mentioned as CGI-I in the eCRF. 
 
It is important to realize that the CGI-S and CGI-C scores per visit for each patient as provided 
by the caregiver may be based on varying caregivers and hence additional variation is 
introduced. No correction for this variation can be done and a footnote will be added to the table 
to describe this situation. 
 


 
 
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6.6.4 Additional exploratory endpoints  
For all exploratory endpoints as described in 4.2.4, descriptive presentations will be made and 
the change from Visit 7 to Visit 10, Visit 9 to Visit 10, Visit 10 to Visit 12, and Visit 1 to Visit 
12 will be evaluated descriptively. No plots will be created, and no statistical analysis done.  
These presentations include the endpoints as mentioned above in sections 6.6.1, 6.6.2, and 6.6.3 
that will be presented as exploratory using only descriptive statistics for the Extension phase on 
data collected after Visit 10. For EQ-5D-5L as well as the EQ-5D-Y, a different questionnaire 
could be used between Visits 10 and 12 if a patient turns 18 before Visit 10, and for this reason 
separate QoL presentations will be created for Extension phase II, using Visit 10 measurements 
as baselines. The EQ-VAS score will be summarized by visit using descriptive statistics in a 
combined manner for patients aged < and ≥18 years (using Visit 10 age values).  
For presentations on efficacy data collected after Visit 10, no imputations or LOCF is considered 
necessary.  
6.6.5 Other additional statistical analyses 
No other additional statistical analyses are foreseen. 
6.7 
Safety and tolerability evaluation 
The safety and tolerability evaluation for the extension study is similar to what is described for 
the Parent study (see Section 5.7), with the remark that the evaluation is limited to the Extension 
phase only and Visit 7 is considered the baseline. For the AE presentation per treatment cycle, 
the cycles for Extension phase are as follows:  
- 
Treatment cycle Extension phase I: the period between start of first treatment 
at Visit 7 and 24 hours after last dose at Visit 9.  
- 
Washout cycle Extension phase I: starts 24 hours after last dose at Visit 9 until 
and includes Visit 10.  
- 
Treatment cycle Extension phase II: the period between start of first treatment 
at Visit 10 and 24 hours after last dose at Visit 12.  
- 
No washout cycle is defined for Extension phase II. 
Note that for those patients that do not transition seamlessly to the Extension phase, additional 
prior medication/adverse events may be collected at the start of the Extension phase, and these 
will be presented separately from the prior medication/adverse events of the Parent phase. 
Physical examination, which is collected twice during the Extension phase, will be presented as 
follows: general physical examination data will be tabulated and listed per visit. The summary 
table will include number/percentage of patients with normal or abnormal observations and 
NCS/CS frequencies/percentages for abnormal observations per visit. 
6.8 
Scheduled visits, dosing, and treatment compliance 
The presentation for the Extension phase is similar to what is described for the Parent study 
phase (see Section 5.8), with the remark that the evaluation is limited to the Extension phase 
only and Visit 7 is considered the baseline. 
7 
CHANGES TO PROTOCOL AND OTHER RELEVANT REMARKS  
Instead of Bland-Altman analyses of outcome scores at Visit 1 vs Visit 2, Visit 3 vs Visit 4, and 
Visit 5 vs Visit 6 as described in the protocol for the Parent study, an ICC method for agreement 


 
 
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between the visits will be used instead to assess the stability of the outcome, as described in 
section 5.6.4. This is because no per-rater information is available in the dataset to be received, 
only an averaged or agreed value. 
 
Regarding CI-S, the protocol is stating that for each assessment, the videos will be labeled as 
Video A, B, C, D, E, F. This is however not present in the DTA and test data from 
 and 
is therefore removed from the SAP. 
 
For Quality-of-Life measures, since the scoring is done for children with the EQ-5D-Y and for 
adults with the EQ-5D-5L, tabulations and analyses will be done separately for the 
corresponding age groups. The presentations on the VAS will be combined for children and 
adults. 
 
For the Parent phase, sparse PK sampling will be collected for biochemical analysis to 
characterize the pharmacokinetics of N-Acetyl-L-Leucine in patients with GM2 Gangliosidosis. 
For the Extension phase, full PK profiles will be collected at Visit 7 and Visit 9. Creation of 
descriptive displays and reporting of these data is outside the scope of this statistical analysis 
plan. PK concentration data and PK parameters (following a population PK analysis) will be 
included in SDTM domains, after receipt. For the Parent phase a listing of PK concentration data 
will be created for inclusion in the Parent phase CSR, since the full PK report will only be 
available after the end of the Extension phase. Furthermore, urine tests for N-Acetyl-D-Leucine 
are handled by the same lab but will be included in the clinical database and will therefore be 
part of the CDISC datasets. 
 
Regarding the sensitivity analysis (imputation of value -1) for missing data in the primary and 
secondary analyses: this is only applied to the primary analysis of the Parent phase.  
Regarding the LOCF/assumption of value 0 for missing data: this is only applied to the primary 
and one key secondary endpoint as specified in the relevant sections in this SAP. 
 
The investigation of the intra-rater correlation cannot be performed, since the 
 data do 
not differentiate the data per rater but rather provide an average or agreed value. Therefore, this 
analysis has been removed from the SAP. 
 
Considering the primary endpoint of the Extension phase is a different one then the primary 
endpoint of the Parent Study, the trial is called successful only when the primary endpoint of the 
Parent Study is positive. All analyses of the Extension phase on data collected until Visit 10 are 
considered secondary to ones of the Parent Study. All presentations in the Extension phase on 
data collected after Visit 10 are exploratory and descriptive. 
 
The analysis on ASIS as described in the protocol has been removed from the SAP, as there are 
too limited datapoints available to perform the analysis. 
 
For some patients, repeat visits were scheduled if measurements could not be fully handled 
during the agreed visit. Repeat visits will be listed for BDRM, and during BDRM or Clean File 
meeting it will be decided how the repeat data will be handled for analysis. Decisions will be 
documented prior to Database lock. 
 
The addition of a short section of Covid-19 details (with reference to an addendum) has been 
added to the SAP and is not mentioned in the protocol.  


 
 
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8 
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 Visit 2 is performed 8 weeks (56 days) or more after Visit 1, some Visit 1 assessments 
must be repeated.  
- 
Visits 3 and 5 can be converted to remote visits (i.e. phone, video conference). 
- 
Visits 4 and 6 can be postponed until the in-person visit is feasible and should be 
performed in person. Where applicable, remote data collection should be collected on the 
date of the original visit. The postponed Visits 4 and 6 will collect all data per protocol. 
- 
For the Extension Phase, no remote visits are allowed. 
 
Currently, the impact of COVID-19 on the proposed statistical analyses is unknown. The 
statistical analysis already allows some flexibility for handling missing data, however, specific 
items/changes related to COVID-19 are being detailed in a separate document (Addendum 1), 
which will be maintained as a living document throughout the study continuation and adjusted 
based on the duration and extent of the impact of the COVID-19 situation.  
9 
DATA RECEIPT 
All clinical eCRF data received from the Data Management provider per transfer agreement will 
be mapped to SDTM files. The information regarding minor/major violations will be received as 
excel file (a so-called “protocol deviations log”) and will be transferred to SDTM as well. The 
blinded results on the video-recordings (blinded rater’s CI-CS and CI-S) will be received from 
 as provider following the transfer agreement and will be mapped to SDTM. The 
received data will include relevant categorizations on missing data. 
 
The SDTM files will be recoded to ADaM format, where necessary. Listings will be 
programmed on the SDTM and ADaM datasets, statistical analyses, tables, and figures will be 
programmed on ADaM datasets.  
 
For all received data, a split will be made between data for the Parent study and the data for the 
Extension phase, to allow submission of the CDISC data and documentation for the Parent study.  
10 TECHNICAL DETAILS 
10.1 Programming conventions 
Programming conventions apply to both the Parent study as well as the Extension phase, unless 
otherwise specified. 
 
Demographics 
BMI will be calculated in SAS as follows: weight/height2, with weight in kg and height in meter 
(unit kg/m2). Durations will be programmed as stated in the respective analysis sections. Where 
applicable, weight and height measurements will be converted to units cm and kg, using the 
following conversion factors: from inch to cm: multiply by 2.54, from lb to kg: multiply by 
0.45359237. Variables with values representing a missing observation (such as -99, 99, 888 or 
999) will be recoded to missing in SAS. 


 
 
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GM2 Diagnosis 
Time since diagnosis will be calculated as the difference in days between first dose date and the 
date of diagnosis +1. Date of diagnosis will be taken as the earliest date from the following two 
records: the (earliest) date of Medical History with MHDECOD= “Tay-Sachs disease” or 
“Sandhoff disease” and the date of genetic confirmation of disease as recorded in the Primary 
Genetic Diagnosis of GM2 Gangliosidosis data. 
If considered more feasible, the duration may be presented in weeks (calculated time divided by 
7), months (calculated time divided by 365.25/12) or years (calculated time divided by 365.25) 
instead of days. For historical data however, it is likely that partial dates are available. If date of 
diagnosis is (partially) missing, the following will be applied: 
• If only day is missing, the first day of the month will be used. 
• If day and month are both missing, 1 January of the same year will be used. 
If full date is missing, no imputation will be done. 
 
Age calculation 
Age at diagnosis will be based on the date of diagnosis (see above for determination) and the 
birth date as collected in the database. For a partial missing date of diagnosis, the rules as stated 
above will be applied. For partially missing birthdate: depending upon the level of precision of 
the collected birth date: if only month and year is available, then imputation of day 15 is used for 
calculation of age. If only birth year is available, 15 June of that year will be used as birthdate. 
 
Age is not collected during the Extension phase, and therefore whenever age is necessary for any 
calculations or presentations at Extension phase visits, it should be calculated using the 
respective visit date combined with the date of birth as collected at Visit 1. The same imputation 
rule as stated above (for calculation of age at diagnosis) will be applied. 
 
Blinded data 
The blinded results on the video-recordings (blinded rater’s CI-CS and CI-S) will be received 
from 
 according to the agreed transfer specifications. Recoding needs to be done using 
the visit schedule provided with the blinded results, since the visit review order is randomly 
assigned. The LOCF for video comparison is already available in the 
 data. 
 
SCAFI 
For 8MWT, assistance of another person or using the wall as support is not allowed. However, 
timed 8MWT trials for participants who used “unallowable support” (another person or the wall)  
are entered in the database, considering these measurements are also necessary due to their 
relation to the primary and a number of secondary endpoints of the study based on videos of the 
test. Therefore, for the SCAFI analysis, the data for these patients that used either the wall or 
person support during the 8MWT should be made missing. 
 
Furthermore, patients for 9HPT, the following clinical rules apply: 
• if proband cannot complete trial in 5 minutes (i.e. 300 seconds) with dominant hand, 
move on to the trials with non-dominant hand 
• if proband cannot complete one trial in 5 minutes (i.e. 300 seconds) with non-dominant 
hand, discontinue 9HPT 
As a consequence, if in the database values >300 are entered for Trial 1 and/or 2, the approach 
for handling these data in regards to SCAFI will be: 


 
 
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• In the case Trial 1 has a value <300 and Trial 2 has a value of >300 seconds, only the trial 
1 with value <300 will be used for further analysis. 
• In the case Trial 1 has a value of >300 seconds and Trial 2 has a value of <300 seconds, 
the data will count as missing and unable to perform due to physical limitations (as per 
the discontinuation rules defined above, Trial 2 should not have been conducted) 
• In other instances, where only one trial is performed with a value >300 seconds, or two 
trials are performed with both values >300 seconds, the data will be considered missing 
due to physical limitations and replaced with a missing value for further analysis. 
 
After the adjustments made for 8MWT and 9HPT as above, SCAFI total score will be calculated 
as follows: 
The mean of the trial1 and trial2 scores are determined for each subtest/hand, and referred to as: 
8MW_avg, 9HPT-D_avg, 9HPT-ND_avg and PATA_avg. In case a subtest is only performed 
once, this value is taken as the mean. Then, the 8MW and 9HPT performance times are 
converted to the same dimension as the PATA rate, as follows: 8MW_recipr = 1/8MW_avg, 
9HPT_recipr = (1/9HPT-D_avg + 1/9HPT-ND_avg)/2. Note that 8MW and 9HPT performance 
times cannot be 0. 
Then each is converted into a Z-score using the following algorithms: 
• 8MW_zscore = (8MW_recipr - BL(mean 8MW_recipr)) / BL(SD 8MW_recipr) 
• 9HPT_zscore = (9HPT_recipr - BL(mean 9HPT_recipr)) / BL(SD 9HPT_recipr) 
• PATA_zscore = ( PATA_avg - BL(mean PATA_avg)) / BL(SD PATA_avg) 
where BL means baseline value and SD means standard deviation. The mean 8MW_recipr and 
SD 8MW_recipr are determined using the SAF analysis population. 
 
In case of missing values, the following applies:  
• The cases with either 8MW, 9HPT (in one or both hands) or PATA tests not performed at 
all (“unable to perform due to physical limitations” or “not performed for other reason”) 
are excluded from the calculation of baseline means. 
• Only when an 8MW score, 9HPT score or PATA score is missing due to “unable to 
perform due to physical limitations”, then a substitution will be applied as follows: 
o When 8MW tests were not performed, then 8MW_recipr will be substituted by 
1/1800 s. 
o When 9HPT tests were not performed: if only data for one hand is missing, then 
9HPT_avg=3000 s for that specific hand; when data for both hands are missing, 
then 9HPT_recipr=1/3000 s. 
o When PATA tests were not performed, then PATA_avg is substituted with 0. 
For agreement on “unable to perform due to physical limitations” or “not performed for other 
reason”, the sponsor will be contacted. The missings created for 8MWT and 9HPT as stated 
above are considered “unable to perform due to physical limitations”. 
 
According to the “SCAFI rating manual”, the SCAFI total score is to be determined as the 
arithmetic mean of the 3 Z-scores. However, following explanation of IntraBio and Dr. Tanja 
Schmitz-Huebsch, the SCAFI score needs to be calculated as the mean of the non-missing Z-
scores. The SCAFI score can only be determined if at least one test is actually performed, i.e. in 
case all tests were imputed because of missing values, no SCAFI score will be determined. This 
contradicts the “SCAFI rating manual”.  
 
SARA 


 
 
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The overall SARA score is reported as provided in the eCRF. For presentation of the subscore 
results, the individual results as provided in the eCRF will be used, where for the subscores 
finger chase, nose-finger test, fast alternating hand movements, heel-shin slide this is the average 
value for the two sides (left and right) as determined per eCRF. 
 
mDRS 
The mDRS composite score is calculated as a sum of the separate subscores divided by 24. If 
one of the subscores is missing, the mDRS composite score is missing as well. As compared to 
the official questionnaire, the eCRF allows values of 0 (‘normal’) for the subscores.   
 
 
Laboratory 
Laboratory safety data measurements that are denoted as smaller/larger than a certain value (e.g. 
< x.x), will be imputed with this value (e.g. x.x) for calculations of descriptive statistics. Listings 
will show the value as collected, and a footnote will be added to the summary tables for 
explanation. 
Comments 
The following data are either not collected or only collected as free text fields in the 
eCRF/database or lack relevant information in the database, and it is therefore necessary that 
these details are added in the programming code manually. The decisions to drive this manual 
coding may be documented and finalized during the BDRM but can already be 
maintained/discussed during the course of the trial for efficiency. 
• The reason for video unavailability is recorded as free text field, and it needs to be 
deducted if any of these reasons consider a “technical issue”. The sponsor will provide 
input. 
• PATA score missing due to “unable to perform due to physical limitations” is not 
available as such in the database but needs to be deducted from a free comment field. The 
sponsor will provide input. 
• Age is not collected during the Extension phase and full birthdate is not provided in the 
Parent study; therefore, the sponsor will provide details which patients turned 13 between 
Visit 7 and 8, and between Visit 10 and 11. 
• SCAFI comments as stated above on SCAFI calculations. The sponsor will provide input 
to which comments relate to “unable to perform due to physical limitations” and which 
relate to “not performed for other reason”. 
• Information to match the supplied bottles and/or sachets of study drug with the returned 
bottles and/or sachets, to be able to differentiate bottles/sachets used for the Parent phase 
and the Extension phase to allow appropriate compliance calculations. 
Other 
Durations, determination of baseline values and handling of missing data will be programmed as 
stated in the respective analysis sections. 
Any other programming conventions that are not foreseen in preparation of this SAP, will be 
handled when encountered and documented separately. 
10.2 Coding 
Coding of adverse events, concomitant medication and medical history will be performed by the 
Data Management provider. Adverse events and medical history are coded with the MedDRA 


 
 
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coding system (version as provided by the DM vendor). Concomitant medication is coded 
according to the WHO drug code and the ATC class code, using WHO ATC/DDD Index 
(version as provided by the DM vendor). Coding will be supplied as part of the data transfer. 
10.3 Analysis software 
The statistical analysis and reporting will be done using SAS® for WindowsTM version 9.4. SAS 
tabular output (tables and listings) will be saved in RTF format. SAS graphs will be saved in 
PNG format. Both will be imported into PDF and/or Word® and supplied to the Medical Writer 
for use in the clinical study report. When the sponsor wants to receive the output before the study 
report, then a PDF document is supplied. 
 
Furthermore, a number of excels will be provided to the client when providing the output. This 
may concern the CI-CS Visit 2 to Visit 6 for each patient and the CI-S primary anchor data for 
each patient at each visit from the Parent Study, and the excels for creation of Forest plots of the 
Parent Study and Extension Phase.  
10.4 Presentation of tables, listings, graphs 
All output will be generated as SAS tables, graphs and listings.  
 
All tables and listings will be created such that they fit landscape pages. The tables for the end-
of-text and listings for the appendix will be created using SAS, following the specifications 
according to the TLF template document that will be created separately.  
 
For graphs, output will be as created as PNG plot. Graphs are preferably created using black, 
grey, and white color only, to facilitate black-and-white printing. Different line patterns and 
symbols will be used to differentiate between classification or treatment levels. If certain plots 
can only be visually improved by using colours, then this will be done using colors as distinct as 
possible. Graphs will be created such (i.e. taking into account line thickness and font size) that 
they can be presented as two (2) per page in the clinical study report. 
 
11 TABLES, LISTINGS, GRAPHS – PARENT STUDY 
11.1 General 
A detailed list of tables, graphs and listings is presented, if applicable, per report section in 
Sections 11.2, 11.3 and 11.4. 
Template tables and listings as well as example plots (as received from client or extracted from a 
relevant paper, if available) will be used as a reference for creation of all output, and a separate 
document will be created for this. Table/graph/listing numbering will be followed, however, if 
the data give cause for combining or splitting tables or listings, the numbering may be adapted as 
necessary. In case there are no data available for a certain table/listing, an empty table will be 
created and ‘No data available’ will be stated. 
 
11.2 In-text tables and graphs 
Not applicable. Will be designed or extracted by the Medical Writer during creation of the 
Clinical Study Report, based on the tables and graphs created for Section 14 of the CSR.  
 




 
 
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Clinical Study Reference: IB1001-202 
 
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14.2.10 
Result of t-test or Wilcoxon test on the key secondary endpoint ‘Change in 
severity score based on averaged CI-S’ (mITT and PPS population), 
14.2.11 
Frequency table of the change in severity score based on averaged CI-S 
scores between baseline and treatment minus the change between treatment 
and washout (mITT and PPS population) 
14.2.12 
Descriptive statistics of the change in severity score based on averaged CI-S 
scores between baseline and treatment minus the change between treatment 
and washout (mITT and PPS population) 
14.2.13 
Bar chart of change in severity score based on averaged CI-S scores between 
baseline and treatment minus the change between treatment and washout 
(mITT and PPS population) 
14.2.14 
Frequency table of the change in severity score based on averaged CI-S 
scores between baseline and treatment minus the change between treatment 
and washout according to subgroups (mITT population) 
14.2.15 
Descriptive statistics of change in severity score based on averaged CI-S 
scores between baseline and treatment minus the change between treatment 
and washout according to subgroups (mITT population) 
14.2.16 
Result of Wilcoxon test on the key secondary endpoint ‘CI-CS score 
reclassified’ (mITT and PPS) 
14.2.17 
Frequency table of the CI-CS score reclassified on a 3-point scale Visit 4 vs 
Visit 2 and separately, the reclassified CI-CS score Visit 6 vs Visit 4 (mITT 
and PPS population) 
14.2.18 
Descriptive statistics of the CI-CS score reclassified on a 3-point scale Visit 4 
vs Visit 2 and separately, the reclassified CI-CS score Visit 6 vs Visit 4 
(mITT and PPS population) 
14.2.19 
Bar chart of CI-CS score reclassified on a 3-point scale Visit 4 vs Visit 2 and 
separately, CI-CS score Visit 6 vs Visit 4 (mITT and PPS population) 
14.2.20 
Frequency table of the CI-CS score reclassified on a 3-point scale Visit 4 vs 
Visit 2 and separately, the reclassified CI-CS score Visit 6 vs Visit 4 
according to subgroups (mITT population) 
14.2.21 
Descriptive statistics of the CI-CS score reclassified on a 3-point scale Visit 4 
vs Visit 2 and separately, the reclassified CI-CS score Visit 6 vs Visit 4 
according to subgroups (mITT population) 
14.2.22 
Frequency table of the CI-CS score for the non-primary anchor test Visit 4 vs 
Visit 2 and separately, the CI-CS score Visit 6 vs Visit 4 (mITT and PPS 
population) 
14.2.23 
Descriptive statistics of the CI-CS score for the non-primary anchor test Visit 
4 vs Visit 2 and separately, the CI-CS score Visit 6 vs Visit 4 (mITT and PPS 
population) 
14.2.24 
Frequency table of the CI-CS score for the non-primary anchor test Visit 4 vs 
Visit 2 and separately, the CI-CS score Visit 6 vs Visit 4 according to 
subgroups (mITT population)  


 
 
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14.2.25 
Descriptive statistics of the CI-CS score for the non-primary anchor test Visit 
4 vs Visit 2 and separately, the CI-CS score Visit 6 vs Visit 4 according to 
subgroups (mITT population) 
14.2.26 
Result of t-test or Wilcoxon test on the change in SARA total score between 
Visit 2 and Visit 4, as well as Visit 4 and Visit 6 (mITT and PPS population) 
14.2.27 
Descriptive statistics of the SARA total score and 8 subscores at each visit 
(mITT and PPS population) 
14.2.28 
Mean or median plot versus time of the SARA total score (mITT and PPS 
population) 
14.2.29 
Stacked bar chart of the 8 SARA subscores at each visit (mITT and PPS 
population) 
14.2.30 
Spaghetti plot of SARA total score at each visit (mITT and PPS population) 
14.2.31 
Descriptive statistics of the SARA total score and 8 subscores at each visit 
according to subgroups (mITT population) 
14.2.32 
Result of t-test or Wilcoxon test on the change in SCAFI total score, and 
subscores 8MW_avg, 9HPT-D_avg and PATA_avg between Visit 2 and Visit 
4, as well as Visit 4 and Visit 6 (mITT and PPS population) 
14.2.33 
Descriptive statistics of the SCAFI total score and subscores 8MW_avg, 
9HPT-D_avg, 9HPT-ND_avg and PATA_avg at each visit (mITT and PPS 
population) 
14.2.34 
Mean or median plot of SCAFI total score versus time (mITT and PPS 
population) 
14.2.35 
Spaghetti plot of SCAFI total score versus time (mITT and PPS population) 
14.2.36 
Descriptive statistics of the SCAFI total score and subscores 8MW_avg, 
9HPT-D_avg, 9HPT-ND_avg and PATA_avg at each visit according to 
subgroups (mITT population) 
14.2.37 
Frequency table of the EQ-5D-5L and EQ-5D-Y health status and 5 
subdomains at each visit (mITT and PPS population) 
14.2.38 
Frequency table of the EQ-5D-5L and EQ-5D-Y health status and 5 
subdomains at each visit according to subgroups (mITT population) 
14.2.39 
Descriptive statistics of the EQ-VAS for -5L and -Y combined at each visit 
(mITT and PPS population) 
14.2.40 
Mean or median plot of EQ-VAS versus time for -5L and -Y combined 
(mITT and PPS population) 
14.2.41 
Spaghetti plot of EQ-VAS versus time for -5L and -Y combined (mITT and 
PPS population) 
14.2.42 
Descriptive statistics of the EQ-VAS for -5L and -Y combined at each visit 
according to subgroups (mITT population) 


 
 
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14.2.43 
Descriptive statistics on the change in mDRS composite score between Visit 
2 and Visit 4, as well as Visit 4 and Visit 6 (mITT and PPS population) 
14.2.44 
Descriptive statistics of the mDRS composite score and 6 components at each 
visit (mITT and PPS population) 
14.2.45 
Mean or median plot versus time of the mDRS composite score (mITT and 
PPS population) 
14.2.46 
Spaghetti plot of the mDRS composite score versus time (mITT and PPS 
population) 
14.2.47 
Descriptive statistics of the mDRS composite score and 6 components at each 
visit according to subgroups (mITT population) 
14.2.48 
Frequency table of the 3 CGI-S scores (treating physician, caregiver and 
patient) at each visit (mITT and PPS population) 
14.2.49 
Descriptive statistics of the 3 CGI-S scores (treating physician, caregiver and 
patient) at each visit (mITT and PPS population) 
14.2.50 
Bar charts of the 3 CGI-S scores (treating physician, caregiver and patient) at 
each visit (mITT and PPS population) 
14.2.51 
Mean or median plot versus time of the 3 CGI-S scores (treating physician, 
caregiver and patient) (mITT and PPS population) 
14.2.52 
Spaghetti plot of the 3 CGI-S scores (treating physician, caregiver and 
patient) versus time (mITT and PPS population) 
14.2.53 
Frequency table of the 3 CGI-S scores (treating physician, caregiver and 
patient) at each visit according to subgroups (mITT population) 
14.2.54 
Descriptive statistics of the 3 CGI-S scores (treating physician, caregiver and 
patient) at each visit according to subgroups (mITT population) 
14.2.55 
Frequency table of the 3 CGI-C scores (treating physician, caregiver and 
patient) between Visit 2 vs Visit 4, and between Visit 4 and Visit 6 (mITT 
and PPS population) 
14.2.56 
Descriptive statistics of the 3 CGI-C scores (treating physician, caregiver and 
patient) between Visit 2 vs Visit 4, between Visit 4 and Visit 6, and Visit 4 vs 
Visit 2 minus the CI-CS score Visit 6 vs Visit 4 (mITT and PPS population). 
14.2.57 
Result of t-test or Wilcoxon test on the change of CGI-C score for treating 
physician Visit 4 vs Visit 2 minus Visit 6 vs Visit 4 (mITT and PPS 
population) 
14.2.58 
Result of t-test or Wilcoxon test on the change of CGI-C score for treating 
physician between Visit 2 and Visit 4, as well as Visit 4 and Visit 6 (mITT 
and PPS population) 
14.2.59 
Bar charts of the 3 CGI-C scores (treating physician, caregiver and patient) 
between Visit 2 vs Visit 4, and between Visit 4 and Visit 6 (mITT and PPS 
population) 
















 
 
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16.2.7.6 
Laboratory safety data – clinical chemistry 
16.2.7.7 
Laboratory safety/pregnancy data – urinalysis 
16.2.7.8 
Listing of urine test for N-Acetyl-D-Leucine 
16.2.7.9 
Listing of PK concentration data 
16.2.7.10 
General comments 
 

Prot_000.pdf: 
 
 
 
 
 
Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease):  
A multinational, multicenter, open-label, rater-blinded Phase II study 
 
 
 
 
NCT Number: NCT03759665 
 
 
Protocol Version and Date: Version 7.0, 30-Nov-2022 


 
 
 
Page 1 of 155 
 
CLINICAL TRIAL PROTOCOL 
Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-Sachs and Sandhoff 
Disease): A multinational, multicenter, open-label, rater-blinded Phase II study. 
 
Protocol Number: 
IB1001-202 
Investigational Medicinal Product: 
N-Acetyl-L-Leucine (IB1001) 
Indication: 
GM2 
Gangliosidosis 
(Tay-Sachs 
and 
Sandhoff Disease) 
Phase: 
II 
 
SPONSOR: 
 
 
 
 
US LEGAL REPRESENTATIVE: 
 
 
 
 
EU LEGAL REPRESENTATIVE: 
 
IntraBio Ltd. 
Begbroke Science Park, Begbroke Hill 
Woodstock Road, Begbroke, Oxfordshire 
OX5 1PF, United Kingdom 
 
IntraBio Inc 
270 Devon Road 
Tenafly NJ 07670 
United States 
 
IntraBio Ireland Ltd 
10 Earlsfort Terrace, 
Dublin 2, 
D02 T380, Ireland 
 
 
EUDRACT Number: 
IND Number: 
 
 
2018-004406-25 
142302 
Protocol Version and Date: 
Version 7.0, 30-Nov-2022  
 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki, and with other applicable 
regulatory requirements. 
This 
document 
contains 
confidential 
information 
of 
IntraBio 
Ltd. 
Do 
not 
copy 
or 
distribute 
without 
written 
permission 
from 
the 
IntraBio 
Ltd. 
CONFIDENTIAL 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 2 of 155 
Version 7.0, 30-Nov-2022 
Protocol Approval 
 
Sponsor: 
IntraBio Ltd. 
Begbroke Science Park, Begbroke Hill 
Yarnton, Oxford OX5 1PF, UK 
Tel: +44 (0) 1865 271858 
Fax: +44 (0) 2079 006607 
E-mail: mfactor@intrabio.com 
 
 
 
__________________________________                      ________________________ 
Signature 
Date 
 
 
Medical Monitor: 
Dr Glyn Belcher, MA, MB, BChir, PhD, FFPM 
Begbroke Science Park, Begbroke Hill 
Yarnton, Oxford OX5 1PF, UK 
Tel: +44 (0) 7484 546479 
E-mail: glynbelcher@pvconsult.co.uk 
 
 
__________________________________                      ________________________ 
Signature 
Date 
 
Biostatistician: 
Dr Richard Kay, PhD 
RK Statistics 
Brook House, Mesne Lane 
Bakewell, DE45 1AL, UK 
Tel: +44 (0)1629 810093 
E-mail: richard.kay@rkstatistics.com 
 
 
 
__________________________________                      ________________________ 
Signature 
Date 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 3 of 155 
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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: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Protocol Versions 
Date 
Amendment 5 
Version 7.0 
30-Nov-2022 
Amendment 4 
Version 6.0 
01-Sep-2020 
Amendment 3 
Version 5.0 
14-Nov-2019 
Amendment 2 
Version 4.0 
5-Sep-2019 
US Specific Amendment 1  
Version 3.0 
27-Jan-2019 
Global Protocol Version 2 
(Original Protocol Submitted) 
Version 2.0 
13-Dec-2018 
Global Protocol Version 1 
Version 1.0 
8-Dec-2018 
 
The Protocol Amendment Summary of Changes is located in the supplementary document, “IB1001-202 
Protocol Summary of Changes Version 2.0, 30-Nov-2022”.  
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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PROTOCOL SYNOPSIS 
Included as Appendix 1.  


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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TABLE OF CONTENTS 
Protocol Amendment Summary of Changes Table.................................................... 4 
PROTOCOL SYNOPSIS .................................................................................................. 5 
TABLE OF CONTENTS .................................................................................................. 6 
LIST OF TABLES AND FIGURES ............................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 13 
1 
INTRODUCTION................................................................................................ 16 
1.1 
Risk/Benefit Considerations ........................................................................... 17 
1.2 
COVID-19 ........................................................................................................ 20 
2 
STUDY OBJECTIVES ........................................................................................ 22 
2.1 
Primary Objective ........................................................................................... 22 
2.2 
Secondary Objective(s) ................................................................................... 22 
2.3 
Exploratory Objective .................................................................................... 22 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 23 
3.1 
Overview .......................................................................................................... 23 
3.1.1 
Trial Design/Patient Population ........................................................... 23 
3.1.2 
Study Design ........................................................................................ 23 
3.1.2.1 
Baseline Period ............................................................................. 23 
3.1.2.2 
Treatment Period........................................................................... 25 
3.1.2.3 
Washout Period ............................................................................. 25 
3.1.2.4 
Extension Phase ............................................................................ 25 
3.1.2.5 
COVID-19 Modifications to the Original Study Schema ............ 25 
3.1.2.6. 
Interim Analyses .................................................................................. 27 
3.1.3 
Target Number of Patients ................................................................... 27 
3.1.4 
Number of Centers ............................................................................... 27 
3.1.5 
Study Duration ..................................................................................... 27 
3.2 
Discussion of Study Design ............................................................................. 28 
3.2.1 
Study Design ........................................................................................ 28 
3.2.2 
Development of the Primary Endpoint: Clinical Impression of Change 
in Severity (CI-CS) .............................................................................. 29 
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 ............................................ 30 
3.2.2.3 
Serial Endpoint Evaluation ............................................................ 31 
3.2.3 
Choice of the Secondary and Exploratory Endpoints .......................... 31 
3.2.4 
Separate Trial Protocols by Indication ................................................. 31 
3.3 
End of Study Definition .................................................................................. 32 
4 
STUDY POPULATION ...................................................................................... 33 
4.1 
Inclusion Criteria ............................................................................................ 33 
4.2 
Exclusion Criteria ........................................................................................... 35 
4.3 
Patient Withdrawal ......................................................................................... 36 
4.4 
Patient Identification ...................................................................................... 37 
5 
STUDY DRUG ..................................................................................................... 38 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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5.1 
Identity ............................................................................................................. 38 
5.2 
Administration................................................................................................. 39 
5.3 
Modification of Dose Schedule ....................................................................... 39 
5.4 
Packaging, Labeling and Storage .................................................................. 40 
5.5 
Blinding and Breaking the Blind ................................................................... 40 
5.6 
Drug Accountability ........................................................................................ 40 
5.7 
Investigational Medicinal Product (IMP; ‘study drug’) Compliance ........ 41 
5.8 
Concomitant Medications and Therapies ..................................................... 41 
5.9 
Treatment of Overdose ................................................................................... 42 
6 
PARAMETERS AND METHODS OF ASSESSMENT .................................. 43 
6.1 
Efficacy Parameters ........................................................................................ 43 
6.1.1 
Measurement of Clinical Impression of Change in Severity ............... 43 
6.1.1.1 
Secondary Efficacy Endpoints That Directly Supplement the 
Analysis of the Primary Endpoint .................................................. 43 
6.1.2 
Measurement of Ataxia and Functioning ............................................. 44 
6.1.2.1 
Spinocerebellar Ataxia Functional Index (SCAFI)........................ 44 
6.1.2.2 
Scale for the Assessment and Rating of Ataxia (SARA) ................. 44 
6.1.3 
Measurement of Health-related Quality of Life................................... 45 
6.1.4 
Measurement of Overall Neurological Status ...................................... 45 
6.1.5 
Measurement of Global Impression ..................................................... 45 
6.1.6 
Remote Assessments ............................................................................ 46 
6.2 
Safety Parameters ........................................................................................... 47 
6.2.1 
Adverse Events .................................................................................... 47 
6.2.1.1 
Adverse Event Intensity ................................................................ 48 
6.2.1.2 
Adverse Event Relatedness ........................................................... 48 
6.2.2 
Serious Adverse Events ....................................................................... 49 
6.2.2.1 
Reporting Serious Adverse Events ............................................... 49 
6.2.2.2 
Responsibilities of the Sponsor ..................................................... 50 
6.2.3 
Pregnancy ............................................................................................. 50 
6.2.4 
Vital Signs ............................................................................................ 50 
6.2.5 
Electrocardiograms (ECGs) ................................................................. 51 
6.2.6 
Physical Examinations ......................................................................... 52 
6.2.7 
Additional Safety Assessments ............................................................ 52 
6.3 
Laboratory Parameters.................................................................................... 52 
6.3.1 
Safety Laboratory Assessments ........................................................... 52 
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 ...................... 54 
6.3.5 
Sample Processing ............................................................................... 54 
7 
STUDY CONDUCT ............................................................................................. 55 
7.1 
Observations by Visit ...................................................................................... 55 
7.1.1 
Screening (Visit 0 or Visit 1) ............................................................... 55 
7.1.1.1 
“Naïve” Patients Screening ........................................................... 55 
7.1.1.2 
“Non-naïve” Patients: Baseline Period ........................................ 56 
7.1.2 
Baseline Visit (Visit 2)......................................................................... 57 
7.1.3 
Treatment 1 (Visit 3) ............................................................................ 58 
7.1.4 
Treatment 2 (Visit 4) ............................................................................ 59 
7.1.5 
Washout 1 (Visit 5) .............................................................................. 59 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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7.1.6 
Washout Visit 2 (Visit 6) ..................................................................... 60 
7.1.7 
Early Termination Visit ....................................................................... 60 
8 
STATISTICAL METHODS ............................................................................... 62 
8.1 
General Analysis Plan ..................................................................................... 62 
8.1.1 
Disposition of Patients ......................................................................... 62 
8.1.2 
Analysis Populations ............................................................................ 62 
8.2 
General Considerations .................................................................................. 62 
8.3 
Demographics, Baseline Characteristics and Concomitant Medications .. 62 
8.4 
Treatment Compliance ................................................................................... 63 
8.5 
Efficacy Analyses ............................................................................................. 63 
8.5.1 
Primary Efficacy Endpoint .................................................................. 63 
8.5.2 
Secondary Efficacy Endpoints ............................................................. 64 
8.5.3 
Exploratory Efficacy Endpoints ........................................................... 66 
8.6 
Missing Data .................................................................................................... 66 
8.7 
Blinding ............................................................................................................ 67 
8.8 
Safety Analyses ................................................................................................ 67 
8.9 
Interim Analyses.............................................................................................. 67 
8.10 
Determination of Sample Size ........................................................................ 67 
8.11 
COVID-19 Details ........................................................................................... 67 
9 
DATA HANDLING AND RECORD KEEPING .............................................. 69 
9.1 
Data Collection ................................................................................................ 69 
9.2 
Data Correction ............................................................................................... 69 
9.2.1 
Deviations from the Protocol ............................................................... 69 
9.3 
Data Quality Assurance .................................................................................. 69 
9.3.1 
Retention of Records............................................................................ 69 
9.4 
Protection of personal data ............................................................................ 69 
9.5 
COVID-19 Protocol Deviations and Missing Data ....................................... 70 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 71 
10.1 
Study Initiation Activities ............................................................................... 71 
10.2 
Training of Site Staff ....................................................................................... 71 
10.3 
Documentation and Filing .............................................................................. 71 
10.3.1 
List of Patients (patient identification log) .......................................... 71 
10.3.2 
Source Data .......................................................................................... 71 
10.3.3 
Investigator Site File / Regulatory Binder ........................................... 71 
10.4 
Alternative Site due to COVID-19 ................................................................. 72 
10.5 
Monitoring ....................................................................................................... 72 
10.6 
Audits and Inspections .................................................................................... 73 
11 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................... 74 
11.1 
Good Clinical Practice .................................................................................... 74 
11.2 
Informed Consent............................................................................................ 74 
11.3 
Protocol Approval and Amendment.............................................................. 75 
11.4 
Archiving Study Records ................................................................................ 75 
11.5 
Data Safety Monitoring Board ....................................................................... 76 
11.6 
Premature Termination of the Study ............................................................ 76 
11.7 
Confidentiality ................................................................................................. 76 
11.8 
Liability and Insurance................................................................................... 77 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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11.9 
Publication Policy ............................................................................................ 77 
12 
REFERENCE LIST ............................................................................................. 78 
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) ........................................................................................................... 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 I ........................................... 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 Secondary Endpoints ................................................... 125 
3.2.3 
Choice of the Exploratory Endpoints ................................................. 125 
3.2.4 
Dose/ Duration of Treatment ............................................................. 126 
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............................................................................................... 130 
5.3 
Modification of Dose Schedule and Transition to Sachet Formulation ... 130 
5.3.1 
Modification of Dose ......................................................................... 130 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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5.3.2 
Transition from IB1001 in Bottles to Sachet Formulation ................ 131 
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) ........................................... 132 
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 ...... 133 
5.8 
Concomitant Medications and Therapies ................................................... 133 
5.9 
Treatment of Overdose ................................................................................. 134 
6 
PARAMETERS AND METHODS OF ASSESSMENT – EXTENSION 
PHASE ................................................................................................................ 135 
6.1 
Updated Efficacy Parameters ...................................................................... 135 
6.1.1 
Measurement of Global Impression ................................................... 135 
6.1.2 
Clinical Impression of Change in Severity ........................................ 136 
6.2 
New Efficacy Parameter Introduced for the Extension Phase .................. 137 
6.2.1 
Annual Severity Increment Score (ASIS) .......................................... 137 
6.3 
Exploratory Endpoints ................................................................................. 137 
6.4 
Safety Parameters ......................................................................................... 137 
6.4.1 
Adverse Events .................................................................................. 137 
6.4.2 
Serious Adverse Events ..................................................................... 137 
6.4.3 
Pregnancy ........................................................................................... 137 
6.4.4 
Vital Signs .......................................................................................... 137 
6.4.5 
Electrocardiograms (ECGs) ............................................................... 138 
6.4.6 
Physical Examinations ....................................................................... 138 
6.4.7 
Medical History ................................................................................. 138 
6.5 
Laboratory Parameters ................................................................................ 138 
6.5.1 
Safety Laboratory Assessments ......................................................... 138 
6.5.2 
Measurement of N-Acetyl-L-Leucine Concentration in Blood on 
FULL PK days ................................................................................... 138 
6.5.3 
Measurement of N-Acetyl-D-Leucine Concentration in Urine ......... 139 
6.5.4 
Additional Laboratory Samples for Research Purposes .................... 139 
6.5.5 
Total Blood Volume .......................................................................... 139 
7 
STUDY CONDUCT – EXTENSION PHASE ................................................. 140 
7.1 
Observations by Visit .................................................................................... 140 
7.1.1 
Visit 7: Extension Phase Baseline Visit ............................................. 140 
7.1.2 
Visit 8: Day 180 (+/- 14 days): First assessment of the Extension 
Phase treatment period I with N-Acetyl-L-Leucine........................... 141 
7.1.3 
Visit 9:  Day 365 (+/- 14 days): Final assessments of the Extension 
Phase treatment period I with N-Acetyl-L-Leucine........................... 141 
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 ............................................................................... 142 
7.1.4 
Visit 10: Extension Phase Washout Visit .......................................... 142 
7.1.5 
Visit 11: Day 587 (+/- 14 days): Interim Extension Phase visit 
treatment period II.............................................................................. 143 
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) .......................................... 144 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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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 
Exploratory Efficacy Endpoints ......................................................... 146 
8.6 
Missing Data .................................................................................................. 148 
8.7 
Blinding .......................................................................................................... 148 
8.8 
Safety Analyses .............................................................................................. 148 
8.9 
Interim Analyses............................................................................................ 148 
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 
 
 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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LIST OF TABLES AND FIGURES 
Tables in Text 
Table 5.1: Prohibited Medications............................................................................................................ 41 
Table 6.1: Safety Laboratory Tests .......................................................................................................... 52 
 
Figures in Text 
Figure 3-1: Study Schema for “Naïve” Patients ........................................................................................... 23 
Figure 3-2: Study Schema for Non-naïve Patients ....................................................................................... 24 
Figure 4-1: Sample ID Format for a IB1001-202 Subject ............................................................................ 37 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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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 
ASIS 
Annual severity increment score 
AST 
Aspartate aminotransferase 
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-CS 
Clinical impression of change in severity 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case report form 
CS 
Clinically significant 
CI-S 
Clinical impression of severity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EQ 
EuroQol 
ET 
Early termination 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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FAS 
Full analysis set 
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 
Last observation carried forward 
LPLV 
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 
mITTe 
Modified intention-to-treat Extension Phase  
MoCA 
Montreal Cognitive Assessment 
NCS 
Not clinically significant 
NPC  
Niemann-Pick disease type C 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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NPC-CSS 
NPC clinical severity scale 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PPS 
Per protocol set 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAFe 
Safety analysis set - Extension Phase 
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: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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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 GM2 
Gangliosidosis (Tay-Sachs and Sandhoff Disease) for the purpose of establishing the 
benefit/risk balance of investigational medicinal product in the proposed clinical setting.  
GM2 Gangliosidosis is a rare, devastating, neurovisceral autosomal-recessive inherited 
metabolic, lysosomal storage disorder (LSD) that predominantly affects pediatric patients [Utz 
et al, 2017]. In general, patients with neurological onset early in life have more severe 
symptoms, deteriorate faster, and die sooner. GM2 Gangliosidosis is estimated to affect 1: 
320,000 live births [Kaback and Desnick, 2011].  There are no authorized treatments approved 
for GM2 Gangliosidosis [Patterson 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 GM2 Gangliosidosis began 
with the investigation of the commercially available racemic mixture, N-Acetyl-DL-Leucine 
(Tanganil®). IntraBio’s collaborators first reported in a case series on 12 patients with the 
lysosomal storage disorder Niemann-Pick Disease type C (NPC) that the modified amino-acid 
Acetyl-DL-Leucine (3 g/day for one week followed by 5 g per day for three weeks) 
significantly improved the symptoms of NPC, measured by the Scale for the Assessment and 
Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI) and EuroQol-
5D-5L. N-Acetyl-DL-Leucine was very well tolerated, and no side effects except intermittent 
dizziness were reported [Bremova et al, 2015]. An additional case series is available in the 
literature describing the disease modifying effect of long-term treatment with N-Acetyl-DL-
Leucine in 10 patients with NPC treated for a median length of 7.7 months (maximum 21.2, 
minimum 2.7 months) [Cortina-Borja et al, 2018]. In all studies, the compound was well-
tolerated with no discernible serious side effects.  
The potential clinical utility of N-Acetyl-DL-Leucine has been observed in compassionate use 
studies for Tay-Sachs and Sandhoff diseases, as well as related lysosomal storage disorders 
and neurodegenerative diseases [Kaya et al, 2020a]. These preliminary findings have been 
corroborated by in vitro studies in GM2 Gangliosidosis patient cell lines and with in vivo 
studies in the Sandhoff HEXB model to explain the pharmacological properties of N-Acetyl-
DL-Leucine in relation to the observed therapeutic effects [Mann, 2018; Platt, 2018; Kaya et 
al, 2020b]. 
 
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 GM2 Gangliosidosis (as well as in patients with other 
lysosomal storage disorders, neurodegenerative and genetic diseases, and further indications).  


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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 GM2 Gangliosidosis.  
The study drug used in the Parent Study is formulated as 1000 mg Powder for suspension in 
40 mL Ora-Blend® and oral administration. Patients aged ≥18 years in the United States and 
patients aged ≥13 years in Europe 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.  
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 overall design of the study is presented and discussed in Section 3.  
1.1 
Risk/Benefit Considerations 
GM2 is a rare, serious, and life-threatening indication that predominantly affects the pediatric 
population. There are no approved therapies for GM2, and therefore a strong need exists for 
the development of an effective therapy to treat this disorder.  
 
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.  
 
The non-clinical (safety pharmacology, PK, and toxicology) profile supports the development 
of IB1001 as a potential treatment for GM2. No mortality and no noteworthy findings were 
observed in rats at the maximum feasible dose level, i.e. 1000 and 2000 mg/kg/day after 
repeated (28 days) intravenous (i.v.) and per oral (p.o.) administration, respectively. The L-
enantiomer and the racemate exhibited the same toxicity profile in rats and Beagle dogs, 
without any adverse systemic effects at the maximum feasible dose levels: i.e., up to 
2500 mg/kg/day after p.o. and up to 1000 mg/kg/day after i.v./intraperitoneal (i.p.) 
administration. The only findings observed in rats after i.v. bolus injections of the racemate at 
2000 mg/kg/day for 7 days were slight to moderate hypomotricity lasting from 30 seconds to 
5 minutes post-dosing as well as cyanosis of the caudal extremity from Day 2 up to the end of 
the study in some rats. In dogs dosed at 750 and 2500 mg/kg/day for 6 weeks, signs of 
gastrointestinal intolerance in form of emesis, increased salivation, and defecation (diarrhea, 
partly greenish discolored) were noted, which resolved within two hours after administration.  
 
The no-observed-adverse-effect-level (NOAEL) of 2000 mg/kg/day derived from a 28-day, 
p.o., repeat-dose toxicity study in rats corresponds to an area under the concentration-time 
curve (AUC) of 59 and 79 µg*h/mL in male and female rats, respectively. The NOAEL of 
2500 mg/kg/day derived from a 6-week, p.o., repeat-dose toxicity study in dogs corresponds to 
an AUC of 590 and 694 µg*h/mL in male and female dogs, respectively. These plasma 
exposures are 3-fold (rats) and 30-fold (dogs) higher than the human mean area under the 
concentration-time curve to the last quantifiable timepoint (AUClast) observed after a p.o. dose 
level of 4 g (21 µg*h/mL). Moreover, in a 4-week repeat-dose toxicity study in dogs, the 
highest dose level of 1000 mg/kg/administration given via 15-minute i.v. administrations 
repeated three times a day (total daily dose = 3000 mg/kg), was the NOAEL. This dose level 
corresponded to maximum observed plasma drug concentration (Cmax)/ AUClast levels in Week 
4 of 2844 µg/mL/1937 µg/mL*h in males and 2936 µg/mL/ 1819 µg/mL*h in females. These 


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systemic exposure levels were more than 60-fold higher than the human exposure values after 
daily p.o. administration of 4 g (administered as one dose per day). 
 
N-Acetyl-L-Leucine induced no genotoxic effect in two in vitro cell systems and one in vivo 
mammalian erythrocytes micronucleus test performed in rat bone marrow up to high dose 
levels. No relevant modification was observed neither in vitro on the N-Acetyl-L-Leucine 
profile on hERG current, nor in vivo to the central nervous system, the cardiovascular and the 
respiratory function after a single i.v. administration in rats or dogs. 
 
The racemate, N-Acetyl-DL-Leucine, has been available in France since 1957 under the trade 
name Tanganil® (Pierre Fabre Labratories) as an oral treatment for acute vertigo. It has 
demonstrated very good tolerability. Contraindications are restricted to hypersensitivity to 
N-Acetyl-DL-Leucine and other ingredients in the Tanganil® formulation. Known side effects 
are rare cases of skin rash (sometimes associated with pruritus) and urticaria. 
 
A broad set of clinical studies with N-Acetyl-L-Leucine in patients with balance disorders, 
have been conducted, demonstrating the clinical safety of the compound. For N-Acetyl-L-
Leucine, two PK studies in 24 (i.v.) and 19 (oral) healthy subjects ([Study No. V00251 IV 101] 
and [Study No. V00251 ST 101], respectively) have been conducted. Further, the safety of N-
Acetyl-L-Leucine was assessed in a multicenter placebo-controlled clinical study conducted in 
107 patients (80 patients randomized to N-Acetyl-L-Leucine) with vestibular neuritis [Study 
No. V00251 IV 201], in which subjects received doses up to 4 g/day i.v. (2 g twice-daily) for 
4 days and in a second multicenter placebo-controlled clinical study in 76 patients (50 
randomized to N-Acetyl-L-Leucine) with vestibular neuritis [Study No. V00251 ST 201], in 
which subjects received 8 g/day p.o. for 14 days. The results showed that N-Acetyl-L-Leucine 
has a good safety profile. It has been further demonstrated that there no interconversion from 
the L to the D-enantiomers. Furthermore, publications with the racemate, N-Acetyl-DL-
Leucine, show that it is well tolerated in patients with the related storage disorder NPC 
[Bremova et al, 2015; Cortina-Borja et al, 2018] and experience with compassionate use 
indicates good tolerability in patients with GM2 as well as other related diseases [Dr Michael 
Strupp, MD, Professor of Neurology LMU Munich, Personal Communication; Kaya et al, 
2020a].  
 
From an efficacy point of view, compassionate use of the racemate suggests N-Acetyl-L-
Leucine may improve ataxia and quality of life in patients with GM2 [Kaya et al, 2020a]. Pre-
clinical studies have demonstrated that N-Acetyl-L-Leucine is the active ingredient that 
medications the long-term, neuroprotective, diseases modifying effect of the racemate, while 
the D-enantiomer is inactive or potentially antagonistic [Kaya et al, 2020b]. 
 
Appropriate patient selection is one factor in considering the balance of risks of adverse events 
(AEs) against potential clinical benefit. The protocol inclusion and exclusion criteria 
appropriately consider the patient’s overall health and medical history.  
 
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 (p.o. 2000 mg/kg/day) 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 is judged to be safe. Women of 
childbearing potential and partners of women of childbearing potential will be required to 
adhere to strict precautions to prevent pregnancy. Women who are pregnant, breast-feeding, or 


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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 potential and urine 
pregnancy tests will be carried out at approximately 6-weekly intervals throughout the trial.  
 
Levels of risk and burden on participants 
 
N-Acetyl-L-Leucine is being developed for the treatment of adults and children with GM2, a 
rare and life-threatening disorder that predominantly affects pediatric patients [Utz et al, 2017]. 
As described above, first evidence of efficacy comes from the long-term compassionate use of 
N-Acetyl-DL-Leucine in patients with GM2, suggesting the prospect of a direct benefit to the 
participating patients over standard of care.  
 
To ensure the feasibility of this trial, GM2 clinical experts [Dr Marc Patterson, MD, Mayo 
Clinic, Professor Pediatric Neurology] and the heads of multinational GM2 patient 
organizations [Daniel Lewi, President, Cure Action for Tay-Sachs Foundation; Rick Karl, 
President Cure Tay-Sachs Foundation USA; Sue Kahn, Director, National Tay-Sachs and 
Allied Disease Organization, USA, Personal Communication] were consulted and involved in 
its design.  
 
The degree of burden to participants in the study is defined by the description of assessments 
in Section 7.  
 
The behavioral tests for evidence of efficacy are routinely used in the evaluation of ataxia and 
disease burden and are relatively fast to perform; in a publication in patients with the related 
lysosomal storage disorder NPC, the individual subtests of the SCAFI rarely took more than 
2 minutes to complete [Bremova et al, 2015]. With regard to the secondary endpoint 
assessments, the Scale for Assessment and Rating of Ataxia (SARA) takes about 15 minutes 
to complete [Dr Marc Patterson, MD, Mayo Clinic, Professor Pediatric Neurology]. The use of 
these tests was determined together with representatives of the patient community and parents 
of patients with NPC and Tay-Sachs disease, as being clinically meaningful for the patients 
and families and reflective of the ability to perform acts of everyday life safety and securely, 
while at the same time not being exhausting [Dr William Evans, Chairman Nieman-Pick UK, 
Personal Communication; Daniel Lewi, President, Cure Action for Tay-Sachs Foundation, 
Personal Communication]. 
 
To minimize blood draws, sparse PK sampling will be carried out at the same times that blood 
is drawn for the safety blood laboratory tests in the Parent Study. Topical anesthesia may be 
applied before blood sampling. The total amount of blood taken per subject during Parent Study 
will be approximately 66 mL (42 mL blood for the safety analyses, 24 mL blood for the PK 
analyses) evenly distributed over the 6 scheduled visits that will take place over a study 
duration of 14 to 20 weeks. Patients will be ≥15 kg and the total blood volume taken in 
accordance with the maximum allowable research-related blood sample volumes provided in 
the incoming EU ethical considerations for clinical trials on medicinal products conducted with 
minors [EudraLex Volume 10, 2017].  
 
The impact of the interventions will be assessed by patient-reported outcomes (measurement 
of global impression, see Section 6.1.5, where feasible, and quality of life assessments (EQ-
5D-5L and EQ-5D-Y, see Section 6.1.3.  
 


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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 for GM2, 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 IB1001-202 clinical trial. 
 
Protocol Version 5.0, 14-November-2020 was active in all countries prior to the widespread 
outbreak of COVID-19 in the US and Europe (continent, including UK). 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 bodies1 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 
 
 
 


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participating Study Sites regarding the management of the COVID-19 pandemic (including 
IntraBio 2020a).  
 
Note: This protocol amendment (Version 6.0 01-Sep-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-
202 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 IB1001-202 clinical trial.   
 


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2 
STUDY OBJECTIVES 
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 GM2 
Gangliosidosis. 
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 GM2 Gangliosidosis; 
o To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in patients 
with GM2 Gangliosidosis, including patients aged ≥18 years in the United States 
and patients aged ≥13 years in Europe, and weight-tiered doses in patients 6 to 12 
years of age in Europe 
2.3 
Exploratory Objective 
The exploratory objective is: 
• To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with 
GM2 Gangliosidosis 
 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
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. 
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 in Europe AND ≥18 years in the United States with a 
confirmed diagnosis of GM2 Gangliosidosis 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 
protocol2, 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 days3.  
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)4.  
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.  
 
Figure 3-2: 
Study Schema for Non-naïve Patients  
 
2 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.  
3 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.  
4 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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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:  
 
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 1), the observed very good tolerability shown to date in this ongoing, open-


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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 1), 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) 
 
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/Skype5 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 
 
5 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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• 
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.  
At the end of the Parent Study (defined as the date of the last visit of the last patient in the 
Parent Study globally; see Section 3.3 End of Study Definition) an interim clinical study 
report will be written which will include the results of 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 
3.1.4  Number of Centers 
The trial will be conducted in a total of approximately 8 centers in the United States, the United 
Kingdom, Germany, or Spain, 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.  


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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 GM2 Gangliosidosis clinical experts and the 
heads of multinational GM2 Gangliosidosis 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, but without study drug for 18 to 24 weeks 
(depending on whether they are considered as “naïve” or “non-naïve” patients).  
- 
Moreover, both GM2 Gangliosidosis clinical experts and the heads of multinational 
GM2 Gangliosidosis patient organizations have questioned the appropriateness of 
initiating randomized, double-blind, controlled studies for ultra-orphan indications like 
GM2 Gangliosides, 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 GM2 Gangliosidosis 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 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 


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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 GM2 Gangliosidosis 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) 
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 in Fields, 
2020. 
3.2.2.1 Anchor Tests: 9-hole Peg Test Dominant Hand (9HPT-D) or 8-meter Walk Test 
(8MWT) 
To account for the clinical heterogeneity of GM2 Gangliosidosis and to better ensure that the 
primary assessment is clinically meaningful for each individual patient, the proposed CI-CS 
asks the treating physician to select, based on the patient’s unique clinical symptoms, either the 
9HPT-D or the 8MWT as an anchor test for the CI-CS. This decision will be made based on 
the treating physician’s assessment of the patient at Visit 1 (Baseline 1), before the start of 
treatment with N-Acetyl-L-Leucine. At the recommendation of the US FDA, a cognitive 
assessment should be performed at Visit 1 according to the 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 [United States Department of Health and Human 
Services, 2018a]. The anchor test will also be selected based on interactions with the patient, 
their family, and caregivers, to ensure the selected scale is considerate of their quality of life.  
As recommended by the US FDA, the 9HPT-D and 8MWT were selected as the anchor tests 
based on concept elicitation interviews with GM2 Gangliosidosis clinical experts and 
representatives of GM2 Gangliosidosis patient organizations worldwide [United States 
Department of Health and Human Services, 2018a]. 
Based on these findings, it is proposed that physicians will be able to select either the 9HPT-D 
or the 8MWT as the anchor by which the CI-CS is assessed. The United Kingdom Medicines 
and Healthcare Products Regulatory Agency [MHRA, 2018], the Dutch Medicines Evaluation 
Board [MEB, 2018], and the Spanish Agency of Medicines and Medical Devices [AEMPS, 
2018] all considered the 9HPT and 8MWT to be relevant, acceptable measures. 
The US FDA initially suggested the 6-Minute Walk Test be used in lieu of the 8MWT. This 
was discussed extensively with the agency, who confirmed in the meeting notes that IntraBio 
provided additional rationale for the 8MWT over the 6-Minute Walk Test [United States 
Department of Health and Human Services, 2018a], including the consideration that from a 
clinical perspective, the 6-minute walk test is a crude measure of gait functionality, as the 


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distance a patient can walk in 6 minutes does not equate to how stable their gait is or how 
secure their movement is. Although readily measurable, the 6-minute walk test is 
predominately a measure of strength and endurance, and therefore an appropriate for muscular 
dystrophy disorders but not muscular atrophy disorders [Dr Marc Patterson, MD, Mayo Clinic, 
Professor Pediatric Neurology, Personal Communication].  
Moreover, as discussed by representatives of the patient community and parents of patients 
with GM2 Gangliosidosis, the 6-minute walk test is described as being a poor measurement 
that is not clinically meaningful for patients or their families, as their interest is for patients’ 
(many of whom are severely impaired) ability to perform acts of everyday life safely and 
securely rather than more exhaustive tasks [Dr William Evans, Chairman Nieman-Pick UK, 
Personal Communication; Daniel Lewi, President, Cure Action for Tay-Sachs Foundation, 
Personal Communication]. 
3.2.2.2 Blinded Raters & Video Assessments  
Because a double-blind, placebo-controlled, crossover study is not believed to be feasible, 
having the primary evaluation of the CI-CS performed by two blinded, independent raters 
based on videos of the anchor test is intended to reduce detection and performance bias.  
This decision was based on MHRA recommendation, which suggested and strongly endorsed 
the plan for blinded evaluation of video recordings of both the 9HPT-D and 8MWT [MHRA, 
2018]. 
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. 


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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 Choice of the Secondary and Exploratory Endpoints 
The proposed secondary endpoints for ataxia, described in Section 8.5.2, were selected on the 
recommendation of the US FDA to narrow the selection of secondary endpoints to minimize 
testing burden [United States Department of Health and Human Services, 2018a]. 
Ultimately, it was decided not to include the Niemann-Pick type C Clinical Severity Scale 
(NPC-CSS) or a modified version of NPC-CSS as a secondary endpoint for the Phase II study 
investigating the efficacy of 6-weeks of treatment with N-Acetyl-L-Leucine. This is because 
the NPC-CSS was designed to be a measure to characterize and quantify disease progression 
and is not a sensitive measure of short-term symptomatic treatment [Yanjanin et al, 2010]. The 
8 subdomains of the NPC-CSS scale are each a 5-point scale recording the trajectory between 
normal functionality and negligible function. For a short-term study of 42 days (+7 days), the 
sub-domain assessments are too crude to detect clinically meaningful effects.  
Therefore, for this Phase II study, the NPC-CSS is too burdensome an endpoint, considering 
its graduation of changes is not fine enough to detect minor but clinically relevant changes in 
functioning / benefit after 42 days (+7 days) of treatment.  
Similarly, although IntraBio has demonstrated in in vitro studies that treatment with N-Acetyl-
L-Leucine and N-Acetyl-DL-Leucine corrects a number of phenotypes, including expanded 
lysosomal volume and the accumulation of sphingosines and glycosphingolipids in fibroblasts 
from patients with GM2 Gangliosidosis [Mann, 2018], for a short-term study of 6 weeks, no 
major changes in lysosomal volume/accumulation of sphingosines and glycosphingolipids can 
be expected to be detected by analyzing biomarkers.  
3.2.4 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).  
In addition, this Phase II study, originally planned in Tay-Sachs disease, has been extended to 
include all GM2 gangliosidosis patients (Tay-Sachs and Sandhoff Disease). This is based on 
the fact that Tay-Sachs and Sandhoff disease are clinically indistinguishable, as well as recent 
compassionate use reports in patients with Sandhoff disease where significant benefit was 
observed [Kaya et al, 2020a], in vitro findings in Sandhoff patient cells where N-Acetyl-D-
Leucine normalized lysosomal volume [Mann, 2018], and in vivo studies in a Sandhoff mouse 


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model (Hexb-/-) where the efficacy of N-Acetyl-D-Leucine for symptomatic and 
neuroprotective treatment was observed [Platt, 2018; Kaya et al, 2020b]. 
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). 
The end of the Parent Study is defined as the date of the last visit of the last patient in the Parent 
Study globally. 
At this time, an interim clinical study report will be written which will include the results of 
the Parent Study. 
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 GM2 Gangliosides. 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 
a) Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a 
confirmed diagnosis of GM2 Gangliosidosis at the time of signing informed 
consent.  Confirmed diagnosis, i.e., clinical features and positive genetic test GM2-
gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in 
the HEXA or HEXB genes 
2. Females of childbearing potential, defined as a premenopausal female capable of 
becoming pregnant, will be included if they are either sexually inactive (sexually 
abstinent6 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. 
3. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
 
6 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. 
4. 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. 
5. If male, patient agrees not to donate sperm from the first dose until 90 days after their 
last dose. 
6. 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. 
7. Weight ≥15 kg at screening. 
8. Patients are willing to disclose their existing medications/therapies for (the symptoms) 
of GM2 Gangliosidosis, 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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9. 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 GM2 Gangliosidosis, but a completely negative result 
on a previous genetic test for GM2 Gangliosidosis 
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) >5x 
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 a 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) 
procedures, preferably 7-14 days following the last dose of the study drug, unless the patient is 


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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 German, 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 (2 for 
the GM2 Gangliosidosis study). The final two digits refer to the patient number. 
The site and patient digits will be separated by a dash, e.g.  4901-201, 4301-205. 
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 a IB1001-202 Subject 


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5 
STUDY DRUG 
5.1 
Identity 
Product: N-Acetyl-L-Leucine (internal development name: IB1001) 
Chemical name: 2(S)-(acetylamino)-4-methylpentanoic acid 
Generic name: N-Acetyl-L-Leucine 
Trade name: to be determined 
Dosage form: N-Acetyl-L-Leucine, 1000 mg powder for oral suspension in 60 mL glass 
bottles (without further excipients) 
Strength: 1000 mg per 60 mL glass bottle 
Manufacturer:  
Manufacture of dosage form, QC testing, Stability studies: 
Patheon UK Limited,  
151 Milton Park, Abingdon, Oxfordshire OX14 4SD, United Kingdom  
 
Secondary packaging, Labelling, IMP release, Clinical distribution 7 
Fisher Clinical Services UK Ltd,  
Langhurstwood Road, Horsham, West Sussex, RH12 4QD, United Kingdom 
 
Description: 
All patients are to receive N-Acetyl-L-Leucine (IB1001) in this single-arm study; there will be 
no comparator or placebo.  
The product is formulated as 1000 mg powder for oral suspension, to be suspended in 40 mL 
Ora-Blend®.  
The suspension vehicle Ora-Blend® contains the following excipients: 
- 
purified water 
- 
sucrose 
- 
glycerin  
- 
sorbitol  
- 
flavoring 
- 
microcrystalline cellulose 
- 
carboxymethylcellulose sodium 
- 
xanthan gum 
- 
carrageenan 
 
7 It is currently planned that in the event of Brexit without further (transitional) rules or in the event Fisher Clinical Services in the United 
Kingdom is no longer able to carry out the importation and the final approval of the investigational drugs within the EU, Fisher Clinical 
Services Germany, with offices at Im Wörth 3, 79576 Weil am Rhein, Germany will assume responsibility for Fisher Clinical Services Ltd. 
UK.  
 


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- 
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 in Europe and aged ≥18 years in the United States 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 day) treatment period. After the 42-day (+7 
day) treatment period, patients will enter a 42-day (+7 day) washout period, which includes 
efficacy and safety assessments.  


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If Visit 4 is postponed due to COVID-19, patients who remain in the study must be dosed 
through the postponed Visit 4. The study drug will therefore be taken longer than the planned 
42 days (+7 days). Based on the known risk/benefit profile of IB1001, the Sponsor’s Medical 
Expert, Medical Monitor, the DSMB, and each Principal Investigator have determined that 
postponing Visit 4 will not compromise the safety of the patient, nor would continuing the 
patient on IMP until the postponed Visit 4. 
 
Note: at the time of the initial COVID-19 outbreak, the Extension Phase (providing patients 
with further access to treatment for one-year) had been accepted by all applicable Competent 
Authorities (CA)/ Institutional Review Boards (IRB)/ Research Ethics Committees (REC) 
where the trial is being conducted, supporting the continued dosing of patients until the 
postponed in person Visit 4. 
 
See Section 5.9 for information on the treatment of overdose.  
5.4 
Packaging, Labeling and Storage 
IB1001 and Ora-Blend® will be supplied in kits. Each kit contains 28 bottles of N-Acetyl-L-
Leucine (each bottle containing 1000 mg N-Acetyl-L-Leucine for a total of 28,000 mg per kit), 
packed with 3 bottles of Ora-Blend® (each bottle contains 473 mL, for a total of 1,419 mL per 
kit). 
 
Study drug will be packaged by Fisher Clinical Services UK Ltd (Langhurstwood Road, 
Horsham, West Sussex, RH12 4QD, United Kingdom) according to all local legal 
requirements. Study drug will be labelled in accordance with applicable regulatory 
requirements. 
All study drug supplies must be stored in accordance with the manufacturer’s instructions. 
Until dispensed to the patients, the study drug will be stored in a securely locked area, 
accessible to authorized personnel only. 
Packaging and labelling of IMP will comply with Good Manufacturing Practice (GMP), Good 
Clinical Practice (GCP) rules, Annex 13, and country-specific regulatory requirements. 
Packaging and labeling of the IMP will be available in the local language. 
 
5.5 
Blinding and Breaking the Blind 
This study is not blinded.  
5.6 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. Study drug accountability will be performed at Visit 3 (only if feasible), 
Visit 4 (or after Visit 4, if the IMP is returned via courier), and, if applicable, at the ET (or after 
ET, if the IMP is returned via courier). Unused or returned drug will be destroyed at the site. 
Alternatively, the study drug may be returned to Fisher Clinical Services UK Ltd 
(Langhurstwood Road, Horsham, West Sussex, RH12 4QD, United Kingdom) 8or Fisher 
 
8  It is currently planned that in the event of Brexit without further (transitional) rules or in the event Fisher Clinical Services in the United 
Kingdom is no longer able to accept unused or returned study drug from European trial sites for destruction. Fisher Clinical Services 
Germany, with offices at Im Wörth 3, 79576 Weil am Rhein, Germany will assume responsibility for Fisher Clinical Services Ltd. UK.  
 


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Clinical Services US (7554 Schantz Rd, Allentown, PA 18106, USA) if sites are unable to 
dispose of the study drug and it cannot be destroyed at the site. The Investigator, institution, or 
the head of the medical institution (where applicable) is responsible for maintaining up to date 
inventory and site accountability logs. Each dispensing of study drug to a patient will be 
documented in the medical records and patient-level accountability logs. 
5.7 
Investigational Medicinal Product (IMP; ‘study drug’) Compliance 
Compliance will be assessed upon a review of the inventory of IB1001 bottles returned from 
patients.  
Urine tests for N-Acetyl-D-Leucine will be done at Visit 1, Visit 2 (baseline period), Visits 5, 
and Visit 6 (washout period) (see Section 6.3.3 for more details). 
If a patient initially classified as “naïve” has a urine sample after the initial screening visit 
which unexpectedly detects levels of N-Acetyl-D-Leucine above the permitted threshold, they 
will (provided eligible) be reclassified as “non-naïve”. These patients are eligible to return for 
Visit 1 (Baseline 1) after a minimum 42-day wash-out.  
“Non-naïve” patients (including “naïve” patients reclassified as “non-naïve”) who test above 
the permitted threshold for N-Acetyl-D-Leucine in their urine at Visit 1 (Baseline 1) will be 
classified as non-compliant and withdrawn from the study.  
5.8 
Concomitant Medications and Therapies 
At Visit 0/Visit 1, all medication taken in the last 60 days prior to the 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 5.1 lists medications 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 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) GM2 Gangliosidosis should remain as constant as possible (at the 
investigator’s discretion) throughout the trial.  
 
Table 5.1: 
Prohibited Medications 
Prohibited medication 
Washout prior to treatment 
(minimum time period) 
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 


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Table 5.1: 
Prohibited Medications 
Sulfasalazine 
42 days 
Rosuvastatin 
42 days 
 
From Visit 0 (non-naïve) or Visit 1 onward, any ongoing or new medication the patient takes 
other than the study drug is considered a concomitant medication. All concomitant medications 
must be recorded in the 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 who changes their previous regimen/dose, is permitted to 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 
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 GM2 
Gangliosidosis, 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). A manual will be provided to each clinical site, which provides instructions for the 
administration of the CI-CS [Fields, 2020]. Similarly, a video-acquisition manual will be 
provided, which provides instructions for making standardized videos of the 8MWT and 9HPT-
D anchor tests [Medpace, 2019]. 
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 Overall Neurological Status 
The modified disability rating scale (mDRS) will be used to evaluate the overall neurological 
status in NPC, a lysosomal storage disorder that displays similar clinical symptoms as GM2 
Gangliosidosis. The original scale developed in 2006 featured four assessment domains: 
ambulation, manipulation, language and swallowing [Iturriaga et al, 2006] and was further 
extended in 2010 to also include seizures and ocular movements [Pineda et al, 2010]. This scale 
can be used to evaluate the severity of disease, as well as monitor GM2 Gangliosidosis 
progression, and the effect of treatment, both symptomatic and disease-specific.  
The mDRS 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 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]. It is currently 
being used in multiple clinical studies for NPC, including a Phase IIb/III clinical study of 2-
hydroxypropyl-β-cyclodextrin (VTS-270; ClinicalTrials.gov ID: NCT02534844) and a 
Phase II/III clinical study of arimoclomol (NCT02612129). 
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. 


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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. 
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 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).  
6.1.6 Remote Assessments 
Due to COVID-19, safety and efficacy parameters may be collected remotely in lieu of in-
person assessments (as feasible).  


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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 
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. 


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• 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.  
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. 
 


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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. 
 
A SAE is any AE that results in any of the following outcomes: 
• 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 


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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 
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 
PrimeVigilance (intrabio@primevigilance.com) and or faxed to +44 (0) 8000 669231. 
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 2, Visit 4, Visit 6, and then 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 


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following measurements must be performed: systolic/diastolic blood pressure and pulse. Vital 
signs will be measured after the subject has been in the supine position for at least 5 minutes. 
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 
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 1), 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 prior to blood draws or other 
invasive procedures. 
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 1), 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.  


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6.2.6 Physical Examinations 
Height and weight will be measured at the initial screening visit, Visit 1 (“naïve” patients) or 
Visit 0 (“non-naïve” patients). 
6.2.7 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 1), and the safety profile observed 
in this ongoing, open-label study (and also in other ongoing IB1001 trials).   
 
The total amount of blood taken per subject during the Parent Study will be approximately 
66 mL (42 mL blood for the safety analyses, 24 mL blood for the PK analyses).  
In the US, the safety laboratory assessments will be performed by 
. Laboratory sampling and processing 
will be defined by 
 standard procedures.  
In Europe, the safety laboratory assessments will be performed by Eurofins Central Laboratory 
in the Netherlands (Bergschot 71, 4817 PA, Breda, The Netherlands). Laboratory sampling and 
processing will be defined by Eurofins Central Laboratory (based in the Netherlands) standard 
procedures.  
If abnormal laboratory values are signs of an AE (e.g., an infection) that has already been 
recorded, the respective abnormal laboratory value does not constitute a separate AE. 
Wherever reasonable the reporting Investigator will use the clinical term rather than the 
laboratory term (e.g., anemia versus low hemoglobin value). 
Table 6.1: 
Safety Laboratory Tests 
Blood Draw: Hematology  
- 
Hemoglobin 
- 
Erythrocytes 
- 
Hematocrit 
- 
Thrombocytes 
- 
Leukocytes 
 


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Blood Draw: Clinical Chemistry  
- 
Sodium 
- 
Lactate dehydrogenase (LDH) 
- 
Potassium 
- 
Creatinine 
- 
Serum bilirubin level  
- 
Aspartate aminotransferase (AST)  
- 
Alanine aminotransferase (ALT)  
- 
Urea 
- 
Alkaline phosphatase (ALP) 
- 
Follicle-stimulating hormone (FSH; for postmenopausal women only) 
 
Urine Safety Laboratories  
- 
Leukocytes 
- 
Nitrite 
- 
Urobilinogen 
- 
Protein 
- 
pH 
- 
Occult blood (erythrocytes, leucocytes) 
- 
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 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 AZ-Biopharm, Berlin, Germany. 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 AZ-Biopharm, Berlin, Germany  
The urine sample provided at Visit 1 will be analyzed after it is received by AZ-Biopharm 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. 


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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 GM2 Gangliosidosis.  
 
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 (continent), 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. 9  
• Informed consent/informed consent form (ICF) signature and patient information 
• Patient demographics10 
• Patient weight and height measurements 
• 60-day drug history including documentation of prior therapies/medications, including 
prohibited medications, concomitant medications/therapies for treatment of study-
 
9 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”. 
10 Demographics for each patient will be collected in line with local regulations 


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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 
• Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT)   11 
• Scale for Assessment and Rating of Ataxia (SARA)  
• 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  
• Modified Disability Rating Scale (mDRS)   
• 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) 
• 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  
• 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-
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 
 
11 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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• Spinocerebellar Ataxia Functional Index (SCAFI)  
• Scale for Assessment and Rating of Ataxia (SARA) 
• 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 visit will 
be treated as Visit 1: the first assessment of the baseline period. 12 
• 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   
• Vital signs  
• Spinocerebellar Ataxia Functional Index (SCAFI)  + Video-Recording for Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 13 
• 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 
• Modified Disability Rating Scale (mDRS) 
• 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 
• 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.  
 
7.1.2 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. 
 
12 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. 
13 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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• 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 
• Modified Disability Rating Scale (mDRS)   
• 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 
• 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 
• Modified Disability Rating Scale (mDRS)   
• 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 
• 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. 
 


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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 check14 
• 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 
• Modified Disability Rating Scale (mDRS)   
• 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 
• 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) 
• 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 
• Modified Disability Rating Scale (mDRS) 
• 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 
• 12-lead ECG  
• Urinalysis (done at central lab) 
• Urine test for N-Acetyl-D-Leucine (done at PK lab) 
 
14 Or after Visit 4 if IMP is returned via courier 


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• 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  
• 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 
• Modified Disability Rating Scale (mDRS)   
• 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 
• 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). 
 
7.1.7 Early Termination Visit 
• Return of study drug and compliance check15 
• Documentation of frequency of therapy (hours per week) 
• Documentation of concomitant medication  
• Vital signs 
 
15  Or after ET if IMP is returned via courier 


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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 
• Modified Disability Rating Scale (mDRS)   
• 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 
• 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.  


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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  
• Age of diagnosis (Infantile, Juvenile, Adult) 
• 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)   
• Tay-Sachs versus Sandhoff patients 
• 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 [Fields, 
2020]. Similarly, a video-acquisition manual will be provided, which provides instructions for 
making standardized videos of the 8MWT and 9HPT-D primary anchor tests [Medpace, 2019]. 


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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?’ 
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. 


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For each video, the independent raters will make their evaluation of the CI-S, which asks: 
“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 <0 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 >0 on the CI-CS will be classified as 
improved (+1). 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 Visits 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 the 
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)16 
• Scale for Assessment and Rating of Ataxia (SARA) score 
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y17 for patients aged <18 
years 
• Modified Disability Rating Scale (mDRS) 
• 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), and the 
mDRS will be evaluated descriptively. 
The CGI-S measures, and caregiver and patient CGI-C measures will be summarized 
descriptively. The physician’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 GM2 Gangliosidosis.  
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 
 
16The 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 
17 European Sites Only 


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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 are unavailable. 
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. At the end of the Parent Study (defined as the date of 
the last visit of the last patient in the Parent Study globally; see Section 3.3 End of Study 
Definition) an interim clinical study report will be written which will include the results of the 
Parent Study. 
 
8.10 
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. 
 
 
8.11 
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) 


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- 
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 
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. 
The extent and nature of monitoring will be described in detail in the monitoring plan. 
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) will be allowed if the site and Principal Investigator 
agree to this method of monitoring due to COVID-19 restrictions for onsite monitoring visits. 
To facilitate remote SDV, scans of source document worksheets, assessment forms, and other 
required documentation will be sent to the monitor. Monitors should be trained on remote 
SDV procedures. No protected health information should be scanned and sent to the 
monitors. If a site allows the monitors to have access to their electronic medical records, this 
should only be available to the monitor during the time of the remote visit. Site staff should 
be available to respond to monitors questions during the remote monitoring visit.  
 


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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 
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 (age 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 patients records. 
A copy of the ICF must be provided to the patient or the patient’s legal guardian. 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 remotely18. 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. 
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirements. 
 
18 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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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. Complications related to pandemics such as COVID-19 
8. Reasons unrelated to the study. 
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. 
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. 


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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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12 REFERENCE LIST 
Agencia Española de Medicamentos y Productos Sanitario (Spanish Agency of Medicines 
and Medical Devices; AEMPS) (2018). N-Acetyl-L-Leucine (IB1001): Meeting minutes 
(unofficial). Unpublished. 
Bremova, T., Malinová, V., Amraoui, Y., Mengel, E., Reinke, J., Kolníková, M., et al. (2015). 
Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology. 85(16), 1368-1375. 
Cortina-Borja, M., te Vruchte, D., Mengel, E., Amraoui, Y., Imrie, J., Jones, S. A., et al. (2018). 
Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease 
type C and for recruitment to clinical trials. Orphanet Journal of Rare Diseases, 13, 143. 
Churchill GC, Strupp M, Galione A, Platt FM. (2020). Unexpected differences in the 
pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical 
relevance. PLUS ONE. 15(2)  
Dutch Medicines Evaluation Board (MEB) (2018). Scientific Advice N-Acetyl-L-Leucine. 
Unpublished. 
EudraLex Volume 10. Ethical considerations for clinical trials on medicinal products 
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human use. To be authorized under Regulation EU No 536/2014, once it becomes applicable. 
Available at: https://ec.europa.eu/health/documents/eudralex/vol-10_en#fragment1. Accessed: 
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Fields, T. (2020). Clinical Impression of Change in Severity Administration and Scoring 
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clinical management guidelines for Niemann-Pick disease type C. Journal of Rare Diseases, 
13(50), 1-19 
 
IntraBio Ltd. (2020a) Guidance on IB1001 Clinical Trials & COVID-19. Version 2.0 30 
March. Internal Document. 
 
IntraBio Ltd. (2020b) Guidance on IB1001 Clinical Trial Monitoring amid COVID-19 
Pandemic . Version 1.0 17 April. Internal Document 
 
International Society for Pharmacoeconomics and Outcomes Research (ISPOR), 
2018.  Available at: https://www.ispor.org/strategic-initiatives/value-assessment-
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Kaback, M. M., & Desnick, R. J. (2011). Hexosaminidase A Deficiency. In GeneReviews. 
NIH. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1218/ 
 


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Kaya, E., Smith, D., Smith, C., Morris, L., Bremova-Ertl, T., et al. (2020a). Acetyl leucine 
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Kaya, E., Smith, D., Fletcher, C., Boland, B., Strupp, M., Platt, F. (2020b). Beneficial effects 
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Barsottini, O., et al. (2017). NESSCA Validation and Responsiveness of Several Rating Scales 
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Patterson, M., Mengel, E., Wijburg, F., Muller, A., Schwierin, B., Drevon, H., et al. (2013). 
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Picone, M. (2018). GM1 & GM2 Tanganil Health Initiative Report. Trend Community, 1-6. 
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rating of ataxia: development of a new clinical scale. Neurology, 66(11), 1717–1720. 
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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 
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Solmi, M., Pigato, G., Kane, J. M., Correll, C. U. (2018). Treatment of tardive dyskinesia with 
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(2013). Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J 
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Application 134369 for N-Acetyl-L-Leucine (IB1001). Food and Drug Administration: 
Division of Gastroenterology and Inborn Errors. Unpublished.  
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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. 
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Recommendation on the diagnosis and management of Niemann-Pick disease type C. Mol 
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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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13 APPENDICES 
13.1 
Appendix 1: Synopsis 
 
CLINICAL STUDY PROTOCOL SYNOPSIS 
 
 
SPONSOR: 
 
 
 
 
US LEGAL 
REPRESENTATIVE: 
 
 
 
EU LEGAL 
REPRESENTATIVE: 
 
IntraBio Ltd. 
Begbroke Science Park, Begbroke Hill 
Woodstock Road, Begbroke, Oxfordshire 
OX5 1PF, United Kingdom 
IntraBio Inc 
270 Devon Road 
Tenafly NJ 07670 
United States 
 
 
IntraBio Ireland Ltd 
10 Earlsfort Terrace, 
Dublin 2, 
D02 T380, Ireland 
 
 
STUDY NUMBER: 
IB1001-202 
 
 
EUDRACT NUMBER: 
IND NUMBER: 
 
 
2018-004406-25  
142302 
 
PRODUCT/COMPOUND: 
 
N-Acetyl-L-Leucine (IB1001) 
 
TITLE: 
 
Effects of N-Acetyl-L-Leucine on GM2-Gangliosidosis 
(Tay-Sachs and Sandhoff Disease): A multinational, 
multicenter, open-label, rater-blinded Phase II study. 
 
Short Title: A safety and efficacy study of N-Acetyl-L-
Leucine on GM2 Gangliosides. 
 
CLINICAL PHASE: 
 
Phase II 
 
 
(TARGET) INDICATION(S): 
 
GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease) 
 
STUDY SITES: 
 
 
US and Europe (continent) 
 
VERSION & DATE: 
 
Version 7.0, 30-Nov-2022 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 82 of 155 
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Name of Sponsor/Company: 
IntraBio Ltd. 
Protocol Number: 
IB1001-202 
Phase of Development: 
Phase II 
Title of the Protocol: 
Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis: 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 GM2 Gangliosidosis 
Purpose: 
The primary purpose of the study is to evaluate the safety and efficacy of N-Acetyl-L-Leucine 
(IB1001) in the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff) disease   
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 GM2 
Gangliosidosis disease 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-D-Leucine for GM2 Gangliosidosis 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 Niemann-Pick disease type C 
(NPC) [Bremova et al, 2015] as well as inherited cerebellar ataxias [Strupp et al, 2013; Schniepp et 
al., 2016]. 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. 
 
The potential clinical utility of N-Acetyl-DL-Leucine has been observed in compassionate use 
studies for Tay-Sachs and Sandhoff diseases, as well as related lysosomal storage disorders and 
neurodegenerative diseases [Dr Michael Strupp, Personal Communication]. These preliminary 
findings have been corroborated by in vitro studies in GM2 Gangliosidosis patient cell lines and 
with in vivo studies in the Sandhoff HEXB model to explain the pharmacological properties of N-
Acetyl-DL-Leucine in relation to the observed therapeutic effects [Mann, 2018; Platt, 2018]. 
 
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. 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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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 Tay-Sachs and Sandhoff disease (as well as in patients 
with other lysosomal storage disorders, neurodegenerative and genetic diseases, and further 
indications) [Dr Michael Strupp, MD, Professor of Neurology LMU Munich, 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 GM2 Gangliosidosis.  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 GM2 Gangliosidosis (Tay-
Sachs and Sandhoff disease). 
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 GM2 Gangliosidosis 
o To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in adults and 
children with GM2 Gangliosidosis, including patients aged ≥18 years in the United 
States and patients aged ≥13 years in Europe, and weight-tiered doses in children 6 to 
12 years of age in Europe 
 
Exploratory Objectives: 
o To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with 
GM2 Gangliosidosis 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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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 GM2 
Gangliosidosis, 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 
(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). 
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)19. 
  
• 
Spinocerebellar Ataxia Functional Index (SCAFI)20 
• 
Scale for Assessment and Rating of Ataxia (SARA) score 
 
19 See the SAP for complete methods of dealing with missing data as well as how secondary endpoints will be 
investigated descriptively.  
20 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. 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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• 
Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y21 for children aged <18 years  
• 
Modified Disability Rating Scale (mDRS) 
• 
Treating Physician Clinical Global Impression of Severity (CGI-S) 
• 
Treating Physician Clinical Global Impression of Change (CGI-C) 22  
• 
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 
GM2. 
Note: in the Extension Phase, physical exams are also conducted. 
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 AZ-Biopharm, Berlin, Germany. 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. 
Note: In the Extension Phase, full PK sampling will take place at baseline (Visit 7B) and after 1-
year treatment (Visit 9B) 
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 AZ-Biopharm, Berlin, Germany.  
The urine sample provided at Visit 1 will be analyzed after it is received by AZ-Biopharm 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. 
 
21 European Sites Only 
22 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. 
 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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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). 
 
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 protocol23, 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 days24.  
 
23 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.  
24 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.  


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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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)25.  
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 
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/Skype26 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 
 
25 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.   
 
26 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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Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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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). 
 
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 IB1001-202 clinical trial. 
 
The global pandemic has had a significant impact on the IB1001-202 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 GM2 Gangliosidosis 
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.27  
 
27 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 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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• 
Informed consent/informed consent form (ICF) signature and patient information 
• 
Patient demographics28 
• 
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) 
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 29 
• 
Scale for Assessment and Rating of Ataxia (SARA)  
• 
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  
• 
Modified Disability Rating Scale (mDRS) 
• 
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) 
• 
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  
• 
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, 
 
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”. 
28 Demographics for each patient will be collected according to local laws 
29 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.  


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
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including frequency of physiotherapy and speech therapy (documented in hours per week) 
• 
Vital signs 
• 
Spinocerebellar Ataxia Functional Index (SCAFI)  
• 
Scale for Assessment and Rating of Ataxia (SARA) 
• 
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. 30 
• 
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  
• 
Vital signs  
• 
Spinocerebellar Ataxia Functional Index (SCAFI) + Video-Recording of Clinical 
Impression of Change in Severity (CI-CS) Anchor Tests (9HPT-D and 8MWT) 31 
• 
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  
• 
Modified Disability Rating Scale (mDRS) 
• 
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 
• 
12-lead EC 
• 
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  
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, 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  
 
30 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. 
31 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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• 
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 
• 
Modified Disability Rating Scale (mDRS) 
• 
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 
• 
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  
 
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 
• 
Modified Disability Rating Scale (mDRS)   
• 
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 
• 
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 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 check32 
• 
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) 
 
32 Or after Visit 4 if IMP is returned via courier 


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• 
Quality of Life EQ-5D-5L for adults aged ≥18 years, EQ-5D-Y for children aged <18 years  
• 
Modified Disability Rating Scale (mDRS) 
• 
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 
• 
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 
• 
Modified Disability Rating Scale (mDRS)   
• 
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 
• 
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  
• 
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 
• 
Modified Disability Rating Scale (mDRS)   
• 
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 


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• 
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 check33 
• 
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 
• 
Modified Disability Rating Scale (mDRS)   
• 
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 
• 
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  
 
Number of Patients: 
• 
To be enrolled: Approximately 39 patients  
 
 
33 Or after ET if IMP is returned via courier 


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• 
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 8 sites 
Number of Participating Countries: 
Approximately 4 countries:  sites in the United States, United Kingdom, Germany, 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 
a) Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a 
confirmed diagnosis of GM2 Gangliosidosis at the time of signing informed 
consent.  Confirmed diagnosis, i.e., clinical features and positive genetic test GM2-
gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the 
HEXA or HEXB genes 
2. Females of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, will be included if they are either sexually inactive (sexually abstinent34 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: 
 
34 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) 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. 
3. 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. 
4. 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. 
5. If male, patient agrees not to donate sperm from the first dose until 90 days after their last 
dose. 
6. 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. 
7. Weight ≥15 kg at screening. 
8. Patients are willing to disclose their existing medications/therapies for (the symptoms) of 
GM2 Gangliosidosis, 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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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. 
9. 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 Tay-Sachs or Sandhoff disease, but a completely negative 
result on a previous genetic test for GM2 Gangliosidosis caused by β-hexosaminidase 
deficiency resulting from mutations in the HEXA or HEXB genes 
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-D-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) >5x 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. 


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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. 
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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IMP, Dose and Mode of Administration: 
N-Acetyl-L-Leucine is a powder for oral suspension, being investigated for the treatment of GM2-
Gangliosidosis. 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 in Europe and aged ≥18 years in the United States 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 evening35. 
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 evening36. 
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)37. 
The study drug should be taken 30 minutes before, or at least two hours after a meal. 
 
In the Extension Phase, patients will transition to taking IB1001 formulated as granules for oral 
suspension in a 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 days (+7 days) washout period, which includes efficacy 
and safety assessments.  
 
35 European Sites only 
36 European Sites only 
37 European Sites only 


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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 medications 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) 
GM2 Gangliosidosis 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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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).  
• 
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: 
 
• 
Spinocerebellar Ataxia Functional Index (SCAFI)38 
• 
Scale for Assessment and Rating of Ataxia (SARA) score 
 
38The 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. 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 102 of 155 
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• 
Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y39 for children aged <18 years 
(visual analogue scale; descriptive system) 
• 
Modified Disability Rating Scale (mDRS) 
• 
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), and the mDRS 
will be evaluated descriptively. 
 
All CGI-S measures, and caregiver and patient CGI-C measures will be summarised descriptively. 
The physician’s 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 GM2.  
 
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. 
No correction for multiple comparisons will be included.  
Missing Data 
 
39 European sites only 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 103 of 155 
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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 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 are unavailable. 
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 ataxia-telangiectasia. 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: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 104 of 155 
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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 Assessments. 
• 
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) 
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.  
References 
Bremova, T., Malinová, V., Amraoui, Y., Mengel, E., Reinke, J., Kolníková, M., et al. (2015). 
Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology, 85(16), 1368-1375. 
Cortina-Borja, M., te Vruchte, D., Mengel, E., Amraoui, Y., Imrie, J., Jones, S. A., et al. (2018). 
Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease 
type C and for recruitment to clinical trials. Orphanet Journal of Rare Diseases. 13:143. 
Mann, M. 2018. Evaluation of Acetyl-leucine analogues in Niemann-Pick disease type C (NPC) 
and other Lysosomal Storage Diseases in vitro. Study Report from IntraBio Ltd Laboratories, 
Oct. 
Patterson, M., Clayton, P., Gissen, P., Anheim, M., Bauer, P., et al. (2017). Recommendation 
for the detection and diagnosis of Niemann-Pick disease type C. An update. Neurology. 
Available from : https://doi.org/10.1212/CPJ.0000000000000399 
Platt, F. 2018. Evaluation of Acetyl-Leucine analogues in mouse models of Niemann-Pick 
disease type C (NPC) and Sandhoff disease. Study Report from Platt Laboratories, Oct. 
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. 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 105 of 155 
Version 7.0, 30-Nov-2022 
Strupp, M., Teufel, J., Habs, M., Feuerecker, R., Muth, C., van de Warrenburg, B., et al. 
(2013). Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J. 
Neurol., 260, 2556-2561. 
 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 106 of 155 
Version 7.0, 30-Nov-2022 
13.2 
Appendix 2: List of Institutions Involved in the Study 
 
Sponsor 
 
 
 
 
 
 
 
Sponsor’s Medical Expert 
IntraBio Ltd. 
Begbroke Science Park, Begbroke Hill 
Yarnton, Oxford OX5 1PF, UK 
Tel: +44 (0) 1865 271858 
Fax: +44 (0) 2079 006607 
Professor Mallory Factor, Director 
mfactor@intrabio.com 
 
Professor Michael Strupp, MD, FRCP, FANA, FEAN 
Professor of Neurology 
Department of Neurology and German Center for 
Vertigo and Balance Disorders 
University Hospital, Munich Campus Großhadern  
Marchioninistr. 15 
81377 Munich Germany 
Tel: +49-89-4400-73678 
Fax: +49-89-4400-76673 
Michael.strupp@med.uni-muenchen.de 
 
 
 
Data Management 
 
 
 
 
 
 
Electronic Case Report Form 
(eCRF) 
LINK Medical Research 
Gjerdrumsvej 19 N-0484 Oslo  
Norway 
Tel: + 4740982493 
Priya Kulkarni 
Priya.Kulkarni@linkmedical.eu 
 
PCG Solutions  
S:t Persgatan 6 
SE – 753 20 Uppsala, Sweden  
Tel: +46 (0)704453157 
Johannes Molin 
johannes.molin@viedoc.com 
 
 
Medical Monitor 
 
 
 
 
PV Consultancy Ltd.  
113 Saint Georges Square Mews 
London, SW1V 3RZ, UK 
Tel: +44 (0) 7484 546479 
Dr Glyn Belcher, MA, MB, BChir, PhD, FFPM 
glynbelcher@pvconsult.co.uk 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 107 of 155 
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Biostatistician 
 
RK Statistics 
Brook House, Mesne Lane 
Bakewell, DE45 1AL, UK 
Tel: +44 (0)1629 810093 
Dr Richard Kay, PhD 
richard.kay@rkstatistics.com 
 
Adverse Event Reporting 
PrimeVigilance 
Oreskoviceva 20A, 10 000 Zagreb, Croatia 
Tel: +385 (0) 1 4628 523 
Kristina Cmrlec 
Kristina.Cmrlec@primevigilance.com 
 
Central Laboratory  
 
 
 
Eurofins Central Laboratory US  
2430 New Holland Pike, Lancaster, PA 17601, USA 
Tel: +1 717 556 7350 
Fax: +1 717 556 3888  
clinicaltrials@eurofins.com 
 
Eurofins Central Laboratory, Netherlands 
Bergschot 71, 4817 PA, Breda, The Netherlands 
Tel: +31 (0)76 572 72 72 
Fax:  +31 (0)76 573 77 78 
clinicaltrials@eurofins.com 
 
 
PK laboratory 
 
 
 
 
 
 
 
PK Modeling  
 
 
 
 
 
 
 
IMP Manufacturing 
 
 
 
 
 
 
 
Analytisches Zentrum Biopharm Berlin GmbH 
Bitterfelder Strasse 19 
12681 Berlin Germany 
Tel: +49 30 936520  
Fax: +49 (30) 93 65 2200 
Dr Martin Reinsch 
m.reinsch@az-biopharm.de 
 
ThinkQ2 
Oberneuhofstrasse 5 
6340 Baar Switzerland 
Tel: +41 79 870 1999 
Dr Thomas Wagner 
thomas.wagner@thinkq2.com 
 
 
Patheon UK Limited,  
151 Milton Park, Abingdon 
Oxfordshire OX14 4SD, United Kingdom  
Tel: +441235 433028 
Stewart Raven 
stewart.raven@patheon.com 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
Page 108 of 155 
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IMP Packaging, Labeling, 
Distribution 
 
 
Patheon France S.A.S. 
40 Boulevard de Champaret 
CS 11006 
Bourgoin Jallieu, 38 300, France 
Tel: +33 4 7493 8700 
Fax: +33 4 7493 8781 
Name Didier Rumeau 
Email: didier.rumeau@thermofisher.com 
 
 
Fisher Clinical Services UK Ltd,  
Langhurstwood Road, Horsham 
West Sussex, RH12 4QD, United Kingdom 
Tel: +441403 224311 
Name: Karen Witten 
Email: Karen.Witten@thermofisher.com 
 
Fisher Clinical Services GmbH,  
Im Woerth 3,  
79576 Weil am Rhein, Germany 
Tel: +41 61 485 23 00 
Name: Karen Witten 
Email: Karen.Witten@thermofisher.com 
 
 
Videotaping 
Medpace Core Laboratories 
5375 Medpace Way 
Cincinnati, OH  45227 
United States 
Victoria Baker 
v.baker@medpace.com 
+1.513.579.9911 
 
 


IntraBio Ltd. 
Study Code: IB1001-202 
                    EUDRACT NUMBER: 2018-004406-25 
                                              IND NUMBER: 142302 
 
CONFIDENTIAL 
 
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13.3 Appendix 3: Schedule of Events 
 


 
CONFIDENTIAL 
 
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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 
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 


 
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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 
Modified Disabling Rating Score (mDRS) 
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 


 
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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 In Europe only 
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) GM2 Gangliosidosis 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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Study Run-In 
Baseline Period  
Treatment Period 
Wash-Out Period 
Early Term. 
Screening 
visit 
Pre-
treatment 
Washout 
Duration of the whole period 
1 Day 
6 Weeks 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 0 
 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening 
 
Baseline 1 
Baseline 2/ 
Start IMP 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -56 
 
Day -14 
Day 1 
Day 28 
Day 42 
Day 70 
Day 84 
na 
Visit Window allowed 
na 
 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+7 days 
na 
Appendix 3B: Schedule of Events for “Non-naïve” Patients 
Patient information and informed 
consent process  
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
X 
X 
 
 
 
X19 
 
Patient weight and height 
measurements 
X 
 
 
 
 
 
 
X19 
 
Confirmation prohibited 
medications have not been used in 
the past 42 days at Visit 1/since 
Visit 1 for Visit 2 
 
 
X 
X3 
 
 
 
 
 
Confirmation prohibited 
medications have been used within 
past 42 days4 
X 
 
 
 
 
 
 
 
 
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 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram (ECG)5 
 
 
X 
 
X 
 
X 
 
X 


 
CONFIDENTIAL 
 
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Study Run-In 
Baseline Period  
Treatment Period 
Wash-Out Period 
Early Term. 
Screening 
visit 
Pre-
treatment 
Washout 
Duration of the whole period 
1 Day 
6 Weeks 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 0 
 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening 
 
Baseline 1 
Baseline 2/ 
Start IMP 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -56 
 
Day -14 
Day 1 
Day 28 
Day 42 
Day 70 
Day 84 
na 
Visit Window allowed 
na 
 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+7 days 
na 
 
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 
serum9 
 
 
X 
 
 
 
 
 
 
Urinalysis8 
 
 
X 
X 
X 
X 
X 
X 
X 
Urine by dipstick for pregnancy 
test10 
 
 
 
X 
 
X 
 
X 
X 
Blood sample for sparse PK6 
 
 
X 
X 
X 
X 
X 
X 
X 
Quality of Life EQ-5D-5L for 
patients aged ≥18 years; 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 
X 
Modified Disabling Rating Score 
(mDRS) 
 
 
X 
X 
X 
X 
X 
X 
X 
Scale for Spinocerebellar Ataxia 
Functional Index (SCAFI)12 
X 
 
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 
 
 
 
 
 
 


 
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Study Run-In 
Baseline Period  
Treatment Period 
Wash-Out Period 
Early Term. 
Screening 
visit 
Pre-
treatment 
Washout 
Duration of the whole period 
1 Day 
6 Weeks 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 0 
 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening 
 
Baseline 1 
Baseline 2/ 
Start IMP 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -56 
 
Day -14 
Day 1 
Day 28 
Day 42 
Day 70 
Day 84 
na 
Visit Window allowed 
na 
 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+7 days 
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 
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 
Documentation of concomitant 
medication14 
X 
 
X 
X 
X 
X 
X 
X 
X 
Documentation of AEs 
X 
 
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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Study Run-In 
Baseline Period  
Treatment Period 
Wash-Out Period 
Early Term. 
Screening 
visit 
Pre-
treatment 
Washout 
Duration of the whole period 
1 Day 
6 Weeks 
2 Weeks 
6 Weeks 
6 Weeks 
1 Day 
Visit number 
Visit 0 
 
Visit 11 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOS 
ET 
Name of the Visit 
Screening 
 
Baseline 1 
Baseline 2/ 
Start IMP 
Treatment 1 
Treatment 2 
Washout 1 
Washout 2 
ET 
Timeline (Days) 
Day -56 
 
Day -14 
Day 1 
Day 28 
Day 42 
Day 70 
Day 84 
na 
Visit Window allowed 
na 
 
na 
+7 days 
+7 days 
+7 days 
+7 days 
+7 days 
na 
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 1 or 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 Analyzed at PK lab 
7 Patients whose Visit 1 urine sample detects limits of N-Acetyl-D-Leucine above the permitted threshold are classified as non-compliant and withdrawn from the study 
8 Analyzed at 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 In Europe only 
12 At Visit 1 through Visit 6 (not Visit 0), 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. From Visit 2, the selected anchor test (9HPT-D or 8MWT) is to be performed first, before the remaining SCAFI subsets.  
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) GM2 Gangliosidosis since the last 60 days prior screening, 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.   


 
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13.4 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” [Fields 2020]. 
 


 
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13.5 Appendix 5: Protocol Amendment History 
 
The Protocol Amendment Summary of Changes is located in the supplementary document, 
“IB1001-202 Protocol Summary of Changes Version 2.0, 30-Nov-2022”. 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 
The Extension Phase study schema allows patients who have completed Visit 6 of the Parent Study 
of IB1001-202 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 3.1.2 of this Appendix 6.40 
 
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 GM2 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 
GM2 is a rare, serious, and life-threatening disorder that predominantly affects the pediatric 
population [Utz et al, 2017]. There are no approved therapies for GM2, 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 (p.o. 2000 mg/kg/day) 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 
 
40 40 Sections referenced in Appendix 6 refer to the Appendix 6 Sections, unless otherwise indicated by “..of the 
Parent Study” 


 
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pregnancy test will be a prerequisite for the inclusion of women of childbearing potential and urine 
pregnancy tests will be carried out at each visit of the Extension Phase.  
 
Levels of risk and burden on participants 
 
N-Acetyl-L-Leucine is being developed for the treatment of adults and children with GM2, a rare 
and ultimately fatal disorder that predominantly affects pediatric patients [Vanier, 2010; Utz et al, 
2017]. As described in Section 1.1 of the Parent Study, compassionate use of N-Acetyl-DL-
Leucine in patients with Tay-Sachs and Sandhoff diseases, as well as related lysosomal storage 
disorders and neurodegenerative disease [Kaya et al, 2020b] and preliminary findings from non-
clinical studies [Platt, 2018; Mann, 2018], suggest the prospect of a direct benefit to the 
participating patients over standard of care.  
 
To ensure the feasibility of this trial, GM2 clinical experts [Dr Marc Patterson, MD, Mayo 
Clinic, Professor Pediatric Neurology] and the heads of multinational GM2 patient organizations 
[Daniel Lewi, President, Cure Action for Tay-Sachs Foundation; Rick Karl, President Cure Tay-
Sachs Foundation USA; Sue Kahn, Director, National Tay-Sachs and Allied Disease 
Organization, USA, Personal Communication] were consulted and involved in its design.  
 
The degree of burden to participants in the Extension Phase is defined by the description of 
assessments in Section 7.  
 
The behavioral tests for evidence of efficacy are routinely used in the evaluation of ataxia and 
disease burden and are relatively fast to perform; in a publication on the related lysosomal storage 
disorder NPC, the individual subtests of the SCAFI rarely took more than 2 minutes for patients 
to complete [Bremova et al, 2015]. The Scale for Assessment and Rating of Ataxia (SARA) takes 
about 15 minutes to complete [Dr Marc Patterson, MD, Mayo Clinic, Professor Pediatric 
Neurology]. The use of these tests was determined together with representatives of the patient 
community and parents of patients with NPC and Tay-Sachs disease, as being clinically 
meaningful for the patients and families and reflective of the ability to perform acts of everyday 
life safety and securely, while at the same time not being exhausting [Dr William Evans, Chairman 
Nieman-Pick UK, Personal Communication; Daniel Lewi, President, Cure Action for Tay-Sachs 
Foundation, Personal Communication]. 
 
To minimize patient fatigue, visits with PK sampling may be conducted over two days, with the 
blood draws for PK taken on the day after the behavioral tests. Topical anesthesia may be applied 
before blood sampling. The total amount of blood taken per subject during the Extension Phase is 
provided in Section 6.5.5. Patients will be ≥15 kg and the total blood volume taken in accordance 
with the maximum allowable research-related blood sample volumes provided in the incoming EU 
ethical considerations for clinical trials on medicinal products conducted with minors [EudraLex 
Volume 10, 2017].  
 
The impact of the interventions will be assessed by patient-reported outcomes (measurement of 
global impression, see Section 6.1.5 of the Parent Study), where feasible, and quality of life 
assessments (EQ-5D-5L and EQ-5D-Y, see Section 6.1.3 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 GM2, 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 introduced 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 objective in the Extension Phase is to evaluate the efficacy of N-Acetyl-L-Leucine 
based on the modified Disability Rating scale (mDRS). 
2.2 
Secondary Objectives 
The secondary objectives are: 
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 
GM2 Gangliosidosis 
o To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with 
GM2 Gangliosidosis 
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 GM2 Gangliosidosis 
• 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 patients with GM2 
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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 
IB1001-202. 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, 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”)41. 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 should 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. 
 
During 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 I 
From Visit 7B onward, all patients will receive treatment with N-Acetyl-L-Leucine for 365 days 
(+/-14 days).  
Visit 8 will occur at Day 180 (+/-14 days). 
 
41 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 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 modified Disability 
Rating Scale (mDRS) from the Extension Phase baseline (Visit 7) to the end of treatment in the 
Extension Phase (Visit 9). The mDRS is described in Section 6.1.4 of the Parent Study.  
 
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. 


 
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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 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 GM2 Gangliosidosis), 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 IB1001-202 globally. 


 
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4 
STUDY POPULATION – EXTENSION PHASE 
The study population comprises patients with GM2 Gangliosidosis who have completed Visit 6 of 
the parent study of IB1001-202. To be eligible, patients must satisfy the following entry criteria:   
4.1 
Inclusion Criteria 
1. Completed Visit 6 of the IB1001-202 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 in 
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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5 
STUDY DRUG – EXTENSION STUDY 
5.1 
Identity 
Product: N-Acetyl-L-Leucine (internal development name: IB1001) 
Chemical name: 2(S)-(acetylamino)-4-methylpentanoic acid 
Generic name: N-Acetyl-L-Leucine 
Trade name: to be determined 
Two IMPs of equal strength and comparable dosage forms may be used during the Extension 
Phase:  
1. The original IMP approved for use in the Parent Study (“Powder for oral suspension”, 
packed in 60 mL glass bottles, see Section 5.1.1) or; 
2. The commercial formulation developed for use in the Extension Phase (“Granules for oral 
suspension in sachet”, see Section 5.1.2) 
Information on both IMPs is provided below.  
 
5.1.1 N-Acetyl-L-Leucine, 1000 mg powder for oral suspension in 60 mL glass bottles 
(without further excipients) 
Strength: 1000 mg per 60 mL glass bottle 
Manufacturer:  
Manufacture of dosage form, QC testing, Stability studies: 
- 
Patheon UK Limited,  
      151 Milton Park, Abingdon, Oxfordshire OX14 4SD, United Kingdom  
 
Secondary packaging, Labelling, IMP release, Clinical distribution  
⁃ 
Fisher Clinical Services UK Ltd,  
Langhurstwood Road, Horsham, West Sussex, RH12 4QD, United Kingdom 
‐ 
Fisher Clinical Services GmbH,  
Im Woerth 3, 79576 Weil am Rhein, Germany 
 
 
Description: 
The product is formulated as 1000 mg powder for oral suspension, to be suspended in 40 mL Ora-
Blend®.  
The suspension vehicle Ora-Blend® contains the following excipients: 
- 
purified water 
- 
sucrose 


 
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- 
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. 
 
Preparation before administration: 
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.  
 
5.1.2 N-Acetyl-L-Leucine, 1000 mg Granules for oral suspension in sachet 
Strength: 1000 mg per sachet 
Manufacturer:  
Manufacture of dosage form, QC testing, Stability studies: 
‐ 
Patheon UK Limited,  
151 Milton Park, Abingdon, Oxfordshire OX14 4SD, United Kingdom  
‐ 
Patheon France S.A.S. 
40 Boulevard de Champaret, Bourgoin Jallieu, 38 300, France 
 
Secondary packaging, Labelling, IMP release, Clinical distribution  
‐ 
Fisher Clinical Services UK Ltd,  
Langhurstwood Road, Horsham, West Sussex, RH12 4QD, United Kingdom 
‐ 
Fisher Clinical Services GmbH,  
Im Woerth 3, 79576 Weil am Rhein, Germany 
 
Description: 
The product is formulated as 1000 mg granules for oral suspension in sachet. 
The granules for oral suspension contain the following excipients:   


 
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- 
Isomalt  
- 
Hypromellose  
- 
Strawberry Flavour  
Strawberry flavour contains natural flavouring substances, flavouring preparations, and carrier 
additives. 
 
Preparation before administration:  
One sachet should be suspended (poured) into 40 mL water (i.e., approximately quarter of a glass 
of water). The granules should be fully suspended (fully mixed) before being consumed 
(swallowed as a drink).  
 
5.2 
Administration 
All patients are to receive N-Acetyl-L-Leucine (IB1001). 
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) 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  
 


 
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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 visit 
(see Section 5.2).  
During the Extension Phase treatment period I, study drug will be taken for 365 days (+/- 14 days). 
After the 365-day (+/- 14 days) 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). 
See Section 5.9 for information on the treatment of overdose.  
5.3.2 Transition from IB1001 in Bottles to Sachet Formulation 
It is planned that all patients will receive the sachet formulation for the duration of the Extension 
Phase treatment period (see Section 5.1.2).  
Patients may receive IB1001 in bottles at the beginning of the Extension Phase treatment period 
depending on the availability of the sachet supply (see Section 5.1.1). In this event, patients will 
transition to the sachet formulation at the instruction of the Investigator during the Extension 
Phase. To receive the sachet formulation, patients should visit the study site for an unscheduled 
visit to be trained on how to administer the sachet formulation.  At this visit, all used, partially 
used, or unused kits (IB1001 bottles and Ora-Blend® bottles) should be returned to the study 
site42. 
Due to the outbreak of COVID-19, there is a great need to minimize immediate risks and 
prioritize the safeguarding of patients, their families, and clinical study teams by minimizing all 
potential exposure to COVID-19. 
 
Accordingly, if necessary, instead of attending the study site for this unscheduled visit, patients 
may be trained remotely on how to prepare the sachet formulation. In this event, the addendum 
to the informed consent regarding the sachet formulation may also be performed remotely.  
5.4 
Packaging, Labeling and Storage 
The IB1001 bottle and sachet formulations will be packaged by Fisher Clinical Services UK Ltd 
(Langhurstwood Road, Horsham, West Sussex, RH12 4QD, United Kingdom) according to all 
local legal requirements. Study drug will be labelled in accordance with applicable regulatory 
requirements.  
 
42 Or after the Visit if IMP is returned via courier 


 
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All study drug supplies must be stored in accordance with the manufacturer’s instructions. Until 
dispensed to the patients, the study drug will be stored in a securely locked area, accessible to 
authorized personnel only.  
Packaging and labelling of IMP will comply with Good Manufacturing Practice (GMP), Good 
Clinical Practice (GCP) rules, EU GMP Annex 13, and country-specific regulatory requirements. 
Packaging and labeling of the IMP will be available in the local language. 
 
5.4.1 N-Acetyl-L-Leucine, 1000 mg powder for oral suspension in 60 mL glass bottles 
(without further excipients) 
IB1001 and Ora-Blend® will be supplied in kits. Each kit contains 28 bottles of N-Acetyl-L-
Leucine (each bottle containing 1000 mg N-Acetyl-L-Leucine for a total of total 28,000 mg per 
kit), packed with 3 bottles of Ora-Blend® (each bottle containing 473 mL, for a total of 1,419 mL 
per kit). 
 
5.4.2 N-Acetyl-L-Leucine, 1000 mg granules for oral suspension in sachet 
IB1001 will be supplied in cartons of either “1-month” or “3-month” supplies43.  
 
The “one-month” carton will contain 124 sachets of N-Acetyl-L-Leucine (each sachet containing 
1000 mg N-Acetyl-L-Leucine for a total of total 124,000 mg per carton). 
 
The “three-month” carton will contain 370 sachets of N-Acetyl-L-Leucine (each sachet containing 
1000 mg N-Acetyl-L-Leucine for a total of total 370,000 mg per carton).  
5.5 
Blinding and Breaking the Blind 
This study is not blinded. Videos collected from each study visit (except Visit 0 or unscheduled 
visits) and associated pairs of videos will be assessed in a blinded way by the independent raters.  
 
5.6 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. Study drug accountability will be performed at Visit 8 and Visit 9 and, if 
applicable, at the Extension Phase early termination visit. Unused or returned drug will be 
destroyed at the site. Alternatively, the study drug may be returned to Fisher Clinical Services UK 
Ltd (Langhurstwood Road, Horsham, West Sussex, RH12 4QD, United Kingdom), Fisher Clinical 
Services Germany (Im Wörth 3, 79576 Weil am Rhein, Germany),  or Fisher Clinical Services US 
(7554 Schantz Rd, Allentown, PA 18106, USA) if the study drug cannot be destroyed at the site. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for maintaining up to date inventory and site accountability logs. Each dispensing of study drug to 
a patient will be documented in the medical records and patient-level accountability logs. 
 
43 Labels based on assumption of a total daily dose of 4 g/day.  


 
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5.7 
Investigational Medicinal Product (IMP; ‘study drug’) Compliance 
At Visit 844 and Visit 11, patients should return all used IB1001 materials (IB1001 bottles, sachets, 
Ora-Blend® bottles). 
At Visit 9 and Visit 12, or Early Termination (if applicable), patients should return all study 
materials (i.e. used and unused IB1001 bottles and sachets and used and unused Ora-Blend® bottles 
[if applicable]) to the trial site for compliance checks.  
Compliance will be assessed upon a review of the inventory of IB1001 bottles/sachets returned 
from patients.  
 
5.8 
Concomitant Medications and Therapies 
All medication taken after Visit 6 will continue to be recorded as concomitant medications. The 
current amount (in hours per week) of therapy (e.g. physiotherapy, speech therapy) needs to 
continue to be recorded. 
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) GM2 Gangliosidosis 
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.  
 
44 If an unscheduled visit occurs during the extension phase treatment period, where patients switch from taking the IB1001 bottles to the IB1001 
sachets, all used, partially used, or unused IB1001 kits (IB1001 bottles + Ora-Blend bottles) must be returned at this visit, or after the visit if the 
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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. 
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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 monitor 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 and change 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 6.1.5. 
 
Physician, Caregivers, and Patients (if able) will be asked to assess the CGI-C at Visit 8, Visit 9, 
Visit 10, Visit 11, 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 
New Efficacy Parameter Introduced for the Extension Phase 
6.2.1 Annual Severity Increment Score (ASIS) 
The Annual Severity Increment Score (ASIS) [Cortina-Borja et al, 2018] is a metric that measures 
the annual increment in clinical severity for individual patients. The ASIS score can be based on 
the assessments performed in the mDRS45 assessment; no additional tests are required. The ASIS 
score is obtained by dividing the total mDRS severity score of a patient by the age of the patient, 
providing a measure of the rate of disease progression in individual patients.  
Cortina-Borja et al (2018) demonstrated in 38 patients with the related lysosomal storage disorder 
NPC from two independent international clinical cohorts that the ASIS based on the Niemann-
Pick disease type C Clinical Severity Scale (NPC-CSS) was stable over several years. They also 
applied the ASIS score to quantify the slowing of the rate of disease progression in 10 NPC patients 
receiving long-term treatment with Acetyl-DL-Leucine. The study demonstrated that the ASIS is 
a reliable predictor of progression of clinical severity and a valuable tool to quantify the effect of 
an experimental therapy for GM2 disease progression. 
The ASIS scale is included to quantify the potential effects of IB1001 as a neuroprotective/disease-
modifying treatment for GM2.  
6.3 
Exploratory Endpoints 
Exploratory endpoints are defined in Section 8.5.2.  
6.4 
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.  
6.4.1 Adverse Events 
See Section 6.2.1 of the Parent Study.   
6.4.2 Serious Adverse Events 
See Section 6.2.2 of the Parent Study.  
6.4.3 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 12 and the Extension Phase 
Early Termination Visit [if applicable]), females of childbearing potential will have a urine 
dipstick pregnancy test (analyzed on site).  
6.4.4 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. 
 
45 The same investigator should perform the mDRS and SARA assessments at all Extension Phase Visits (Visit 7 – 
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6.4.5 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.  
6.4.6 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). 
6.4.7 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 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.  
 
6.5 
Laboratory Parameters 
6.5.1 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 6.5.5.  
6.5.2 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 
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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 7, 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 I). 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 6.5.5. 
6.5.3 Measurement of N-Acetyl-D-Leucine Concentration in Urine 
Urine tests for N-Acetyl-D-Leucine will be done pre-dose at Visit 746 and pre-dose at Visit 10. 
Data will be analyzed in batches and used for sensitivity analyses only.  
6.5.4 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 GM2 Gangliosidosis. 
 
Blood samples will be obtained for possible research purposes to provide more information on 
the disease GM2 Gangliosidosis according to the Extension Phase schedule of events (Table 
6.1).   
6.5.5 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, and 72 mL for the PK analysis, 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). 
 
 
46 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-
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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”)47. 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 must be carried out and Visit 7 may be 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 
• 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) 
• Modified Disability Rating Scale (mDRS) 
• 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 
• 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 
• Documentation of adverse events. 
 
 
 
47 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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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. 
• Physical examination  
• 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 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) 
• Modified Disability Rating Scale (mDRS) 
• 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 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 Visit 7 
• 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 with N-Acetyl-L-Leucine 
The assessments comprising Visit 9 may be conducted over a two-day period (“Part A” and 
“Part B”). 
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) 


 
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• Modified Disability Rating Scale (mDRS) 
• 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 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) 
• 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 examination 
• 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: Extension Phase Washout Visit  
The final day/first assessment of Extension Phase washout period. 
• 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) 
• Modified Disability Rating Scale (mDRS) 
• Quality of Life EQ-5D-5L for patients aged ≥18 years, EQ-5D-Y for patients aged <18 years 
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• 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 
• 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) 
• Modified Disability Rating Scale (mDRS) 
• 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.  
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 


 
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• 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) 
• Modified Disability Rating Scale (mDRS) 
• 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 
• Documentation of adverse events.  
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 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) 
• Modified Disability Rating Scale (mDRS) 
• 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 
• 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 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) and modified intention-to-treat analysis set (mITTe) 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 
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 Extension Phase analysis set (mITTe) will consist of all 
patients in the SAF with a modified Disability Rating Scale 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 sachet 
of Study Drug dispensed and return bottle or sachets counts, will be calculated. Overall compliance 


 
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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 mITTe. 
For the primary endpoint there will be separate analyses within key subgroups. The subgroups to 
be considered will be defined by: 
• Naïve versus non-naïve: trial classification as determined at screening 
• Tay-Sachs versus Sandhoff Patients 
• Age (pediatric versus adult) 
• Age/weight/dosing group  
• Age of diagnosis (Infantile, Juvenile, Adult) 
• Disease severity based on SARA below/ above the median SARA score at Visit 1 
• Gender (male versus female) 
• Primary Anchor Test (9HPT-D or 8MWT)   
• Composite of SARA Subtests 1-4 (Gait, Stance, Sitting, Speech)  
• Stratification based on Annual Severity Increment Score (ASIS). 
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 will however be a planned series of meta-analyses 
that will bring together the data from the studies for the primary and selected exploratory 
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 modified Disability Rating Scale (mDRS) 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 mDRS 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 mDRS 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: 
 
• Spinocerebellar Ataxia Functional Index (SCAFI)48 score 
 
48The 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. 


 
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• Scale for Assessment and Rating of Ataxia (SARA) score 
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y49 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 
• Annual Severity Increment Score based on the modified Disability Rating Scale50 
 
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 the Extension Phase Treatment period 
II, will be evaluated based on descriptive statistics. 
 
 
49 European Sites Only 
50 Provided a mDRS score is available from Visit 1 of the Parent Study, additional analysis will be performed comparing the mDRS 
at Visit 1, Visit 7, Visit 9, Visit 10, Visit 11, and Visit 12 using the ASIS scale 
 


 
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8.6 
Missing Data 
Analyses based on the mITTe analysis set will utilize a last observation carried forward (LOCF) 
approach for a missing score at Visit 9.  
For the primary mDRS endpoint this implies that the  score of Visit 8 will be 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 
Interim Analyses 
There may be an analysis of the primary and exploratory endpoints relating to the Extension Phase 
once all patients have completed Visit 10. 
8.10 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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12 LIST OF REFERENCES – EXTENSION PHASE 
Bremova, T., Malinová, V., Amraoui, Y., Mengel, E., Reinke, J., Kolníková, M., et al. (2015). 
Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology, 85(16), 1368-1375. 
Cortina-Borja, M., te Vruchte, D., Mengel, E., Amraoui, Y., Imrie, J., Jones, S. A., et al. (2018). 
Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type 
C and for recruitment to clinical trials. Orphanet Journal of Rare Diseases, 13, 143. 
EudraLex Volume 10. (2017). Ethical considerations for clinical trials on medicinal products 
conducted with minors: Recommendations of the expert group on clinical trials for the 
implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for 
human use. To be authorized under Regulation EU No 536/2014, once it becomes applicable. 
Available at: https://ec.europa.eu/health/documents/eudralex/vol-10_en#fragment1. Accessed: 
2019 August 05. 
Fields, T. (2020). Clinical Impression of Change in Severity Administration and Scoring Manual. 
IntraBio Ltd Internal Document. 
Geberhiowt, T., Moro, A., Dardis, A., Ramaswami, U., Sirrs, S., et al. (2018). Consensus clinical 
management guidelines for Niemann-Pick disease type C. Journal of Rare Diseases, 13(50), 1-19.  
Kaya, E., Smith, D., Smith, C., Morris, L., Bremova-Ertl, T., et al. (2020). Acetyl leucine slows 
disease progression in lysosomal storage disorders. Journal of Clinical Medicine. BioRxiv. doi: 
https://doi.org/10.1101/2020.05.20.105973  
Mann, M. 2018. Evaluation of Acetyl-leucine analogues in Niemann-Pick disease type C (NPC) 
and other Lysosomal Storage Diseases in vitro. Study Report from IntraBio Ltd Laboratories, Oct. 
MCL Medpace Laboratories. (2019). Video Acquisition Manual. IntraBio Ltd. Internal Document. 
Picone, M. (2018). GM1 & GM2 Tanganil Health Initiative Report. Trend Community, 1-6. 
Platt, F. 2018. Evaluation of Acetyl-Leucine analogues in mouse models of Niemann-Pick disease 
type C (NPC) and Sandhoff disease. Study Report from Platt Laboratories, Oct. 
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. 
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), 132–14 
 
 
 
 
 
 
 


 
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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 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 
General note: due to COVID-19, deviations from the schedule of visits and assessments may be necessary. Any changes to the schedule of visits/assessments should be discussed between the PI and 
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 
Modified Disability Rating Scale 
(mDRS) 
X 
X 
X 
X 
 
X 
X 
X 
X 
Clinical Global Impression of 
Severity (CGI-S) by Physician 
X 
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 
 
 
 
 
Return of study drugviii 
 
 
X 
 
X 
 
X 
X 
X 
Study drug compliance check 
 
 
X 
 
X 
 
X 
X 
X