An Open-label Safety, Pharmacokinetic, and Efficacy Study of the Combination of Miglustat for the Treatment of CLN3 Disease in Patients 17 Years of Age and Older
Phase: PHASE1
Conditions: Batten Disease
Sponsor: Beyond Batten Disease Foundation

 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
An Open-label Safety, Pharmacokinetic, and Efficacy Study of Miglustat for the Treatment of 
CLN3 Disease in Patients 17 Years of Age and Older 
Protocol Number: 
Batten-1-01 
Intervention: 
Miglustat 
Compound Number: 
Batten-1 
Indication: 
Juvenile Batten (CLN3) Disease 
Phase: 
1/2  
Sponsor: 
Beyond Batten Disease Foundation 
P.O. Box 50221 
Austin, TX 78763 
Principal Investigators: 
 
 
IND Number: 
152646 
NCT Number: 
05174039 
Protocol version; date: 
Version 5; 6 February 2024 
 
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 the Sponsor 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 

Beyond Batten Disease Foundation 
Clinical Protocol 
Batten-1-01 
CONFIDENTIAL 
 
2 
SIGNATURE PAGES 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: An Open-label Safety, Pharmacokinetic, and Efficacy Study of Miglustat for the Treatment 
of CLN3 Disease in Patients 17 Years of Age and Older 
 
This study protocol was subjected to critical review. The information it contains is consistent with 
current knowledge of the risks and benefits of the investigational product, as well as with the 
moral, ethical and scientific principles governing clinical research as set out in the Declaration of 
Helsinki, and the guidelines on Good Clinical Practice. 
 
 
_____________________________________ 
_____________________ 
 
 
 
_____________________________________ 
_____________________ 
 
 

Beyond Batten Disease Foundation 
Clinical Protocol 
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CONFIDENTIAL 
 
3 
Declaration of the Investigator 
 
Title: An Open-label Safety, Pharmacokinetic, and Efficacy Study of Miglustat for the Treatment 
of CLN3 Disease in Patients 17 Years of Age and Older 
All documentation for this study that is supplied to me and that has not been previously published 
will be kept in the strictest confidence. This documentation includes the study protocol, 
Investigator’s Brochure, Case Report Forms, and other scientific data.  
The study will not begin without the prior written approval of a properly constituted Institutional 
Review Board (IRB). No changes will be made to the protocol without the prior written approval 
of Beyond Batten Disease Foundation, the Regulatory Authority and the IRB, except where 
necessary to address an immediate hazard to the subjects.  
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol, including:  
• To adhere to the Declaration of Helsinki, and the principles on Good Clinical Practice (GCP), 
the local laws and applicable regulatory requirements  
• To obtain informed consent prior to performing any study procedures  
• To use the study drug and all study materials only within the framework of this clinical study  
• To comply with the obligations for reporting adverse events.  
 
 
 
_____________________________________ 
_____________________ 
Name 
Date 
Title 
Institution 
 
 

Beyond Batten Disease Foundation 
Clinical Protocol 
Batten-1-01 
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4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Version 1.0 
25 June 2021 
Version 2.0 (Amendment 1) 
27 August 2021 
Version 3.0 (Amendement 2) 
30 September 2021 
Version 3.1 (Amendement 2.1) 
19 November 2021 
Version 4.0 (Amendement 3) 
15 April 2022 
Version 4.1 (Amendement 3.1) 
7 July 2023 
Version 5.0 (Amendement 4) 
6 February 2024 
 
AMENDMENT 1 (27 August 2021) 
Overall Description for the Amendment 
Brief Rationale 
Section Number and 
Name 
Description of Change 
 
Front page, synopsis, 
section 4 
University of Rochester Medical Center added as 
Principal Investigator 
 
University of Rochester Medical Center 
responsible of the UBDRS rating 
 
Section 1.3 
Safety labs added at Week 52, Week 78 and Week 
104 as per protocol 
Safety labs are to be checked every 3 months 
during maintenance as per protocol 
Synopsis, sections 3. 
and 8.8 
Additional PK parameters to analyze at Week 10 
and 18 in Scheme A for miglustat, and at Week 10 
and 18 in Scheme B for trehalose 
PK parameters analysis to be also provided 
from the same subject for trehalose, miglustat 
administered alone and in combination 
Section 5.3.2 
Additional statement re. re-assessment of the 
benefit/risk ratio of therapy and consideration of 
treatment discontinuation in case of symptoms such 
as numbness and tingling 
Alignment 
with 
Zavesca 
prescriber 
information 
Section 7.3.1 
Addition of total volume of blood drawn 
Specification needed of the total volume of 
blood collected during the whole study 
Section 8.8 
Correction of typos in Statistical section regarding 
time of PK assessment 
Ensure consistency between the different PK 
Sections (synopsis, Sections 7.2.1, 7.2.2, 8.8) 
 
AMENDMENT 2 (30 September 2021) 
Overall Description for the Amendment 
Brief Rationale 
Section Number and Name 
Description of Change 
 
Cover 
page, 
Section 
Study 
Design, Section 4 
Removal 
of 
Rochester 
University 
Medical Center as Principal Invetigator 
site 
UBDRS Rating performed remotely, no 
involvement of the site in recruitment and 
patient visits 
Synopsis and Section 6.2 
Integration 
of 
Direct 
to 
Patient 
Investigational Product Shipment 
To introduce Direct-To-Patient shipment 
option in case of operational need  
Synopsis and Section 3 
Addition of clearance in PK parameters 
PK assessment exhaustiveness 
Section 1.3 Schedule of activities 
Clarification of wording 
Clarification of wording 
Section 5.3 and Section 7.1.8 
Inclusion of a “Screen Failure” section 
and a “Unanticipated Problems” section 
Integration from NIH Addendum 
Section 11.5 
Introduction 
of 
DSMB 
rules 
for 
escalation 
Rules validated by DSMB 

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AMENDMENT 2.1 (19 November 2021) 
Overall Description for the Amendment 
Brief Rationale 
Section Number and Name 
Description of Change 
 
Synopsis, Section 6.2 and 
Appendix 8 
Addition of the procedure for home 
administration of investigational 
product 
Related procedure for home administration following 
introduction of Direct-To-Patient shipment option 
 
 
AMENDMENT 3.1  ( 7 July 2023) 
Overall Description for the Amendment 
Brief Rationale 
Section Number and Name 
Description of Change 
 
Section 1.3 page 17: Schedule 
of activities 
 
Add collection of blood biomarkers 
at Week 78 
To add an exploratory endpoint at Week 78 to increase 
the knowledge of biomarkers evolution in blood under 
long-term miglustat treatment  
Section 1.3 page 23: Schedule 
of activities 
Dates expressed in weeks instead of 
days  
Simplification of schedule presentation 
Section 
7.1.3 
Laboratory 
parameters 
Change in volume of blood drawn in 
the study 
Change in volume following additional blood 
biomarker dosing 
 
AMENDMENT 4.0  (6 February 2024) 
Overall Description for the Amendment 
Brief Rationale 
Section Number and Name 
Description of Change 
 
Synopsis, schedule of 
activities, Sections 4.1, 
6.9.2, 7.2 and 8.8. 
Early termination of the study with 
removal of the Week 104 efficacy 
visit at NIH and early termination 
visit placed at TCH  
Collection of safety and efficacy data considered 
sufficient after 18 months of treatment in a population 
of young adults. Patients will be switched to an early 
access program after study termination to ensure 
treatment continuity.  
Section 8.8 
Through PK and miglustat dosage in 
CSF removed 
Protocol simplification’s sake ; data redundancy 
 

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Clinical Protocol 
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CONFIDENTIAL 
 
6 
TABLE OF CONTENTS 
SIGNATURE PAGES ....................................................................................................... 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ......................................... 4 
TABLE OF CONTENTS .................................................................................................. 6 
1 
PROTOCOL SUMMARY .................................................................................. 11 
1.1 
Synopsis ............................................................................................................ 11 
1.2 
Schema ............................................................................................................. 16 
1.3 
Schedules of Activities ..................................................................................... 17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 26 
2 
INTRODUCTION................................................................................................ 28 
2.1 
Rationale .......................................................................................................... 28 
2.2 
Background ...................................................................................................... 29 
2.3 
Risk-Benefit Assessment ................................................................................. 30 
2.3.1 
Anticipated Risks ................................................................................. 30 
2.3.1.1 
Miglustat ........................................................................................ 30 
2.3.1.2 
Study Procedures ........................................................................... 31 
2.3.2 
Anticipated Benefits............................................................................. 33 
2.3.3 
Summary .............................................................................................. 33 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 34 
4 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 35 
4.1 
Overall Design ................................................................................................. 35 
4.2 
Rationale for Study Design ............................................................................. 36 
4.3 
Justification for Dose ...................................................................................... 36 
4.4 
End of Study Definition .................................................................................. 36 
5 
STUDY POPULATION ...................................................................................... 37 
5.1 
Inclusion Criteria ............................................................................................ 37 
5.2 
Exclusion Criteria ........................................................................................... 37 
5.3 
Screen failures ................................................................................................. 38 
5.4 
Discontinuation of Study Intervention and Participant Discontinuation / 
Withdrawal ...................................................................................................... 38 
5.4.1 
Discontinuation of Study Intervention ................................................. 38 
5.4.2 
Participant Discontinuation .................................................................. 39 
5.4.3 
Lost to follow-up.................................................................................. 39 
5.5 
Temporary discontinuation ............................................................................ 40 
5.6 
Lifestyle Considerations ................................................................................. 40 
6 
STUDY INTERVENTION .................................................................................. 41 
6.1 
Identity ............................................................................................................. 41 

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6.2 
Administration ................................................................................................. 41 
6.2.1 
Miglustat .............................................................................................. 41 
6.3 
Packaging, Labelling and Storage ................................................................. 42 
6.4 
Measures to Minimize Bias: Randomization and Blinding ......................... 42 
6.5 
Compliance ...................................................................................................... 42 
6.5.1 
Miglustat .............................................................................................. 42 
6.6 
Concomitant Therapy ..................................................................................... 43 
6.6.1 
Permitted Concomitant Therapy .......................................................... 43 
6.6.2 
Prohibited Concomitant Therapy ......................................................... 43 
6.7 
Rescue Medication .......................................................................................... 43 
6.8 
Dose Modification ............................................................................................ 43 
6.9 
Treatment of Overdose ................................................................................... 44 
6.9.1 
Miglustat .............................................................................................. 44 
6.9.2 
Intervention After the End of the Study ............................................... 44 
7 
STUDY ASSESSMENTS AND PROCEDURES .............................................. 45 
7.1 
Safety Assessments .......................................................................................... 45 
7.1.1 
Adverse Events .................................................................................... 45 
7.1.1.1 
Definitions ...................................................................................... 45 
7.1.1.2 
Recording Adverse Events ............................................................. 47 
7.1.1.3 
Responsibilities of the Investigator ................................................ 48 
7.1.1.4 
Notifying of Serious Adverse Events .............................................. 49 
7.1.1.5 
Laboratory Values ......................................................................... 50 
7.1.2 
Pregnancy ............................................................................................. 50 
7.1.3 
Laboratory Parameters ......................................................................... 50 
7.1.4 
Vital Signs ............................................................................................ 51 
7.1.5 
Electrocardiograms .............................................................................. 51 
7.1.6 
Physical Examination........................................................................... 51 
7.1.7 
Additional Safety Assessments ............................................................ 52 
7.1.8 
Unanticipated problems ....................................................................... 52 
7.2 
Other Parameters ............................................................................................ 52 
7.3 
Efficacy Assessments ....................................................................................... 53 
7.3.1 
Unified Batten Disease Rating Scale ................................................... 53 
7.3.2 
Seizure Frequency ................................................................................ 53 
7.3.3 
Vineland-3............................................................................................ 54 
7.3.4 
Ophthalmic Assessments Including Optical Coherence Tomography 54 
7.3.5 
Magnetic Resonance Imaging .............................................................. 54 
7.3.6 
Lumbar Puncture .................................................................................. 54 
7.3.7 
CSF, blood and urine Biomarkers ........................................................ 55 
8 
STATISTICAL METHODS ............................................................................... 56 
8.1 
Disposition of Subjects .................................................................................... 56 
8.2 
Protocol Deviations ......................................................................................... 56 
8.3 
Analysis Populations ....................................................................................... 56 
8.4 
General Considerations .................................................................................. 56 
8.5 
Demographics, Baseline Characteristics and Concomitant Medications .. 57 
8.6 
Treatment Compliance ................................................................................... 57 

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8.7 
Safety Analyses ................................................................................................ 57 
8.8 
Pharmacokinetic Analyses .............................................................................. 58 
8.9 
Efficacy Analyses ............................................................................................. 58 
8.10 
Determination of Sample Size ........................................................................ 58 
8.11 
Interim Analysis .............................................................................................. 58 
9 
DATA MANAGEMENT ..................................................................................... 59 
9.1 
Data Collection ................................................................................................ 59 
9.2 
Data Correction ............................................................................................... 59 
9.3 
Data Handling .................................................................................................. 59 
9.3.1 
Deviations from the Protocol ............................................................... 59 
9.4 
Data Quality Assurance .................................................................................. 59 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 61 
10.1 
Study Initiation Activities ............................................................................... 61 
10.2 
Training of Site Staff ....................................................................................... 61 
10.3 
Documentation and Filing .............................................................................. 61 
10.3.1 
eCRF System ....................................................................................... 61 
10.3.2 
List of Subjects (subject identification log) ......................................... 61 
10.3.3 
Source Data .......................................................................................... 61 
10.3.4 
Investigator Site File / Regulatory Binder ........................................... 62 
10.4 
Monitoring ....................................................................................................... 62 
10.5 
Audits and Inspections .................................................................................... 62 
11 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................... 63 
11.1 
Good Clinical Practice .................................................................................... 63 
11.2 
Informed Consent ............................................................................................ 63 
11.3 
Protocol Approval and Amendment .............................................................. 63 
11.4 
Archiving Study Records ................................................................................ 63 
11.5 
Data Safety Monitoring Board ....................................................................... 63 
11.6 
Premature Termination of the Study ............................................................ 64 
11.7 
Confidentiality ................................................................................................. 64 
11.8 
Liability and Insurance ................................................................................... 65 
11.9 
Publication Policy ............................................................................................ 65 
12 
REFERENCE LIST ............................................................................................. 66 
13 
APPENDICES ...................................................................................................... 69 
13.1 
Appendix 1: Dietary Guidelines for people taking Miglustat (Updated May 
2013) ................................................................................................................. 69 
13.2 
Appendix 2: Unified Batten Disease Rating Scale ........................................ 71 
13.3 
Appendix 3: Seizure Diary ............................................................................. 79 
13.4 
Appendix 4: Vineland Adaptive Behavior Scales Scoring Sheet, Third Edition
 ........................................................................................................................... 82 
13.5 
Appendix 5: Lumbar Puncture/CSF Collection ......................................... 100 
13.6 
Appendix 6: Contraception Guidance ......................................................... 101 

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13.7 
Appendix 7: Extract of Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 .................................................................................... 104 
13.8 
Appendix 8: Plan for miglustat administration .......................................... 106 
 
 
 

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Tables in Text 
 
Table 1-1 Miglustat Dose Escalation ................................................................................. 13 
Table 1-2 Activities at TCH and NIH CC (Screening, Enrollment, Baseline, Weeks 26, 52, 
78, EOT/ET, and End of Study Visit ......................................................... 17 
Table 1-3 Miglustat Dose-titration and Pharmacokinetic Sampling Period – Local Health 
Center or Subject’s Home (Weeks 1 Through 9)....................................... 21 
Table 1-4 Maintenance Period – Local Health Center/Subject’s Home Visit and Phone Calls 
(Week 10 Through End of Treatment) 1/2 ................................................ 23 
Table 1-5 Maintenance Period – Local Health Center/Subject’s Home Visit and Phone Calls 
(Week 10 Through End of Treatment) 2/2 ................................................ 24 
Table 2-1 - Activity of miglustat, trehalose and their combination on Cln3–/– mouse 
neuropathology .......................................................................................... 29 
Table 6-1 Identity of Investigational Product .................................................................... 41 
Table 6.-2 Miglustat Dose Escalation ................................................................................ 41 
Table 7-1 Laboratory Parameters....................................................................................... 50 
Table 13-1 Highly Effective Contraceptive Methods ...................................................... 101 
 
Figures in Text 
 
Figure 1-1 Schema of the Study Design ............................................................................ 16 
 
 

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Clinical Protocol 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
An Open-label Safety, Pharmacokinetic, and Efficacy Study of Miglustat for the Treatment 
of CLN3 Disease in Patients 17 Years of Age and Older 
Rationale: 
 
The Sponsor has identified a novel therapy that it believes holds particular promise for the treatment of CLN3 disease. 
The Sponsor’s product, Batten-1  is oral miglustat.  
Juvenile Batten (CLN3) disease is an ultra-rare, genetic, lysosomal storage disease that primarily affects the nervous 
system and is fatal. Children with CLN3 disease develop normally, even excelling in school until ages 4 to 7 years, 
when progressive vision loss becomes noticeable. Concomitantly, or shortly thereafter, parents report personality 
changes and behavioral issues. Typically, within 2–3 years after symptom onset, total vision loss occurs, and seizures 
begin. This is followed by declining speech, progressive loss of motor coordination, and cardiac involvement. 
Psychosis, hallucinations and/or dementia can appear anytime during the disease. Eventually, children become 
wheelchair-bound, then bedridden, and die in their late teens or early twenties. 
Miglustat (Batten-1), an iminosugar, has been shown to inhibit the accumulation of gangliosides implicated in disease 
pathogenesis of related lysosomal storage diseases Type 1 Gaucher Disease and Niemann-Pick disease, type C. In 
addition, anti-inflammatory effects have also been reported. Miglustat is approved in the United States (US) and in 
the European Union (EU) for adult Type I Gaucher Disease at doses of 300mg/d. Miglustat is also approved in the 
EU for treatment of adult and pediatric patients with Niemann-Pick Type C Disease at doses up to 600mg/d. Over 18 
years of safe use is available for miglustat, whose most common adverse effect is gastro-intestinal which can be 
mitigated with changes in diet and appears to lessen over time.  
CLN3 disease pathology also includes accumulation of gangliosides and chronic neuroinflammation and therefore, 
patients may benefit from daily miglustat therapy. These assertions are supported by studies in CLN3 animal models 
and in vitro cerebellar cells from those models demonstrating significant increases in GM3 ganglioside levels over 
wild type, which are significantly reduced by treatment with miglustat as well as a reduction of globoside Gb3, Gb4, 
and ganglioside GM1 accumulation in vitro.  
In a model of Batten disease, in Cln3–/– mice, microglial and astrocyte activation was analyzed along with apoptosis 
(BBDF-04042022 internal report). In this model, Cln3–/– mice display astrocytosis and microglial activation in brain 
regions where neuronal loss is subsequently most pronounced. Previous work had established that astrocyte and 
microglial activation may be causally related to neuronal loss (Parviainen et al, 2017).. Thus, quantification of glial 
activation is an appropriate proxy for disease state. Finally, brain atrophy is among the hallmarks of Batten disease 
and is the result of progressive neurodegeneration. Cln3–/– mice recapitulate this feature, which can be observed as a 
global loss of brain weight with age, or decreased neuronal number in various regions including the thalamus, 
cerebellum, and the somatosensory regions of the cortex (BBDF-04042022). 
Miglustat alone and the combination of trehalose and miglustat similarly exerted their beneficial effects on the 
pathological hallmarks of Batten disease. Trehalose treatment given alone also significantly reduced microglial and 
astrocytic activation as well as apoptosis, but in a limited number of brain regions. Miglustat has a clear modifying 
action on Cln3–/– mouse neuropathology that is stronger than that of trehalose alone. Miglustat is currently approved 
for the treatment of Gaucher disease and Niemann-Pick type C in various countries, based on its potent effects as an 
inhibitor of the synthesis of glycosphingolipids, molecules that accumulate in these and other lysosomal storage 
diseases. 
The potent neuroprotective effects exerted by miglustat suggest that certain biochemical products of the 
glycosphingolipid pathway may also accumulate in Batten disease and contribute to its pathogenesis. However, it 
seems that the combination of trehalose and miglustat did not demonstrate any difference versus the use of miglustat 
alone. Indeed, treatment with miglustat alone presented the same impact on Cln3–/– mice phenotype as the 
combination of miglustat and trehalose. 
 

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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To assess the safety and tolerability of 
the Batten-1 treatment regimen over the 
study period  
• 
Incidence of treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs);  
• 
changes from baseline in clinical laboratory tests 
(hematology, chemistry, and urinalysis), 12-lead 
electrocardiogram 
(ECG) 
findings, 
slit 
lamp 
evaluation, vital signs (heart rate and blood pressure) 
as well as physical and neurological examinations 
Secondary 
 
• 
To assess the pharmacokinetics (PK) of  
miglustat in subjects with CLN3 disease 
• 
Week 1 first dosing: Maximum plasma concentration 
(Cmax), Time to Cmax (Tmax), area under the 
concentration-time curve calculated to the last 
observable concentration at time t (AUC 0-t), area 
under the concentration-time curve extrapolated to 
infinity (AUC0-∞), elimination half-life (T1/2) 
• 
Week 9 - Repeated dose (steady state): Cmin, Cmax, 
Tmax, AUC 0-8hr 
 
 
• 
To assess the effect of the Batten-102 
treatment regimen on the longitudinal 
progression of clinical symptoms of 
CLN3 disease. 
• 
Unified Batten Disease Rating Scale (UBDRS)  
• 
Seizure frequency (diaries) 
• 
Vineland Adaptive Behavior Scales, Version 3 
(Communication, Daily Living Skills, Socialization, 
and Motor Skills domains)  
• 
Ophthalmic assessments including visual acuity, 
visual fields (if feasible), and optical coherence 
tomography (OCT) 
• 
Magnetic resonance imaging (MRI) 
Exploratory 
 
• 
To assess potential biomarkers of CLN3  • 
Measure biomarkers in cerebrospinal fluid (CSF), 
blood and urine.  
 
Study Design: 
This is an open label study in approximately 6 subjects in 2 centers to assess the safety, PK, and efficacy of the 
maximum tolerable dose (MTD) of oral miglustat (100 mg once daily [QD] to 200 mg 3 times daily [TID]) in subjects 
≥ 17 years of age with CLN3 disease. Patients will have their last efficacy visit at NIH at week 78 and their last on-
treatment visit at TCH, and will continue to be treated until they can be switched to an early access program.. 
The study sites are Texas Children’s Hospital (TCH) and National Institutes of Health Clinical Center (NIH CC): 
• 
Screening visit, screening confirmation and the end-of-study visit for follow-up safety assessments will be 
conducted by the TCH. Eligibility will be confirmed by TCH after all inclusion/exclusion criteria are 
assessed; screening confirmation decision will be communicated to subject via telephone call by TCH. TCH 
will also review all subject safety data throughout the duration of the study. TCH will also confirm remotely 
the final enrollment after NIH baseline (V2).  

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• 
Baseline, every 6 months visit and end-of-treatment visit for efficacy assessments will be conducted at NIH 
CC. 
• 
Additional safety assessments will be performed at the Local Health Center / Subject’s Home and at the NIH  
• 
CC as per protocol. 
This study includes a dose-titration period of 9 weeks. Subjects will be assigned to miglustat at Week 1 and dosing 
will be escalated weekly as presented in Table 1-1. 
Table 1-1 Miglustat Dose Escalation 
Dose Escalation Step 
Morning (8 AM) 
Afternoon (2 PM) 
Evening (8 PM) 
Step 1  
X 
X 
100 mg 
Step 2 
100 mg 
X 
100 mg 
Step 3 
100 mg 
100 mg 
100 mg 
Step 4 
100 mg 
100 mg 
200 mg 
Step 5 
200 mg 
100 mg 
200 mg 
Step 6 
200 mg 
200 mg 
200 mg 
 
Treatment with miglustat will begin at a dose of 100 mg QD. If the initial dose of miglustat is well tolerated, then the 
dose will be increased weekly until the MTD for a subject is reached. The dose increment is 100 mg. If needed for 
tolerability reasons, a dose may be repeated for 1 or more weeks prior to increasing. If a dose is not tolerated (based 
on the occurrence of TEAEs and at the discretion of the TCH PI), the dose may be adjusted downward to the previous 
dose. Dose increases may resume if there is time left in the titration scheme and at the discretion of the TCH PI; 
otherwise, this lower dose becomes the subject’s MTD. If a subject has not reached the maximum dose (600 mg/d) by 
Week 8, the Week 8 dose will be subject’s MTD. 
Once the dose titration and PK sampling period are completed, subjects will continue their MTDs during the 
maintenance period. Temporary or permanent dose reductions of miglustat for tolerability are permitted at any time 
during the maintenance period of the study. 
An  early access program is planned for subjects who wish to continue the treatment. This  early access program will 
be described in a separate protocol. 
Study Population: 
Inclusion Criteria: 
1. 
Have provided informed consents (TCH and NIH) by subject or parent/legal guardian/legally authorized 
representative (as appropriate). 
2.  
Are males or females ≥ 17 years of age at the time of screening 
3. 
Have genetically confirmed diagnosis of syndromic CLN3 disease with EITHER: 
A. Two pathogenic mutations in the CLN3 gene, OR 
B. One confirmed pathogenic AND one variant of unknown significance, OR 2 variants of 
unknown significance, PLUS secondary confirmation with evidence of characteristic inclusions 
on electron microscopy 
AND characteristic clinical course. 
There is no restriction on the specific CLN3 mutations for eligibility to enroll in the study. The mutations 
will be recorded in the electronic case report form (eCRF) for potential use in determining if CLN3 
genotype is associated with tolerability or effectiveness of Batten-102 therapy. 
4. 
Male and female participants must use a highly effective method of contraception and must continue for 
the duration of the trial (and for 30 days after the end of treatment). 
Appropriate methods of contraception are described in appendix 6. 
5. 
Are able to complete study assessments (subject and/or caregiver) and return to the clinic as scheduled 

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Exclusion Criteria: 
1. 
Have a medical condition that in the opinion of the PI would interfere with the safety assessments or 
increase the subject’s risk of AEs 
2. 
Use of any therapy (approved, off-label, or unapproved) intended to modify the course of any neuronal 
ceroid lipofuscinosis disease, including but not limited to flupirtine or flupirtine derivatives, cerliponase 
alfa (Brineura) 
3. 
Have, in the opinion of the PI, a clinically significant abnormality in their clinical laboratory values 
(hematology, chemistry, or urinalysis) at screening that would preclude their participation in the study 
4. 
Have a known allergy or hypersensitivity to miglustat, or any component of the study drug 
5. 
Have a severe renal disease (creatinine clearance < 30 ml/min/1.73 m2) 
6. 
Have a history of substance abuse or alcohol abuse within 2 years before screening 
7. 
Have a medical history of HIV, hepatitis B, hepatitis C, or positive results at screening 
8. 
Have any active malignancy of any type except non-melanoma skin cancer 
9. 
Have a medical history of major mental illness that, in the opinion of the PI may affect the ability of the 
subject to participate in the study. Institutionalized subjects are not eligible for participation. 
10. 
Have received gene therapy intended to modify the course of CLN3 disease 
11. 
Have been exposed to any miglustat or investigational agent, including but not limited to, flupirtine or 
flupirtine derivatives, within 30 days or 5 half-lives (whichever is longer) prior to check-in for the Week 
1 visit, or is scheduled to receive an investigational device or drug (other than test product) during the 
course of the study 
12. 
Participation in another interventional study during the last three months before screening. 
 
Number of Participants and Duration of Participation: 
Approximately 6 subjects are expected to enroll in the study. Subject participation will be  up to 120 weeks (Screening 
to first dosing approximately 4 weeks, treatment duration up to 116 weeks for the longest treatment duration). Subjects 
who withdraw or are withdrawn from the study during the titration period may be replaced. The total study duration 
will be determined based on the early access program actual start for the last patient that will take place within 116 
weeks of treatment.  
Safety Assessments: 
Safety will be assessed by the incidence of treatment emergent adverse events and serious adverse events, safety labs, 
ECG, slit lamp evaluation, vital signs and physical and neurological examination. 
PK Assessments: 
Pharmacokinetic data will be assessed at first miglustat dosing, and at the maximum tolerated dose (MTD) during the 
titration period. 
Efficacy Assessments: 
Efficacy assessments include Unified Batten Disease Rating Scale (UBDRS); seizure frequency (diary), Vineland-3; 
ophthalmic assessments including visual acuity, visual field, and retinal thickness using optical coherence tomography 
(OCT); and volumetric assessments using magnetic resonance imaging (MRI); they will be assessed at baseline and 
during the maintenance period. Cerebrospinal fluid (CSF), blood and urine biomarkers will also be assessed as 
exploratory endpoints of treatment activity.  
 
 

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Statistical Methods: 
Safety Analysis: Safety data will be summarized using descriptive statistics by visit or time point, as appropriate. 
Treatment-emergent AEs and SAEs will be tabulated and summarized by system organ class, preferred term, severity, 
and relationship to study drug. 
PK Analysis: Single-dose and steady-state descriptive statistical analyses will be performed for miglustat plasma  
concentration data. A specific pharmacokinetic SAP will be prepared.  
Efficacy Analysis: Efficacy will be assessed as a secondary outcome using descriptive statistics.  

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1.2 
Schema 
Figure 1-1 Schema of the Study Design 
 
 
 
 
 
 
 
 
 
 
Enrollment 
Period 
 
 
 
Maintenance Period 
 
 
 
 Titration 
Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V1 
Screening/ 
baseline 
Week -6 
 
 
V2 
Baseline 
Week -2 
 
 
First dosing 
Week 1 
 
 
Start maintenance 
period 
Week 10 
 
 
V3 Week 26 
V4 Week 52 
V5 Week 78 
 
 
 
V6 
Last dosing 
 at early Access Program 
start 
 
 
 
 
 
  
 
 
 
 
 
 
TCH 
 
NIH 
 
(Local Health 
Center / 
Subject’s Home) 
 
(Local Health Center / 
Subject’s Home) 
NIH 
 
 TCH 
 
 
 
EOT=end of treatment; ET= Early Termination; NIH=National Institutes of Health; TCH=Texas Children’s Hospital; V=visit 
 

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1.3 
Schedules of Activities  
Table 1-2 Activities at TCH and NIH CC (Screening, Enrollment, Baseline, Weeks 26, 52, 78, EOT/ET, and End of Study Visit 
 
Visit 1  
Assessments 
at TCH  
(Screening 
and 
Baseline 
Safety) 
Screening 
confirmation 
by TCHA 
(Phone Visit) 
Visit 2 
Assessments 
at NIH CC B 
and final 
enrollment  
(Baseline 
Efficacy 
Assessments) 
Treatment 
start 
 Local 
Health 
Center/ 
Subject’s 
Home 
 
Visit 3 
NIH CC B 
Visit 4 
NIH CC B 
Visit 5 
NIH CC B 
 
Visit 6  
Early 
termination 
TCH B 
Days -42 to -1 
Day 1 
Week 1 
Up to 14 
days 
between 
V2 and 
first dose  
Week 26 
(± 1 
month) 
Week 52 
(± 1 
month) 
Week 78 
(± 1 
month) 
Early Access 
Program 
start  
General Assessments 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
X 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
Enrollment  
X 
 
X 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medications/procedures 
(history) 
X 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
Vital signs C 
X 
 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 

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Visit 1  
Assessments 
at TCH  
(Screening 
and 
Baseline 
Safety) 
Screening 
confirmation 
by TCHA 
(Phone Visit) 
Visit 2 
Assessments 
at NIH CC B 
and final 
enrollment  
(Baseline 
Efficacy 
Assessments) 
Treatment 
start 
 Local 
Health 
Center/ 
Subject’s 
Home 
 
Visit 3 
NIH CC B 
Visit 4 
NIH CC B 
Visit 5 
NIH CC B 
 
Visit 6  
Early 
termination 
TCH B 
Days -42 to -1 
Day 1 
Week 1 
Up to 14 
days 
between 
V2 and 
first dose  
Week 26 
(± 1 
month) 
Week 52 
(± 1 
month) 
Week 78 
(± 1 
month) 
Early Access 
Program 
start  
Neurological examinationD 
 
 
X 
X 
X 
X 
X 
12-lead ECG E 
 
 
X 
X 
X 
X 
X 
Slit-lamp evaluation 
 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
Adverse events F 
X 
 
X 
X 
X 
X 
X 
Contraception (if applicable)   
Laboratory Assessments 
 
 
 
 
 
 
 
Pregnancy test (females)  
X 
 
X 
 
X 
X 
X 
X 
Chemistry, 
hematology,  
urinalysis G 
X 
 
XB 
X 
X 
X 
X 
HIV and hepatitis B and C 
testing H 
X 
 
 
 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
UBDRSI 
 
 
X 
 
X 
X 
X 
 
Vineland 3J 
 
 
X 
 
 
X 
 
 
Ophthalmic exams including, 
OCTK 
 
 
X 
X 
X 
X 
 

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Visit 1  
Assessments 
at TCH  
(Screening 
and 
Baseline 
Safety) 
Screening 
confirmation 
by TCHA 
(Phone Visit) 
Visit 2 
Assessments 
at NIH CC B 
and final 
enrollment  
(Baseline 
Efficacy 
Assessments) 
Treatment 
start 
 Local 
Health 
Center/ 
Subject’s 
Home 
 
Visit 3 
NIH CC B 
Visit 4 
NIH CC B 
Visit 5 
NIH CC B 
 
Visit 6  
Early 
termination 
TCH B 
Days -42 to -1 
Day 1 
Week 1 
Up to 14 
days 
between 
V2 and 
first dose  
Week 26 
(± 1 
month) 
Week 52 
(± 1 
month) 
Week 78 
(± 1 
month) 
Early Access 
Program 
start  
MRIK 
 
 
X 
 
X 
 
 
Seizure diary dispentiationL 
X 
 
 
 
 
 
 
Blood for biomarkers 
 
 
X 
 
 
X 
X 
 
Spot urine for biomarkers 
 
 
X 
 
X 
 
 
Lumbar puncture for CSF 
collection (biomarkers)K 
 
 
X 
 
X 
 
 
A 
After TCH PI determination of subject eligibility,  study staff will inform the subject and will schedule NIH CC baseline visit. 
B 
In cases of any event precluding safe travel by participants to NIH (i) for inclusion visit: beyond 1.5 months, the safety labs will be repeated at NIH. However, 
the total duration between the 2 inclusion visits should not exceed 3 months. Time between NIH visit and first drug administration should be also maintained 
within a reasonable timeframe (1 month). (ii) during the course of the study: evaluations will be performed (1) at the Local Health Center / Subject’s Home 
for: labs, ECG (if feasible), physical exam, vital signs, weight, adverse events, or (2) via remote methods for : history, UBDRS, Vineland-3, adverse events, 
concomitant meds, seizure diary or (3) could be deferred (+/- 1 month) for: neurological exam, ophthalmology exam, MRI, lumbar puncture.  
C 
Vital signs include systolic and diastolic blood pressure [sitting for 5 minutes] and pulse rate. 
D 
A standardized neurological exam will be performed by a pediatric neurologist or qualified individual. The neurological exam will take into account potential 
visual impairment. The evaluation will include, but is not limited to mental status, cranial nerves, motor function, and sensory and cerebellar functions. 
E 
The subject must be in supine position in a rested and calm state for at least 5 minutes before ECG assessment is conducted. Electrocardiograms should be 
performed in a standardized method, in triplicate, and approximately 30 seconds apart, prior to blood draws or other invasive procedures. Each ECG must 
include the following measurements: QRS, QT, QTc, RR, and PR intervals. 
F 
Since last Local Health Center/ Subject’s Home visit. 

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G 
Chemistry laboratory parameters include HbA1c, creatinine, total bilirubin (direct and indirect if values were above normal ranges), alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, creatine kinase, sodium, potassium, cholesterol, and triglycerides. 
Hematology laboratory parameters include hemoglobin, hematocrit, erythrocytes, thrombocytes, and white blood cell count with differential (for an absolute 
neutrophil count, lymphocyte count and monocyte count). Dipstick urinalysis includes glucose, nitrate, hemoglobin, leukocytes, protein, pH, ketones, and 
specific gravity. 
H 
All subjects will be assayed for anti-hepatitis C antibody, hepatitis B surface antigen, and human immunodeficiency virus.  
I 
Assessment will be done either before or > 24 hours after sedation. All domains are administered at baseline. If video interview is not possible for technical 
reasons, patients will be assessed at the NIH by a UBDRS trained rater. In cases of any event precluding safe travel by participants to NIH, the assessment will 
be performed remotely according to instructions delivered by URMC 
J 
Assessment will be done either before or > 24 hours after sedation. The Communication, Daily Living Skills, Socialization and Motor Skills domains are 
assessed. 
K 
Subjects who cannot cooperate with the MRI study, ophthalmology exam, or lumbar puncture procedure may be sedated. Baseline OCT will be obtained in all 
study participants.  In those participants with no light perception vision, dense cataracts, or other ophthalmologic findings that produce significant artifacts in 
the OCT images, OCT imaging will not be repeated. 
L 
A seizure diary will be completed on a daily basis, beginning at screening. The baseline seizure frequency will be calculated based on data collected from 
screening to first dose of study drug. 
 
 
 
 

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Table 1-3 Miglustat Dose-titration and Pharmacokinetic Sampling Period – Local Health Center or Subject’s Home (Weeks 1 
Through 9) 
 
Day 1 – 
Week 1 
(Within 
42 days of 
screening) 
Dose-titration Period 
Day 8±2 
Week 2 
  
Day 15±2 
Week 
3 
  
Day 22±2 
Week 
4 
 
Day 29±2 
Week 5 
 
Day 36±2 
Week 
6 
 
Day 43±2 
Week 7 
Day 50±2 
Week 
8 
 
Day 57±2 
Week 
9 
 
General Assessments 
 
 
 
 
 
 
 
 
 
Abbreviated physical examination A 
X 
 
 
 
X 
 
 
 
X 
Vital signs B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone follow-up by TCH PI C 
 
 
 
 
X 
 
 
 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
Pregnancy test (females)D 
(X) 
 
 
 
 
X 
 
 
 
Chemistry E 
(X)  
 
 
 
 
X 
 
 
 
Hematology F 
(X)  
 
 
 
 
X 
 
 
 
Urinalysis G 
(X)  
 
 
 
 
X 
 
 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
Miglustat doseH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Miglustat supplied I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK 
 
 
 
 
 
 
 
 
 
Draw blood 
X J 
 
 
 
 
 
 
 
X K 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
Seizure diary collection L 
 
 
 
 
X 
 
 
 
X 
Seizure diary dispentiation 
 
 
 
 
X 
 
 
 
X 
A 
An abbreviated physical examination will assess only the general appearance of the patient and is only required when a complete exam is not indicated. 

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B 
Vital signs include systolic and diastolic blood pressure [sitting for 5 minutes] and pulse rate. 
C 
The TCH PI will conduct monthly telephone safety check-ins during the dose-titration period and every 2 to 4.5 months thereafter to discuss AEs and 
concomitant medications. If the subject cannot be reached. TCH will contact the Local Health Center to organize the call. 
D 
Urine test is acceptable. If first dosing visit is scheduled > 28 days after the NIH visit, pregnancy test should be repeated within 7 days prior to the first dosing 
visit  
E 
Chemistry laboratory parameters include HbA1c, creatinine, total bilirubin (direct and indirect if values were above normal ranges), alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, creatine kinase, sodium, potassium, cholesterol, and triglycerides. Those 
tests are to be repeated prior to the first dosing visit only if first dosing visit is scheduled >42 days after the TCH visit.   
F 
Hematology laboratory parameters include hemoglobin, hematocrit, erythrocytes, thrombocytes, and white blood cell count with differential (for an absolute 
neutrophil count, lymphocyte count and monocyte count). Those tests are to be repeated prior to the first dosing visit only if first dosing visit is scheduled > 42 
days after the TCH visit.  
G 
Dipstick urinalysis includes glucose, nitrate, hemoglobin, leukocytes, protein, pH, ketones, and specific gravity. If first dosing visit is scheduled > 42 days 
after the TCH visit, safety labs should be repeated prior to the first dosing visit.  
H 
Miglustat dose initiated at 100 mg QD; dose assess weekly according to titration scheme and subject tolerance. Week 8 is the last permitted time point for 
miglustat dose titration. On PK sample collection days for miglustat measurement at Weeks 1 and 9, the first miglustat dose is administered at the Local Health 
Center / Subject’s Home if there is no Health Center near subject’s home. All other miglustat doses may be administered at home. 
I 
Miglustat will be supplied according to the subject’s MTD. Miglustat accountability will be performed weekly during this time. 
J 
Blood will be obtained at the following nominal time points: pre-miglustat dose (0), 1, 2, 2.5, 3, 4, 6, 8, and 24 hours. Confinement between the 8-hour and 
24-hour time points is not required. Blood drawn for the 24-hour time point should be done prior to the Day 2 miglustat morning dose. 
K 
Blood will be obtained at the following nominal time points: pre-miglustat dose (0), 1, 2, 2.5, 3, 4, 6, and 8 hours. Subsequent daily miglustat doses, if 
applicable will be administered after PK sampling is completed and may be taken at home. 
L 
A seizure diary will be completed all along the study and will be shared as collected with TCH. 
 
 
 
 

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Table 1-4 Maintenance Period – Local Health Center/Subject’s Home Visit and Phone Calls (Week 10 Through End of 
Treatment) 1/2 
 
Maintenance Period 
Week 10 
±2 days 
 Visit 
Week 12 ±2 
days 
Phone 
Week 14 ±4 
days 
Visit 
Week 18 
±1 Week 
Phone 
Week 22 ±1 
Week 
Visit 
Week 30 ±1 
Week 
Phone 
Week 34 ±1 
Week 
Visit 
Week 38 
±1 Week 
Phone 
Week 42 
±1 Week 
Visit 
Week 46 
±1 Week 
Phone 
General assessments 
 
 
 
 
 
 
 
 
 
Vital signs A 
X 
 
X 
 
X 
 
X 
 
X 
 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone follow-up by PIB 
 
 
X 
 
X 
 
X 
 
X 
 
Abbreviated physical examC 
X 
 
X 
 
X 
 
X 
 
X 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Pregnancy testD 
X 
 
X 
 
X 
 
X 
 
X 
 
Study Drug Administration 
 
 
 
 
 
 
Miglustat doseE 
 
Miglustat suppliedF, E 
X 
 
X 
 
X 
 
X 
 
X 
 
Efficacy assessments 
 
 
 
 
 
 
 
 
 
Seizure diary issuedG 
X 
 
X 
 
X 
 
X 
 
X 
 
Seizure diary collectedG 
X 
 
X 
 
X 
 
X 
 
X 
 
A  Vital signs include systolic and diastolic blood pressure [sitting for 5 minutes] and pulse rate.  
B 
The PI will conduct telephone safety check-ins  between site visits to discuss concomitant medications, AEs and in case of premature discontinuation 
C 
An abbreviated physical examination will assess only the general appearance of the patient and is only required when a complete exam is not indicated. 
D 
Female with childbearing potential only. Urine test is acceptable. 
E 
Miglustat dose may be administered at home. Subjects should take their daily miglustat dose as usual. 
F 
Miglustat will be supplied according to the subject’s MTD. Miglustat accountability will be performed at each in-person visit 
G 
Seizure diaries will be completed and will be collected by the Local Health Center where the new seizure diary will be issued. 
 

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Table 1-5 Maintenance Period – Local Health Center/Subject’s Home Visit and Phone Calls (Week 10 Through End of 
Treatment) 2/2 
 
Maintenance Period 
 
W58 
±1 
week 
Visit 
W64 
±1 
week 
Phone 
W70 
±1 
week 
Visit 
W76 
±1 
week 
Phone 
W82 
±1 
week 
VisitA 
W88 
±1 
week 
PhoneA 
W94 
±1 
week 
VisitA 
W100 
±1 
week 
PhoneA 
Premature 
discontinuation 
(before early access 
program start) 
General Assessments 
 
 
 
 
 
 
 
Complete Physical exam 
 
 
 
 
 
 
 
 
X 
Vital signsB 
X 
 
X 
 
X 
 
X 
 
X 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone follow-up by 
PI C 
X 
 
X 
 
X 
 
X 
 
X 
Abbreviated 
physical 
examD 
X 
 
X 
 
X 
 
X 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Pregnancy test E 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry, hematology, 
urinalysis F 
 
 
 
 
 
 
 
 
X 
Study Drug administration 
 
 
 
 
 
 
 
Miglustat dose  
 
Miglustat supplied G 
X 
 
X 
 
X 
 
X 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
Seizure diary issued H 
X 
 
X 
 
X 
 
X 
 
 
Seizure diary collected 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Note: Weeks 26, 52, and 78have site visits as outlined in Table 1-3.  

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A 
Additional phone calls and visits may be performed according to the duration of treatment after Week 78 Visit and up to the switch to the early access program 
B 
Vital signs include systolic and diastolic blood pressure [sitting for 5 minutes] and heart rate. 
C 
The PI will conduct telephone safety check-ins every three months between site visits to discuss concomitant medications, AEs and in case of premature 
discontinuation. 
D 
An abbreviated physical examination will assess only the general appearance of the patient and is only required when a complete exam is not indicated 
E 
Female only. Urine test is acceptable. 
F 
Chemistry laboratory parameters include HbA1c, creatinine, total bilirubin (direct and indirect if values were above normal ranges), alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, creatine kinase, sodium, potassium, cholesterol, and triglycerides. 
Hematology laboratory parameters include hemoglobin, hematocrit, erythrocytes, thrombocytes, and white blood cell count with differential (for an absolute 
neutrophil count, lymphocyte count and monocyte count). Dipstick urinalysis includes glucose, nitrate, hemoglobin, leukocytes, protein, pH, ketones, and 
specific gravity. 
G 
Miglustat will be supplied according to the subject’s MTD. Miglustat accountability will be performed during each in-person visit. 
H 
Seizure diaries will be completed and will be collected by the Local Center where the new seizure diary will be issued.  
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AUC0-8hr 
Area under the concentration-time curve from time 0 to 8 hours 
AUC0-∞ 
Area under the concentration-time curve extrapolated to infinity  
AUC0-t 
Area under the concentration-time curve calculated to the last observable 
concentration at time t 
AUC0-tau 
Area under the concentration-time curve calculated for the dosing interval 
BBDF 
Beyond Batten Disease Foundation 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum plasma concentration 
CSF 
Cerebral spinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
EAP 
Early Access Program 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOT 
End Of Treatment  
ET 
Early Termination 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
IV 
Intravenous 
LDL 
Low density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 

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Abbreviation 
Definition 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
NCL 
Neuronal ceroid lipofuscinoses 
NIH CC 
National Institutes of Health Clinical Center 
OCT 
Optical coherence tomography 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SPECT 
Single-photon emission computed tomography 
T1/2 
Elimination half life 
TCH 
Texas Children’s Hospital 
TEAE 
Treatment-emergent adverse event 
TID 
Three times daily 
Tmax 
Time to maximum plasma concentration 
UBDRS 
Unified Batten Disease Rating Scale 
URMC 
University of Rochester Medical Center 
US 
United States 
WHO 
World Health Organization 
 
 

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2 
INTRODUCTION 
2.1 
Rationale 
The Sponsor has identified a novel therapy that it believes holds particular promise for the 
treatment of CLN3 disease. The Sponsor’s product, Batten-1 is oral miglustat.  
Miglustat, an iminosugar, has been shown to inhibit the harmful accumulation of gangliosides 
implicated in disease pathogenesis of related lysosomal storage diseases Type 1 Gaucher Disease 
and Niemann-Pick Type C disease. Lesser-known anti-inflammatory effects have also been 
reported (Dechecchi et al., 2008). Miglustat is approved in the United States (US) and in the 
European Union (EU) for adult Type I Gaucher Disease at doses of 300mg/d. Miglustat is also 
approved in the EU for treatment of adult and pediatric patients with Niemann-Pick Type C 
Disease at doses up to 600mg/d. Over 18 years of safe use is available for miglustat, whose most 
common adverse effect is gastro-intestinal which can be mitigated with changes in diet and appears 
to lessen over time (Pineda et al., 2009).  
Patients with CLN3 disease also have increased systemic accumulation of gangliosides and 
chronic neuroinflammation (Bosch & Kielian.2015) and therefore, may benefit from daily 
miglustat therapy. These assertions are supported by studies in CLN3 animal models and in vitro 
cerebellar cells from those models demonstrating significant increases in GM3 ganglioside levels 
over wild-type, which are significantly reduced by treatment with miglustat as well as a reduction 
of globoside Gb3, Gb4, and ganglioside GM1 accumulation in vitro (Somogy et al., 2018 and 
Lloyd-Evans & Waller-Evans, 2020). This accumulation of Gb3 appears to be key in the 
pathophysiology of the disease with this element being recently confirmed by Soldati et al. (2021).  
In the previous versions of the protocol (Version 1 to Version 3.1), the combination of miglustat 
and trehalose was considered as the Investigation Products. Recent additional preclinical data 
strongly indicate that the therapeutic effect in CLN3 can be obtained with miglustat alone, as 
presented below. 
In a model of Batten disease, in Cln3–/– mice, microglial and astrocyte activation were analyzed 
along with apoptosis (BBDF-04042022 internal report). In this model, Cln3–/– mice display 
astrocytosis and microglial activation in brain regions where neuronal loss is subsequently most 
pronounced. These regions include thalamic nuclei that relay somatosensory information to the 
primary somatosensory cortex (ventral posterior medial and lateral nuclei, VPM/VPL), the 
somatosensory barrelfield cortex (S1BF), the primary visual (V1) cortex, and the dorsolateral 
geniculate (dLG). 
 
Previous work had established that astrocyte and microglial activation may be causally related to 
neuronal loss ((Parviainen et al, 2017). Thus, quantification of glial activation is an appropriate 
proxy for disease state. Finally, brain atrophy is among the hallmarks of Batten disease and is the 
result of progressive neurodegeneration. Cln3–/– mice recapitulate this feature, which can be 
observed as a global loss of brain weight with age, or decreased neuronal number in various regions 
including the thalamus, cerebellum, and the somatosensory regions of the cortex (BBDF-
04042022). 
Miglustat alone and the combination of trehalose and miglustat similarly exerted their beneficial 
effects on the pathological hallmarks of Batten disease. Trehalose treatment given alone also 

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significantly reduced microglial and astrocytic activation as well as apoptosis but only in a limited 
number of brain regions (BBDF-04042022). 
Miglustat alone has a clear modifying action on Cln3–/– mouse neuropathology similar to the 
combination of miglustat and trehalose, and that is significantly stronger than that of trehalose 
alone. Miglustat is currently approved for the treatment of Gaucher disease and Niemann-Pick 
type C in various countries, based on its potent effects as an inhibitor of the synthesis of 
glycosphingolipids, molecules that accumulate in these and other lysosomal storage diseases. 
Table 2-1 - Activity of miglustat, trehalose and their combination on Cln3–/– mouse 
neuropathology 
 
Microglial activation 
Astrocyte activation 
Apoptosis 
VPM/ 
VPL 
dLG 
S1BF 
V1 
VPM/ 
VPL 
dLG 
S1BF 
V1 
VPM/ 
VPL 
dLG 
S1BF 
V1 
Trehalose 
- 
- 
 
- 
- 
 
- 
- 
- 
 
- 
 
Miglustat 
 
 
 
- 
 
 
- 
- 
 
 
- 
 
Combination 
trehalose/ 
miglustat 
 
 
 
- 
 
 
- 
- 
 
 
- 
 
- : no effect,  : significant decrease. 
The potent neuroprotective effects exerted by miglustat suggest that certain biochemical products 
of the glycosphingolipid pathway may also accumulate in Batten disease and contribute to its 
pathogenesis. Treatment with miglustat alone presented the same impact on Cln3–/– mice 
phenotype as the combination of miglustat and trehalose. These results are summarized in the table 
above. 
2.2 
Background 
First described in 1826, juvenile Batten (CLN3) disease is an ultra-rare, genetic, lysosomal storage 
disease that primarily affects the nervous system and, is fatal. Children with CLN3 disease develop 
normally, even excelling in school until ages 4-7 years, when progressive vision loss becomes 
noticeable (Bozorg et al., 2009 and Aberg et al., 2011). Concomitantly, or shortly thereafter, 
parents report personality changes and behavioral issues. Typically, within 2–3 years after 
symptom onset, total vision loss occurs, and seizures begin. This is followed by declining speech, 
progressive loss of motor coordination, and cardiac involvement. Psychosis, hallucinations or 
dementia can appear anytime during the disease. Eventually, children become wheelchair-bound, 
then bed-ridden, and die in their late teens or early twenties (Bozorg et al., 2009, Aberg 2001, and 
Ostergaard 2016).  
CLN3 disease is not preventable, and although a cure is desperately needed for these patients, no 
treatment that can slow, halt or reverse the symptoms of CLN3 disease has been identified to date. 
Therefore, there is a significant unmet medical need for meaningful treatment options for these 
patients. 
On a molecular level, CLN3 disease is the result of loss-of-function mutations in the CLN3 gene 
and the absence or dysfunction of its gene product, CLN3 protein. This disease is characterized by 
lysosomal accumulation of fatty, granular autofluorescent material (ceroid, lipofuscin) within cells 
of the brain and all other tissues of the body. The normal function of CLN3 protein is unknown; 

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however, CLN3 deficiency has been linked to defects in microtubule-dependent antero- and 
retrograde trafficking, autophagy, and endocytosis (Cotman & Staropoli, 2012 and Tecedor et 
al., 2013).  
Most cases of CLN3 disease are the result of a 966 bp deletion removing exons 7 and 8 from the 
transcript. Approximately 74% of patients are either homozygous for this deletion or heterozygous 
for the deletion with a less common mutation in their other CLN3 allele. Carriers of CLN3 
mutations have no known CLN3-type disease or susceptibility to other diseases. It is possible there 
may be common disease pathophysiology between neuronal ceroid lipofuscinoses (NCLs) and 
late-onset conditions. The symptoms of Parkinson disease and parkinsonism, such as bradykinesia 
and rigidity, are known to occur in CLN3 disease (Jarvela et al., 1997). Functional evidence for 
nigrostriatal pathology in these patients has been demonstrated via single-photon emission 
computed tomography (SPECT) imaging using the labelled cocaine analogue [131I]β-CIT 
(Ruottinen et al., 1997 and Aberg et al., 2000). Extrapyramidal symptoms of juvenile NCL have 
been shown, in some cases, to respond to antiparkinsonian therapy (Aberg et al., 2001).  
CLN3 protein has been shown in vitro to exhibit anti-apoptotic properties in response to serum 
starvation, and proapoptotic agents vincristine, etoposide and staurosporine (Puranam et al., 1999). 
In cancer tissues, CLN3 mRNA and protein are overexpressed in glioblastoma, neuroblastoma, 
prostate, ovarian, breast, and colon cancer cell lines. Indeed, CLN3 expression is 22%–330% 
higher in 8 of 10 solid colon tumors when compared to the corresponding normal colon tissue 
control (Rylova et al., 2002, An Haack et al., 2011, and Zhu et al., 2014). Together, these results 
suggest that the protective function of CLN3 is lost in CLN3 disease.  
The pathological hallmark of CLN3 disease is the accumulation of cellular waste in lysosomes, 
resulting in a block in autophagic flux (Fossale et al., 2004 and Cotman & Staropoli, 2012) which 
is amplified by chronic neuroinflammation (Nixon & Yang 2012). Recent preclinical evidence 
suggests that these defects in autophagy may underlie the enhanced levels of α-synuclein 
oligomers and gangliosides GM1, GM2, and GM3 (Lloyd-Evans & Waller-Evans 2020), as well 
as reduced levels of sphingomyelin and autophagy observed in cellular models of CLN3 disease 
(Kang et al., 2014). 
Further details can be found in the Investigator's Brochure (Batten-1 Edition 3.0) which contains 
comprehensive information on the investigational product. 
2.3 
Risk-Benefit Assessment 
2.3.1 Anticipated Risks 
This protocol involves the use of an investigational drug with limited data in animal models and 
in humans with the disease thus, there may be risks that cannot be identified. There is no available 
data on its reproductive toxicity and its effect on pregnant/lactating women. Thus, all participants 
will use effective contraceptive measures and all women of childbearing potential will undergo a 
pregnancy test to exclude those identified as being pregnant from enrolling in the study. 
2.3.1.1 Miglustat 
Miglustat has been shown, in both clinical trials and real-world use, to cause gastrointestinal 
adverse events (diarrhea, abdominal pain/discomfort, flatulence) due to inhibition of intestinal 
disaccharide enzymes (see Section 2.2). Transient weight loss is often observed and has been 

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attributed to carbohydrate malabsorption and a corresponding decrease in effective caloric intake. 
These side effects typically are seen during the initiation of miglustat dosing and resolve over time 
with continued use. A low-carbohydrate diet, initiated at the time or just prior to initiation of 
miglustat dosing, has been shown to improve gastrointestinal tolerability of miglustat and lessen 
the magnitude of weight loss. Taking miglustat on an empty stomach (between meals) and an 
initial dose escalation of miglustat are also recommended by some physicians as another factor in 
reducing the severity of side effects, although the efficacy of these measures has not been tested 
in clinical trials (Belmatoug at al., 2011).  
If a low carbohydrate diet (Section 13.1) does not sufficiently prevent diarrhea during miglustat 
dose escalation, miglustat dose adjustments or antidiarrheal treatment (e.g., loperamide) may be 
considered.  
In clinical trials of people with Gaucher disease, cases of peripheral neuropathy have been reported 
in 3% of patients treated with miglustat. All subjects receiving miglustat treatment should undergo 
baseline and repeat neurological evaluations at approximately 6-month intervals. Subjects who 
develop symptoms of peripheral neuropathy such as pain, weakness, numbness and tingling should 
have a careful re-assessment of the risk/benefit of miglustat therapy, and cessation of treatment 
may be considered (Actelion Pharmaceuticals 2017). 
Approximately 30% of people with Gaucher disease have reported tremor or exacerbation of 
existing tremor on miglustat treatment. These tremors were described as an exaggerated 
physiological tremor of the hands. Tremor usually began within the first month of therapy and in 
many cases resolved between 1 to 3 months during treatment. Reduce dose to ameliorate tremor 
or discontinue treatment if tremor does not resolve within days of dose reduction 
(Actelion Pharmaceuticals 2017). 
2.3.1.2 Study Procedures 
Blood draws 
Blood draws are associated with discomfort, bruising, vasovagal syncope, and, rarely, bleeding 
and infection.  
 
ECG 
The adhesive used to conduct electrocardiograms may result in local irritation, as well as 
discomfort when the contacts are removed. 
 
MRI 
MRI may cause anxiety, due to the noise of the machine and the enclosed space. If sedation is 
used, there are additional risks associated with the use of the specific sedative agent. Imaging 
procedures carry the possibility of incidental findings. In the event of incidental findings on the 
MRI, results will be shared with the patient’s primary care physician for appropriate follow-up.   
 
Ophthalmic Evaluation 
Iris dilatation can make patients transiently sensitive to light. If done while awake, patients will be 
asked to remain still for approximately 15 minutes, which may be uncomfortable. If done under 
sedation, patients may experience drying of the eyes.  This will be minimized by application of 
eye drops lubrication.   
 

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Lumbar puncture 
The risks associated with lumbar puncture include headache, backache, infection, bleeding, and 
medullary herniation. Up to one third of adults experience headache after a lumbar puncture. In 
NIH CC experience, post-lumbar puncture headaches occur in ~5% of pediatric cases. Most are 
very transient. This is thought to be due to CSF leakage at the site of the procedure. To minimize 
this, small bore needles will be used, and the bevel of the needle will be kept parallel to the fibers 
of the ligamentum flavum if using a cutting needle. Atraumatic needles may also be used. If 
possible, the patient will be asked to lie flat for 1–2 hours after the procedure. Analgesics, such as 
Tylenol, will also be used if clinically indicated. Rarely, headaches can persist for a prolonged 
period of time. In these cases, the CSF leakage is treated by a “blood patch”. 
The lumbar puncture will be performed as a sterile technique to minimize the possibility of 
infection. Medullary herniation is a complication that is encountered when raised intracranial 
pressure is present. This is unlikely in individuals with CLN3 disease; if clinically indicated, 
neuroimaging will be done to exclude the rare possibility of an intracranial mass. The lumbar 
puncture will not be done in a child with marked spinal deformity or evidence of an overlying skin 
infection.  
 
Sedation 
Young and impaired patients who cannot cooperate with the MRI study, ophthalmology exam, or 
lumbar puncture procedure may be sedated. If possible, procedures for blood drawing will be 
coordinated or the IV catheter placed for sedation will be used for blood drawing. The major risk 
associated with sedation is respiratory compromise. 
In order to minimize risk, sedation will be performed by an NIH CC anesthesiologist. An 
anesthesiologist experienced with pediatric patients will perform the sedation if indicated due to 
patient’s size, age, or medical condition. Facilities for maintenance of a patent airway, artificial 
ventilation, and circulatory resuscitation will be immediately available and ready for use. 
Depending upon the clinical situation, as judged by the anesthesiologist, patients may receive 
oxygen via nasal cannula or have their airway protected using either a laryngeal airway or by 
intubation. The anesthesiologist will also select the anesthetic agent used based on their clinical 
judgment. Criteria used in making this judgment include patient age, size, history of reflux, history 
of difficult airway management, and overall medical status. Another risk of sedation is aspiration. 
If clinically indicated, intubation will be used to protect against aspiration. 
As fasting is required prior to sedation, study participants may develop symptoms relating to this 
(including but not limited to hypoglycemia and hypovolemia) if oral intake is inadequate following 
recovery from sedation. Death is a rare complication of sedation when performed by a licensed 
anesthesiologist under controlled conditions. 
The effects on fetuses of repeated or prolonged anesthesia are unclear. Thus, a urine or serum 
pregnancy test will be done in female patients 10 years of age or older prior to sedated procedures. 
 
General 
Study visits involve an associated inconvenience and are time-consuming. Participation in any 
drug study may create anxiety, as the effects of the drugs in the study population are unknown. 
There is a risk to privacy, due to the use of personal health information for study purposes.   

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2.3.2 Anticipated Benefits 
If miglustat is effective in reducing the aggregation of compounds that lead to the pathology and 
symptoms of CLN3 disease, potential benefits include slowing or halting the progression of 
disease symptoms, which may significantly improve the quality of life for individuals with CLN3 
disease. 
2.3.3 Summary 
Given the progressive and ultimately fatal nature of CLN3 disease and the lack of available 
treatments for the condition, the potential for Batten-1 to ameliorate the cellular accumulation of 
compounds that are believed to cause the progressive symptoms of the disease outweighs the risks 
associated with the known risks of the study drugs. While the study involves greater than minimal 
risk to potential subjects, it also provides the prospect of direct benefit to study subjects.   

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3 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To assess the safety 
and tolerability of 
the 
Batten-1 
treatment 
regimen 
over 
the 
study 
period  
• Incidence of treatment-emergent adverse events (TEAEs) 
and serious adverse events (SAEs); changes in baseline in 
clinical laboratory tests (hematology, chemistry, and 
urinalysis), 12-lead electrocardiogram (ECG) findings, slit 
lamp evaluation, vital signs (heart rate and systolic and 
diastolic blood pressure) as well as physical and 
neurological examinations 
Secondary 
 
• To 
assess 
the 
pharmacokinetics 
(PK) of miglustat in 
subjects with CLN3 
disease 
• Week 1 (first dosing: Maximum plasma concentration 
(Cmax), Time to Cmax (Tmax), area under the 
concentration-time curve calculated to the last observable 
concentration at time t (AUC 0-t), area under the 
concentration-time curve extrapolated to infinity (AUC0-
∞), elimination half-life (T1/2) 
• Week 9 Repeated dose (steady state): Cmin, Cmax, Tmax, 
AUC 0-8hr 
• To assess the effect 
of 
the 
Batten-1  
treatment 
regimen 
on the longitudinal 
progression 
of 
clinical 
signs 
or 
symptoms of CLN3 
disease. 
• Unified Batten Disease Rating Scale (UBDRS)  
• Seizure frequency (diaries) 
• Vineland 
Adaptive 
Behavior 
Scales, 
Version 
3 
(Communication, Daily Living Skills, Socialization, and 
Motor Skills domains)  
• Ophthalmic assessments including visual acuity, visual 
fields (if applicable), and optical coherence tomography 
(OCT) 
• Magnetic resonance imaging (MRI) 
Exploratory 
 
• To assess potential 
biomarkers of CLN3  
• Measure biomarkers in cerebrospinal fluid (CSF), blood  and 
urine.  

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4 
OVERALL DESIGN AND PLAN OF THE STUDY 
4.1 
Overall Design 
This is an open label study in approximately 6 subjects in 2 centers to assess the safety, PK, and 
efficacy of the maximum tolerable dose (MTD) of oral miglustat (100 mg once daily [QD] to 
200 mg 3 times daily [TID]) in subjects ≥ 17 years of age with CLN3 disease..  
The study sites are Texas Children’s Hospital (TCH) and National Institutes of Health Clinical 
Center (NIH CC): 
• Screening, enrollment, and end-of-treatment visits for follow-up safety assessments will 
be conducted by TCH. Eligibility will be confirmed by TCH after all inclusion/exclusion 
criteria are assessed; enrollment decision will be communicated to subject via telephone 
call by TCH. If the subject is eligible, the study staff will schedule NIH CC baseline visit. 
TCH will also review all subject safety data throughout the duration of the study.  
• Baseline, every 6 months visit for efficacy assessments will be conducted at NIH CC. 
• 
Additional safety assessments will be performed at the Local Health Center / Subject’s 
Home and at the NIH CC as per protocol. 
This study includes a dose-titration period of 9 weeks.  
Once the dose titration and PK sampling period is completed, subjects will continue their MTDs 
during the maintenance period. Temporary or permanent dose reductions for tolerability are 
permitted at any time during the remainder of the study in the dose increments shown in 
Section 6.2. As not all subjects will have the same duration of treatment, additional safety phone 
calls and visits  will be organized as need at regular timepoints for patients with longer duration of 
treatment.  
Safety will be assessed at all study visits, and safety labs will be collected at baseline, during 
titration at Week 6 and every 6 months during maintenance phase. The TCH Principal Investigator 
(PI) will also conduct monthly telephone safety checks during the dose-titration period and every 
2 to 4.5 months calls thereafter to discuss adverse events (AEs).   
Efficacy assessments include UBDRS; seizure frequency (diary); Vineland-3; ophthalmic 
assessments including visual acuity, visual field (if feasible), and retinal thickness using OCT; and 
volumetric assessments using MRI. They will be assessed at baseline and during the maintenance 
period. Baseline OCT will be obtained in all study participants.  In those participants with no light 
perception vision, dense cataracts, or other ophthalmologic findings that produce significant 
artifacts in the OCT images, OCT imaging will not be repeated.  
Blood, urine and cerebrospinal fluid biomarkers of neurodegeneration will also be assessed as 
exploratory endpoints of treatment activity. 
In case of any event precluding safe travel by participants to NIH after the baseline visit, 
evaluations could be done at the Local Health Center/ Patient’s Home (labs, ECG (if feasible), 
physical exam, vital signs, weight) or via remote methods (history, UBDRS, Vineland-3, adverse 
events, concomitant meds, seizure diary) or be deferred (+/- 1 month: neurological exam, 
ophthalmology exam, MRI, lumbar puncture). 
After the Week 78 efficacy assessment, patients will continue to be treated with miglustat until 
they can be included, if they wish to continue to receive the treatment, in the early access 
program. 

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4.2 
Rationale for Study Design 
The current study is designed to evaluate the safety and pharmacokinetics of the Batten-1 regimen 
for the treatment of CLN3 disease using up-titration to MTDinvestigational drug. Given the rarity 
of the disease an open-label design in a small subject sample was chosen for feasibility reasons. 
4.3 
Justification for Dose 
Miglustat is approved by the EMA for treatment of a related lysosomal storage disorder, Niemann-
Pick type C disease, in adult and pediatric subjects. The dose and dosing regimen for adults and 
pediatric subjects 12 years of age and older is 200 mg TID (Janssen Cilag 2020). Accordingly, 
Batten-1 will use the same dose/dosing regimen as for Niemann-Pick type C disease. 
4.4 
End of Study Definition 
End of Study is defined as the last subject’s last visit in the study. 

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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible to participate in the study. 
1. 
Have provided informed consent by subject or parent/legal guardian/legally 
authorized representative (as appropriate). 
2.  
Are males or females ≥ 17 years of age at the time of screening 
3. 
Have genetically confirmed diagnosis of syndromic CLN3 disease with EITHER: 
A. Two pathogenic mutations in the CLN3 gene, OR 
B. One confirmed pathogenic AND one variant of unknown significance, OR 
2 variants of unknown significance, PLUS secondary confirmation with 
evidence of characteristic inclusions on electron microscopy 
AND characteristic clinical course. 
There is no restriction on the specific CLN3 mutations for eligibility to enroll in the 
study. The mutations will be recorded in the electronic case report form (eCRF) for 
potential use in determining if CLN3 genotype is associated with tolerability and/or 
effectiveness of Batten-1 therapy. 
4. 
Male and female participants must use a highly effective method of contraception 
and must continue for the duration of the trial (and for 30 days after the end of 
treatment). 
Appropriate methods of contraception are in appendix 6. 
5. 
Are able to complete study assessments (subject or caregiver) and return to the 
clinic as scheduled 
5.2 
Exclusion Criteria 
Individuals who meet any of the following criteria are not eligible to participate in the study. 
1. 
Have a medical condition that in the opinion of the PI would interfere with the safety 
assessments or increase the subject’s risk of AEs 
2. 
Use of any therapy (approved, off-label, or unapproved) intended to modify the 
course of any neuronal ceroid lipofuscinosis disease, including but not limited to 
flupirtine or flupirtine derivatives, cerliponase alfa (Brineura) 
3. 
Have, in the opinion of the PI, a clinically significant abnormality in their clinical 
laboratory values (hematology, chemistry, or urinalysis) at screening that would 
preclude their participation in the study 
4. 
Have a known allergy or hypersensitivity to miglustat, or any component of the 
study drug 
5. 
Have a severe renal disease (creatinine clearance < 30 ml/min/1.73 m2) 
6. 
Have a history of substance abuse or alcohol abuse within 2 years before screening 

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7. 
Have a medical history of HIV, hepatitis B, hepatitis C, or positive results at 
screening 
8. 
Have any active malignancy of any type except for non-melanoma skin cancer 
9. 
Have a medical history of major mental illness that, in the opinion of the PI may 
affect the ability of the subject to participate in the study. Institutionalized subjects 
are not eligible for participation 
10. 
Have received gene therapy intended to modify the course of CLN3 disease 
11. 
Have been exposed to any miglustat or investigational agent, including but not 
limited to,  flupirtine or flupirtine derivatives, within 30 days or 5 half-lives 
(whichever is longer) prior to check-in for the Week 1 visit, or is scheduled to 
receive an investigational device or drug (other than test product) during the course 
of the study 
12. 
Participation in another interventional study during the last three months before 
screening 
5.3 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of an 
acute or reversible medical finding may be rescreened.. Rescreened participants will be assigned 
with a different participant number. 
 
5.4 
Discontinuation of Study Intervention and Participant Discontinuation / 
Withdrawal 
5.4.1 Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). 
If study intervention is definitively discontinued, the participant will perform an early termination 
visit at the NIH CC for efficacy assessments as soon as this visit can be organized, and an end of 
study visit at TCH 30 days after the last dosing. 
If not possible, a remote visit could be organized via telemedicine for applicable evaluations or at 
least a phone contact will be established with the participant or the caregiver to collect safety 
information (AEs). See the schedule of activities for data to be collected at the time of 
discontinuation of study intervention and follow-up for any further evaluations that need to be 
completed. In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further receipt of 
study intervention or also from study procedures, and/or future collection of additional 

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information. Participants can continue their participation in the NIH cohort study and will continue 
to be assessed. 
5.4.2 Participant Discontinuation 
The participation of an individual subject may be discontinued prematurely for reasons such as: 
• Any condition which in the opinion of the investigator no longer permits safe participation in 
the study, in particular, if a participant develops a CTCAE Grade 3 or higher (See section 
7.1.1.1). Participants who develop symptoms such as numbness and tingling should have a 
careful re-assessment of the risk/benefit of therapy and cessation of treatment may be 
considered. 
• Subject becomes pregnant 
• Lack of study compliance 
A subject may discontinue participation in the clinical study at his/her own request at any time 
without stating a reason.  
At the time of discontinuing from the study, if possible, an early termination visit and a 30-day 
end of study visit should be conducted, as shown in the schedule of activities. If not possible, a 
remote visit could be organized via telemedicine for applicable evaluations or at least a phone 
contact will be established with the participant or the caregiver to collect safety information (AEs).  
See schedule of activities for data to be collected at the time of study discontinuation and follow-
up and for any further evaluations that need to be completed. 
The reason for withdrawal of the subject must be documented by the investigator together with all 
data collected until the day of premature study discontinuation including laboratory results and 
assessment of AEs.  
Subjects who withdraw or are withdrawn from the study before exposure to the study drugs or 
during the titration period may be replaced. 
If a participant withdraws from the study, he/she may request destruction of any remaining samples 
taken and not tested, and the investigator must document any such requests in the site study records 
and notify the sponsor accordingly. If the participant withdraws from the study and also withdraws 
consent for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data collected 
before such withdrawal of consent. Lack of completion of all or any of the withdrawal/early 
termination procedures will not be viewed as protocol deviations so long as the participant’s safety 
was preserved. 
5.4.3 Lost to follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the site for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and advise the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the subject wishes to and/or should continue in the study. 

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• In cases in which the subject is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.  
5.5 
Temporary discontinuation 
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. For all temporary intervention discontinuations, duration should be recorded by 
the Investigator in the appropriate pages of the eCRF. 
5.6 
Lifestyle Considerations 
If the low carbohydrate diet (section 13.1) does not sufficiently prevent diarrhea during miglustat 
dose escalation, miglustat dose adjustments and/or antidiarrheal treatment (e.g., loperamide) may 
be considered.  
 

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6 
STUDY INTERVENTION 
6.1 
Identity 
Batten-1 is an oral miglustat capsule (100 mg). Information about the investigational product is 
presented in Table 6-1. 
Table 6-1 Identity of Investigational Product 
Intervention Name 
Miglustat  
Type  
Drug  
Dose Formulation 
Dry  
Unit Dose Strength(s) 
100 mg  
Dosage Level(s) 
From 100 mg QD to 200 TID 
Route of Administration 
Oral 
Excipients 
Magnesium stearate  
Gelatine 
Titanium dioxide (E171)  
Black iron oxide (E172)  
Potassium Hydroxide Shellac 
Propylene glycol (E1520)  
Manufacturer  
Delpharm 
6.2 
Administration 
The proposed dosing regimen is a daily oral miglustat (MTD, up to 200 mg TID). 
o Subjects will be dispensed miglustat at Week 1 and dosing will be escalated as 
presented in Table 62. If a subject has not reached the maximum dose (600 mg/d) 
by Week 8, the Week 8 dose will be subject’s MTD.  
The appropriate miglustat doses will be distributed either by the Local Health Centers at these 
visits or directly shipped at patient’s home. Appendix 8 provides the details of the procedure for the 
IPs home administration. 
Once the dose titration and PK sampling period is completed, subjects will continue their MTDs 
during the maintenance period. Temporary or permanent dose reductions of miglustat for 
tolerability are permitted at any time during the maintenance period of the study in the dose 
increments shown in Table 6-2 (miglustat dose escalation).  
6.2.1 Miglustat 
A supply of miglustat capsules will be provided to subjects/caregivers to administer orally. If 
subjects cannot swallow miglustat capsules whole, the capsules may be opened, and the contents 
mixed with unsweetened fruit juice and consumed immediately. The contents of the capsule should 
not be crushed. 
Table 62 Miglustat Dose Escalation 
Dose Escalation Step 
Morning (8 AM) 
Afternoon (2 PM) 
Evening (8 PM) 
Step 1  
X 
X 
100 mg 

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Dose Escalation Step 
Morning (8 AM) 
Afternoon (2 PM) 
Evening (8 PM) 
Step 2 
100 mg 
X 
100 mg 
Step 3 
100 mg 
100 mg 
100 mg 
Step 4 
100 mg 
100 mg 
200 mg 
Step 5 
200 mg 
100 mg 
200 mg 
Step 6 
200 mg 
200 mg 
200 mg 
 
Treatment with miglustat will begin at a dose of 100 mg QD. If the initial dose of miglustat is 
tolerated then the dose will be increased weekly until the MTD for a subject is reached. The dose 
increment is 100 mg. If needed for tolerability reasons, a dose may be repeated for 1 or more weeks 
prior to increasing. If a dose is not tolerated (based on the occurrence of TEAEs and at the 
discretion of the TCH PI), the dose may be adjusted downward to the previous dose. Dose increases 
may resume if there is time left in the titration scheme and at the discretion of the TCH PI; 
otherwise, this lower dose becomes the subject’s MTD. 
6.3 
Packaging, Labelling and Storage 
Miglustat will be supplied by the sponsor according to all local legal requirements. Study drug will 
be labelled in accordance with applicable regulatory requirements.  
Miglustat will be provided as commercial product in boxes containing several blisters.  
All study drug supplies must be stored in accordance with the manufacturer’s instructions 
(< 30°C). Until dispensed to the subjects, the study drug will be stored in a securely locked area, 
accessible to authorized personnel only. 
Packaging and labelling of study drug will comply with Good Manufacturing Practice (GMP), 
GCP rules, Annex 13, and country specific regulatory requirements; this information will be 
available in the local language. 
6.4 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label, single-arm  study. All subjects will receive miglustat. Drug Accountability 
The Local HealthCenter is responsible for maintaining accurate study drug accountability records 
throughout the study. 
Each dispensing of study drug will be documented in the eCRF. 
The Local HealthCenter is responsible for returning all unused or partially used study drug to the 
Sponsor and must verify that all unused or partially used drug supplies have been returned by the 
subject and that there is no remaining supplies at the Local Center / Subject’s Home. 
6.5 
Compliance 
6.5.1 Miglustat 
During the dose-titration period, subjects will be instructed either to bring their miglustat to the 
Local Health Center or to keep it at home in case of visit at Subject’s home. The subject’s 
parent/caregiver will be asked about any missed doses or other deviations from the planned dosing 
schedule, and an assessment (count) or any unused capsules will be performed.  

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Information regarding missed doses/dosing deviations and the result of the unused drug assessment 
will be recorded. 
During the Maintenance Period, subjects will be instructed to bring their miglustat at the time of 
the visit to the Local Health Center and an assessment (count) of any unused capsules will be 
performed. Alternatively, this accountability can be performed at home in case of visits at 
Subject’s Home. 
At each visit to the Local Health Center / Subject’s Home, the subject’s parent/caregiver will be 
asked about any missed doses or other deviations from the planned dosing schedule.  
6.6 
Concomitant Therapy 
Any medication the subject 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. If possible, subjects should try to remain on the pre-
study dose(s) of concomitant medication(s) throughout the study. Any changes in the dosage or 
regimen of a concomitant medication must be recorded in the eCRF. 
At screening, subjects will be asked what medications they have taken during the last 3 months. 
At each subsequent study visit, subjects will be asked what concomitant medications they are 
currently taking. 
6.6.1 Permitted Concomitant Therapy 
Any treatments (including alternative treatments) that the subject is taking to manage symptoms 
at the time of study entry may be continued and must be documented at the time of screening and 
upon any changes to the doses.  
Initiation of new treatments should be avoided if possible. Subjects or caregivers should check 
with the PI before starting any new treatments; any new treatments should be documented at the 
next study visit. 
Antidiarrheal treatments may be allowed in case of a TEAE (e.g., loperamide). 
Participants must use a highly effective method of contraception during the study treatment period 
and until 30 days after end of treatment. 
6.6.2 Prohibited Concomitant Therapy 
The use of any of the following is prohibited at inclusion and during the study: 
• therapy (approved, off-label, or unapproved) intended to modify the course of any neuronal 
ceroid lipofuscinosis disease, including but not limited to flupirtine or flupirtine 
derivatives,cerliponase alfa (Brineura) 
6.7 
Rescue Medication 
Not applicable. 
6.8 
Dose Modification 
Please see Section 6.2.1 for dose escalation instructions for miglustat. 

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6.9 
Treatment of Overdose 
6.9.1 Miglustat 
No information regarding miglustat overdosage is provided in the current FDA-approved labeling 
for Zavesca. However, the EU labeling for Zavesca states the following (Janssen Cilag 2020): 
Symptoms 
No acute symptoms of overdose have been identified. Zavesca has been administered at doses up 
to 3000 mg/d for up to 6 months in HIV-positive subjects during clinical trials. Adverse events 
observed included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have 
also been observed in a similar group of subjects receiving 800 mg/d or higher dose. 
Management 
In case of symptomatic overdose, general medical care is recommended. 
For this study miglustat overdose is defined as >800 mg/d for SAE reporting. 
6.9.2 Intervention After the End of the Study 
An early access program will be proposed to subjects who wish to continue treatment. This  early 
access program will be described in a separate protocol. 
 

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7 
STUDY ASSESSMENTS AND PROCEDURES 
7.1 
Safety Assessments 
Safety will be assessed at all study visits. Safety labs will be collected at Week 6 during miglustat 
titration and every 6 months during maintenance phase. An ECG will be performed at baseline and 
every 6 months. The TCH PI or designated sub-investigator(s) will also conduct monthly telephone 
safety checks during the dose-titration period and every 2 to 4.5 month calls thereafter to discuss 
AEs.  
7.1.1 Adverse Events 
7.1.1.1 Definitions 
Adverse events and laboratory parameters will be graded using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v5, sample of which is provided in 
Appendix 7 (US Department of Health and Human Services, 2017). 
 
Per ICH, an AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. The AE may be any of the following: 
• A new illness 
• An exacerbation of a sign or symptom or the underlying condition or of a concomitant illness 
under treatment  
• Unrelated to participation in the clinical study or an effect of the study medication or 
comparator drug 
• A combination of one or more of the above factors 
No causal relationship with the study medication is implied by the use of the term adverse event. 
Planned or elective surgical or invasive procedures for pre-existing conditions that have not 
worsened are not AEs. However, any complication that occurs during a planned or elective surgery 
is an AE. Conditions leading to unplanned surgical procedures may be AEs.  
When an AE occurs after written consent has been obtained but before the first dose of study drug, 
the AE will be considered a non-treatment emergent AE. An AE that occurs from the time the 
subject receives his/her first dose of study drug until his/her last study visit will be considered a 
treatment-emergent AE regardless of the assessed relationship to the administration of the study 
drug.  
For the recording of pregnancy and relevant laboratory data see Section 7.1.1.2. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence or effect that at any dose: 

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• Results in death 
• Is life-threatening 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect  
• Is another medically important condition  
 
An important medical event that is not immediately life threatening or will result in death or 
hospitalization, but which may jeopardize the subject or may require medical intervention to 
prevent one of the outcomes listed above, should be reported as “serious” as well. 
Medical and scientific judgment should be exercised in deciding whether a case is serious. 
“Occurring at any dose” does not imply that the subject is receiving study drug at the time of the 
event.  
Severity of Adverse Event:  
Severity will be categorized using criteria based on CTCAE v.5:  
 
Grade 1 Mild 
asymptomatic or mild symptom; clinical or diagnostic observation only; intervention 
not indicated 
Grade 2 Moderate 
minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL 
Grade 3 Severe 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated, disabling; limiting self-care ADL 
Grade 4 Life-threatening 
consequences 
Urgent intervention indicated  
Grade 5 death 
Death related to AE 
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. 
Causality of Adverse Event:  
Refers to the relationship of the AE to study drug. Causality will be categorized according to the 
following criteria: 
 
Unrelated: 
A clinical event with no evidence of any causal relationship. 
Unlikely: 
A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 

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Possible: 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
Probable: 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal (de-challenge). 
Re-challenge information is not required to fulfil this definition. 
Definite: 
A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (de-challenge) should be 
clinically plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory re-challenge procedure if necessary. 
 
Outcome of the Event: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal 
Action Taken with Regard to the Event 
• None 
• Study drug dose decreased 
• Study drug withdrawn 
• Subject Temporarily/permanently discontinued from study 
7.1.1.2 Recording Adverse Events 
Period: Subject Screening to the First Administration of Study Drug: Non-treatment emergent 
AEs will be recorded from the time when the subject is screened into the study (date of signature 
of the informed consent) until first administration of study drug.  
Period: First Administration of Study Drug to Subject's Last Study Visit: Thereafter all AEs 
are TEAEs (see Definitions, Section 7.1.1.1) and will be recorded until the end of study visit has 
been performed. 
Period After Last Study Visit: Any SAE occurring after the subject's last study visit that the 
investigator becomes aware of but considered to be related to the study drug will be reported to 
the sponsor. 
If an AE (serious or not) started during the study but did not end before the final follow-up visit, 
the investigator should make a reasonable effort to establish the outcome and the end date. If this 
is not possible, the outcome recorded at the final follow-up visit will be assumed to be the final 
outcome. 

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If an event stops and later restarts, all the occurrences must be reported. Adverse events assessed 
as related to study medication by the investigator and all SAEs must be followed up until 
resolution. 
Signs/symptoms should be documented if a definite diagnosis cannot be established. The 
investigator should attempt to establish a diagnosis of the event based on signs, symptoms and/or 
other clinical information. In such cases, the diagnosis should be documented as the AE and/or 
SAE and not the individual signs/symptoms. If a diagnosis is accompanied by unusual symptoms, 
the diagnosis itself and the symptoms have to be reported separately. 
7.1.1.3 Responsibilities of the Investigator 
Adverse event data should be obtained through observation of the subject, from any information 
volunteered by the subject or caregiver, or through subject or caregiver questioning. The general 
type of question asked could be similar to: “Do you have any health problems?” or “Have you had 
any health problems since your last clinic visit?” 
Adverse events are to be documented/recorded accurately and completely on the AE pages of the 
respective eCRF and in the subject's source data.  
All non-treatment and treatment-emergent AEs will be recorded. 
This is true even if the study drug was not administered according to the study protocol. 
For conditions leading to unplanned surgical procedures the underlying condition, should be 
documented as an AE, but not the procedure.  
Reporting SAEs:  
For AEs that are "serious" (SAEs) additional separate documentation is required using the 
electronic SAE Forms.  
The following variables will be recorded on the electronic SAE Form and on the eCRFs provided 
in accordance to the eCRF completion guidelines:  
• Description of the event, including its duration (date of onset and resolution),  
• Whether the event constitutes a SAE or not (if yes, see event seriousness criteria in 
Section 7.1.1.1) 
• Any action taken (e.g., changes to study treatment, other treatment given and follow up tests) 
• Outcome of the event 
• Investigator’s assessment of causality (the relationship to the study treatment[s] and study 
procedures)  
• Severity  
For all SAEs where important or relevant information is missing, active follow-up should be 
undertaken. 
The assumption of a causal relationship between the study drug/study conduct and the AE is 
irrelevant to the obligation to record AEs and notifying AEs to the Sponsor. 

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For withdrawals due to AEs the eCRF page "Study completion / Study termination Form" and a 
copy of the eCRF AE page needs to be completed and forwarded to Pharm-Olam’s Drug Safety 
Department. 
Overdose needs to be reported to Pharm-Olam’s Drug Safety Department following the criteria 
for SAE reporting. For this study miglustat overdose is defined as > 800 mg/d. 
If additional information is required by the Pharm-Olam’s Drug Safety Department, then as a 
representative of the Sponsor/Pharm-Olam must be granted access to the medical records.  
7.1.1.4 Notifying of Serious Adverse Events 
In the event of an SAE, the investigator must inform the Pharm-Olam’s Drug Safety department 
via e-mail or fax using the SAE report/ eCRF page within 24 hours of the study site being informed 
of the event. At a later date, the Pharm-Olam Safety Contact will report to the Sponsor, the Clinical 
Study Manager, and the Principal Investigator.  
Adverse Event Reporting Contact: 
Pharm-Olam Drug Safety 
E-mail: POISafetyDesk@pharm-olam.com 
For questions regarding SAEs, or to provide information that cannot be provided electronically, or 
to notify the Sponsor of an SAE in the event of technical failure, the investigator should contact 
Pharm Olam’s Drug Safety Department. Contact information will be provided in a separate 
document. 
Investigators or other site personnel should inform Pharm-Olam’s Drug Safety department of any 
follow-up information that becomes available for a previously reported SAE immediately but no 
later than 24 hours of becoming aware of the information. Follow-up reports (as many as required) 
should be completed and faxed or e-mailed following the same procedure above. Any requested 
supporting documentation (e.g., ECG, laboratory results, autopsy report) should be sent to the 
Pharm-Olam’s Drug Safety department. 
Prior to forwarding any personal data for safety reporting, the documents need to be coded in a 
way that keeps the subject's identity confidential (e.g., by using the subject's identification code, 
randomization number, etc.). 
For fatal and life-threatening SAEs, Pharm-Olam’s Drug Safety department will work with the 
investigator to ensure that any additional information is provided by the investigator within 
1 business day. The investigator will ensure that all the necessary information for all other SAEs 
will be provided within the timelines stipulated by the Sponsor when the request for information 
is made. 
If required, the investigator is responsible for informing local Institutional Review Boards (IRBs) 
of safety reports in compliance with applicable regulatory requirements. Copies of all 
correspondence relating to reporting of any safety reports to the IRB should be maintained in the 
Investigator Site File (ISF) / Regulatory Binder.  
The Sponsor’s representative is responsible for fulfilling all obligations regarding notification of 
Regulatory Authorities and IRBs according to applicable regulatory requirements (expedited and 
periodic reporting, e.g., serious unexpected suspected adverse reactions, Development Safety 

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Update Report). In addition, the Sponsor will provide safety information to investigators according 
to the current regulations.  
7.1.1.5 Laboratory Values  
Laboratory values are also defined as AEs if they are outside the normal and if, in the opinion of 
the investigator, they represent a clinically relevant change versus pre-treatment values. 
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). 
7.1.2 Pregnancy 
Occurrence of pregnancy in a subject during a clinical study must be recorded.  
Each pregnancy that starts during the study must be reported by the investigator to Pharm-Olam’s 
Drug Safety department within 24 hours of the investigator’s knowledge of the pregnancy by using 
the Pregnancy Reporting Form. Study treatment should be stopped immediately after being aware 
of the event. Any adverse outcome of the pregnancy must be recorded and notified on the "Drug 
Exposure via Parent Report Form" or SAE Form if this meets SAE reporting criteria. The 
investigator should make any reasonable effort to follow any pregnancy until birth of the child. 
Blood test at baseline then urine test is acceptable. 
7.1.3 Laboratory Parameters 
Laboratory assessments will be performed by a central laboratory. The tests listed in Table 7-1 
will be conducted on samples collected and analyzed by standard laboratory procedures at the time 
points designated on the Schedules of Activities (Section 1.3). Tests that are not done must be 
reported as such on the eCRFs. The total volume of blood drawn per patient for the entire duration 
of the study is planned to be approximately 440 ml.  
Table 7-1 Laboratory Parameters 
Hematology 
 
 
Hemoglobin 
Hematocrit 
Erythrocytes 
Leukocytes 
Differential white blood cell count 
Thrombocytes 
 
 
Biochemistry 
 
 
Creatinine 
Total bilirubin (direct and 
indirect if values were 
above normal ranges) 
HbA1C 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyl transpeptidase 
Creatine kinase 
Sodium 
Potassium 
Cholesterol (total, HDL, LDL) 
Triglycerides 
 

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Urine  
 
 
Glucose 
Nitrate 
pH 
Hemoglobin 
Leukocytes 
Specific gravity 
Protein 
Ketones 
Other Tests 
 
 
HIV A 
Hepatitis B A 
Hepatitis C A 
Pregnancy test in women of childbearing potential 
HbA1c=hemoglobin A1c; HDL=high-density lipoprotein; LDL=low-density lipoprotein 
A 
Only if there is no medical history of these diseases or no previous testing. 
7.1.4 Vital Signs 
Vital signs will be measured before any IP intake and recorded at the time points designated on 
the Schedules of Activities (Section 1.3). The following measurements must be performed: 
systolic/diastolic blood pressure and heart rate. Vital signs will be measured after the subject has 
been in the sitting 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. When vital signs, ECGs, and/or blood sample collection 
occur at the same time, vital signs should be performed before ECGs and/or blood sample 
collection. 
7.1.5 Electrocardiograms 
During the study, 12-lead ECGs will be performed at the time points designated on the Schedules 
of Activities (Section 1.3). 
The subject must be in a supine position in a rested and calm state for at least 5 minutes before 
ECG assessment is conducted. If the subject is unable to be in the supine position, the subject 
should be in the most recumbent position possible. All ECGs should be performed in a 
standardized method, in triplicate, and approximately 30 seconds apart, prior to blood draws or 
other invasive procedures. Each ECG must include the following measurements: QRS, QT, 
corrected QT, RR, and PR intervals.  
A designated cardiologist will review and sign all ECGs. Results must be summarized in writing 
and classified as normal; abnormal; abnormal, clinically relevant; or abnormal, not clinically 
relevant. Once signed, the original ECG tracing will be retained with the subject’s source 
documents. At the request of the Sponsor, a copy of the original ECG will be made available. 
7.1.6 Physical Examination 
The investigator or qualified designee will perform a physical examination (genitourinary 
examination not required) at screening and baseline and at the time points designated on the 
Schedules of Activities (Section 1.3). Pre-dose abnormal findings will be reported on the medical 
history eCRF. Any adverse change from the baseline physical examination will be documented on 
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A physical examination will include inspection of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, musculoskeletal 
system, and nervous system.  
An abbreviated physical examination will assess only the general appearance of the patient and is 
only required when a complete exam is not indicated. 
A standardized neurological exam will be performed by a pediatric neurologist or qualified 
individual. The neurological exam will take into account potential visual impairment. The 
evaluation will include, but is not limited to mental status, cranial nerves, motor function, and 
sensory and cerebellar functions. 
7.1.7 Additional Safety Assessments 
Slit-lamp evaluation will be performed during ophthalmic efficacy assessment to monitor ocular 
cataracts and ocular opacity. 
7.1.8 Unanticipated problems 
Definition 
Any incident, experience, or outcome that meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research staff, 
family members or other individuals not directly participating in the research) at a greater risk 
of harm (including physical, psychological, economic, or social harm) than was previously 
known or expected. 
 
Unanticipated problems reporting 
See Section 7.1.1.3 Responsibilities of the Investigator 
 
7.2 
Other Parameters 
Blood samples for analysis of miglustat will be taken at first dose  (Week 1) and at end of titration.  
The following windows pertain to the PK draw times: 
Scheduled PK Draw Time 
Allowed Window 
Pre-dose (0) to 3 hours 
± 5 minutes 
4 hours–8 hours 
± 30 minutes 
24 hours 
± 2 hours 
 

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Blood draws will occur at the following time points. 
• Week 1: pre-miglustat dose (0), 1, 2, 2.5, 3, 4, 6, 8, and 24 hours. Confinement between 
the 8- and 24-hour time points is not necessary. Subjects may return to the Local Health 
Center / stay at Subject’s Home the following day with a window of 24 ± 2 hours. The 
24-hour time point must be done before the Day 2 dose of miglustat is taken. 
• Week 9: pre-miglustat dose (0), 1, 2, 2.5, 3, 4, 6, and 8 hours. Subsequent daily miglustat 
dose(s) (if applicable) will be administered after the 8-hour blood draw has been 
performed. 
7.3 
Efficacy Assessments 
Efficacy assessments (UBDRS; seizure frequency (diary); Vineland-3; visual acuity, visual field 
(if feasible) , and retinal thickness using OCT; volumetric assessments using MRI;  CSF, blood 
and urine biomarkers for neurodegeneration) will be conducted at the time points outlined on the 
Schedules of Assessments (Section 1.3). 
7.3.1 Unified Batten Disease Rating Scale 
The UBDRS is a scale specifically developed to assess symptoms in CLN3 subjects 
(Marshall 2005 et al., Kwon et al., 2011, Cialone et al., 2012., Masten et al., 2020). The UBDRS 
consists of 7 different domains: (1) physical, (2) seizure, (3) behavioral, (4) capability  normal 
vision (will not be assessed) (5) capability  actual vision, (6) NCL history and (7) clinical summary  
including 7 global impression scales (Appendix 2). The physical domain consists of 20 different 
items based on a neurological assessment; higher scores indicate more severe disease. The seizure 
domain consists of 12 different assessments based on parent/caregiver information: frequency of 
seizure types (8 items), medical consequences of seizures (4 items), higher scores indicate more 
severe disease. The behavior domain consists of 10 different assessments based on 
parent/caregiver information; higher scores indicate more severe disease. The capability domain 
has 5 different assessments based on parent/caregiver information; lower scores indicate more 
severe disease, and NCL history including 8 items to document the onset of typical symptoms. 
The UBDRS assessments via live video -interview will be performed at the time points outlined 
on the Schedules of Assessments, if video interview is not possible for technical reasons, patients 
will be assessed at the NIH by a UBDRS trained rater. In cases of any event precluding safe travel 
by participants to NIH, the assessment will be performed remotely according to instructions 
delivered by Rochester University (Section 1.3). A copy of the UBDRS is provided in Section 13.2 
. In case of sedation for other examinations (e.g. MRI, OCT, lumbar puncture), UBDRS will be 
performed either before or > 24 hours after sedation. 
7.3.2 Seizure Frequency 
Subjects will receive a seizure diary to be completed at screening. Diaries will be collected during 
the Local Health Center / Subject’s Home visits and will be shipped to TCH. The baseline seizure 
frequency will be calculated based on data collected from screening to first dose of study drug. 
The report template is provided in 
. 

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7.3.3 Vineland-3 
The Vineland-3 measures the personal and social skills of individuals from birth through age 
90 years (Sparrow 2016, FDA Proceedings 2015). It can be administered as a comprehensive 
interview with the care giver as it will be in this study. The Vineland consists of multiple domains 
(with subdomains), as follows: Communication (receptive, expressive, written), Daily Living 
Skills (personal, domestic, community), Socialization (interpersonal relationships, play and 
leisure, coping skills), Motor Skills (gross, fine), and Maladaptive Behavior (internalizing, 
externalizing). The Maladaptive Behavioral domain will not be used as part of the trial because it 
is not specific to this disease process. Vineland interviews will be performed at the time points 
outlined on the Schedules of Assessments (Section 1.3). A copy of the Vineland-3 interview form 
is provided in Section 13.4. 
7.3.4 Ophthalmic Assessments Including Optical Coherence Tomography 
In some cases of CLN3 disease, OCT has enabled unambiguous detection of prominent 
morphologic abnormalities (degeneration) of the retina that occur over the natural progression of 
the disease (Hansen et al., 2016). These degenerative retinal changes are known to occur 
irrespective of different mutations of the CLN3 gene (Bergholz et al., 2015). Thus, OCT can be a 
valuable tool to evaluate changes in retinal morphology and visual acuity in this population. Dulz 
et al have evaluated retinal thickness in subjects with CLN3 disease (Dulz et al., 2016) 
demonstrating both temporal and nasal parafoveal thickness decrease. Retinal thickness will be 
measured at the time points outlined on the Schedules of Assessments (Section 1.3).  
Baseline OCT will be obtained in all study participants.  In those participants with no light 
perception vision, dense cataracts, or other ophthalmologic findings that produce significant 
artifacts in the OCT images, OCT imaging will not be repeated. 
Functional assessments including visual acuity, and visual fields (if feasible) will be performed at 
the same time points. 
7.3.5 Magnetic Resonance Imaging 
Grey matter atrophy due to neuronal loss is a striking feature of subjects with CLN3 disease 
(Hochstein 2017). Subjects will have brain MRI examinations at the time points outlined on the 
Schedules of Assessments (Section 1.3). 
7.3.6 Lumbar Puncture 
This procedure is done for the collection of CSF for biomarker analysis. It will be done on an 
annual basis under sedation in conjunction with other evaluations. The lumbar puncture will be 
performed by a provider credentialed by the NIH CC for this procedure at the time points outlined 
on the Schedules of Assessments (Section 1.3). Information about lumbar puncture is provided in 
Section 13.5 
 
Subjects who cannot cooperate with the MRI study, ophthalmology exam, or lumbar puncture 
procedure may be sedated. Baseline OCT will be obtained in all study participants.  In those 
participants with no light perception vision, dense cataracts, or other ophthalmologic findings that 
produce significant artifacts in the OCT images, OCT imaging will not be repeated. 

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7.3.7 CSF, blood and urine Biomarkers 
CSF, blood and urine will be collected for analysis of biomarkers. Applicable technologies include 
but are not limited to proteomics, lipidomics, expression analysis, gene / exome / genome / 
transcriptome sequencing, metabolomics, and multi-analytes profiling. 
 
 

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8 
STATISTICAL METHODS 
Further details of the proposed statistical analysis will be documented in the statistical analysis 
plan (SAP), which will be written following completion of the protocol and finalized prior to 
locking the database. 
8.1 
Disposition of Subjects 
A tabulation of subject disposition will be provided for the Safety Population and will include: 
• Number of subjects screened 
• Number of screen failures 
• Number of subjects enrolled  
• Number of subjects treated 
• Number of subjects who completed the treatment 
• Number of subjects who withdrew prior to completing the treatment, and reasons for 
withdrawal 
8.2 
Protocol Deviations 
Protocol deviations are defined as activities on a study that diverge from the approved protocol.  
Prior to database lock, the Sponsor will produce the final protocol deviation file in collaboration 
with the data monitoring group; this file will include a description of the protocol deviation, the 
occurrence date, the categorization as minor / major. This file will be finalized prior to hard 
database lock. 
All protocol deviations will be presented in a data listing. 
8.3 
Analysis Populations 
The Safety Population will consist of all subjects who enroll in the study and receive at least 1 dose 
of study medication. 
The PK Population will consist of subjects who received at least 1 dose of study drug and had a 
full PK sample set drawn per protocol for that day. 
The Efficacy Population will consist of the subjects who received at least 1 dose of study 
medication and had at least 1 follow-up efficacy assessment. 
8.4 
General Considerations 
Tabulations will be produced for appropriate demographic, safety, efficacy, and PK parameters. 
For categorical variables, summary tabulations of the number and percentage within each category 
of the parameter will be presented. For continuous variables, the mean, median, standard deviation, 
minimum and maximum values will be presented.  
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4 
or higher), unless otherwise noted. Medical History and AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA; dictionary Version 21.1). Concomitant 

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medications will be coded using World Health Organization (WHO) Drug Dictionary Version SEP 
2018 B3 GLOBAL. 
8.5 
Demographics, Baseline Characteristics and Concomitant Medications 
Demographics information will be summarized using descriptive statistics for the Safety 
Population and will include: 
• Age (years) at screening as continuous summary  
• Gender  
• Ethnicity 
• Race 
• Weight [kg] 
• Height [cm] 
• Body Mass Index (BMI) [kg/m²]: defined as Weight (kg)/(Height (m))2 
 
Baseline Disease characteristics will be summarized using descriptive statistics for the Efficacy 
Population and will include baseline information regarding the: 
• UBDRS  
• Seizure frequency  
• Vineland 3  
• Ophthalmic exams including the OCT 
• MRI 
• Biomarker information based on CSF 
 
8.6 
Treatment Compliance 
Compliance willbe analyzed. By-subject listings of each study drug administration will be 
produced. 
8.7 
Safety Analyses 
All subjects who enroll in the study and receive at least 1 dose of study medication will be included 
in the safety population. Safety will be evaluated by AEs, clinical laboratory tests, vital signs, 
ECGs, slit lamp evaluation and physical examinations. Safety data will be summarized using 
descriptive statistics by visit or timepoint, as appropriate. Treatment-emergent AEs and SAEs will 
be tabulated and summarized by system organ class, preferred term, severity, and relationship to 
study drug. 

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8.8 
Pharmacokinetic Analyses 
Descriptive statistical analyses will be performed for  miglustat plasma concentration data. The 
following PK parameters will be analyzed: 
o Week 1 first dosing: Cmax, Tmax, AUC 0-t, AUC0-∞, T1/2 
o Week 9 (Repeated dose (steady state), Cmin, Cmax, Tmax, AUC 0-8hr 
8.9 
Efficacy Analyses 
Efficacy will be evaluated as a secondary outcome. Efficacy data will be summarized using 
descriptive statistics by visit or timepoint, as appropriate as detailed in the SAP. 
8.10 Determination of Sample Size 
Approximately six subjects will be enrolled in the study. Due to the ultra-rare nature of CLN3 
disease, sample size is based on subject availability and not a statistical determination. 
8.11 Interim Analysis 
An interim analysis will be performed one month after all first three participants have enrolled and 
completed the titration period for each respective titration scheme, to provide preliminary safety 
results before the start of the Phase 3 study.  
 

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9 
DATA MANAGEMENT 
9.1 
Data Collection 
The trained investigator site staff will enter the data required by the protocol into the eCRFs from 
source documents (e.g., medical records and study-specific data capture tools as needed) directly 
into the study database on a central server. All information in the eCRFs must be traceable to these 
source documents. Clinical Research Associates and a Data Manager will review eCRFs entered 
by investigational staff for completeness and accuracy. Automatic quality programs check for data 
discrepancies in the eCRFs and the resulting queries will be notified to the investigational site 
using an electronic data query process within the Electronic Data Capture (EDC) system. 
Designated investigator site staff are required to respond to queries and make any necessary 
changes to the data. Details of the data correction process will be specified in the Data Management 
Plan.  
A validated, electronic database will be employed from the EDC system. 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. 
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 
in advance within a data handling plan/ data management plan together with a description of the 
personnel responsible for data entry. 
9.2 
Data Correction 
Automatic and manual queries will be defined according to the data validation plan. These queries 
will be generated by the Pharm-Olam Data Management Department and sent through the EDC 
system for clarification. Corrections will be entered directly into the system. This procedure will 
be repeated until all queries are resolved. All query forms will be linked to the eCRF in the EDC 
system. 
9.3 
Data Handling 
The final data will be transferred to the SAS-system for data analyses in accordance with the SAP. 
The MedDRA dictionary will be used for coding of AEs and concomitant diseases. Concomitant 
medication will be coded using the World Health Organization Drug Dictionary A(natomical) 
T(herapeutical C(hemical) code. 
9.3.1 Deviations from the Protocol 
Deviations from the protocol will be judged during the study and/or when an individual subject’s 
eCRF is completed (monitored).  
9.4 
Data Quality Assurance 
The Sponsor or designee 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. 

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The investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each study participant. All 
information recorded on the eCRFs for this study must be consistent with the subjects’ source 
documentation (i.e., medical records). 

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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 a Pre-Study Visit by the monitor (if necessary), 
an investigators’ meeting, and during the Site Initiation Visit by the monitor. 
10.2 Training of Site Staff 
The investigator will ensure that everyone assisting with the clinical study is adequately informed 
about the protocol, the investigational product(s), and their study-related duties and functions. 
Furthermore, the investigator will maintain a list of qualified persons to whom the investigator has 
delegated study-related duties. 
10.3 Documentation and Filing 
10.3.1 eCRF System 
All data recorded according to this study protocol must be documented in an eCRF. The 
investigator and persons authorized by the investigator will be instructed about how to complete 
the eCRF. Entries in the eCRF must only be made by the investigator or persons authorized by the 
investigator. A list of all persons who are allowed to make entries in the eCRF must be available 
in each study site. 
The investigator must verify that all data entries in the eCRF are accurate and correct. Entries will 
be checked against appropriate source documentation by the monitor. 
10.3.2 List of Subjects (subject identification log) 
The investigator will keep a confidential list of names of all subjects participating in the study, so 
that the subjects' records can be identified if necessary.  
In addition, the investigator will keep a list of all subjects screened on a screening log to document 
identification of subjects who entered pre-study screening. If someone is not eligible to participate 
in the study, a reason must be provided. 
10.3.3 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, subjects' 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, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical study). 

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10.3.4 Investigator Site File / Regulatory Binder 
Before site initiation Pharm-Olam will provide an ISF/ Regulatory Binder to each site. The ISF 
will include essential documents as defined by the ICH GCP guideline and applicable local 
requirements. 
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 legal requirements. 
Prior to destruction of study-related documents, the investigator will contact the Sponsor for 
approval and confirmation. 
10.4 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 subject’s source data. 
The extent and nature of monitoring will be described in detail in the monitoring plan. 
10.5 Audits and Inspections 
Audits will be performed according to the corresponding audit program. The Sponsor’s Quality 
Assurance Department or designee 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 IRBs are possible at any time, even after 
the end of 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 IRB and/or 
Regulatory Authorities and will allow direct access to source data and source documents for 
monitoring, audits, and inspections. 

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11 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
11.1 Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
investigator abide by the principles of the GCP guidelines of the ICH, and of the Declaration of 
Helsinki. The study also will be carried out in keeping with local legal requirements.  
11.2 Informed Consent 
Before each subject is admitted to the study, informed consent will be obtained from the subject 
(or his/her legally authorized representative) according to the regulatory and legal requirements of 
the participating country (i.e., the Declaration of Helsinki, ICH GCP, US Code of Federal 
Regulations [CFR] for Protection of Human Subjects (21 CFR 50.25 (a) and (b), CFR 50.27, and 
CFR Part 56, Subpart A), and other applicable local regulations). This consent form must be dated 
and retained by the investigator as part of the study records. The investigator will not undertake 
any investigation specifically required only for the clinical study until valid consent has been 
obtained. The terms of the consent and when it was obtained must also be documented in the eCRF. 
If a protocol amendment is required, the informed consent form may need to be revised to reflect 
the changes to the protocol depending on the requirements of the IRB. If the consent form is 
revised, it must be reviewed and approved by the appropriate IRB and signed by all subjects 
subsequently enrolled in the study as well as those currently enrolled in the study. 
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 IRB/Regulatory Authorities, in accordance with local legal requirements. The Sponsor must 
ensure that all ethical and legal requirements have been met before the first subject 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 IEC/Regulatory Authority approval prior to 
implementation (if appropriate).  
Administrative changes (not affecting the subject benefit/risk ratio) may be made without the need 
for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
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 legal requirements. 
11.5 Data Safety Monitoring Board 
Not applicable 

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11.6 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to subjects if the study continues, the study may be terminated after 
appropriate consultation between the relevant parties. The study may also be terminated early at 
the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• For study termination: 
o The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study; in particular if a patient develops a CTCAE-related Grade 4 
or higher 
o Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
o A decision on the part of the Sponsor to suspend or discontinue the development of 
the drug. 
• For site termination: 
o Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
o Total number of participants accrued earlier than expected 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
11.7 Confidentiality 
All study findings and documents will be regarded as confidential. The investigator and members 
of his/her research team must not disclose such information without prior written approval from 
the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified on eCRFs 
and other documents submitted to Pharm-Olam by their subject number, initials and/or birth date, 
not by name. Documents not to be submitted to Pharm-Olam that identify the subject (e.g., the 
signed informed consent) must be maintained in confidence by the investigator.  
Subject names or any information which would make the participant identifiable will not be 
transferred. 
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
participant who will be required to give consent for their data to be used as described in the 
informed consent  

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The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
11.8 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the investigator, the persons instructed by him and 
the hospital, practice or institute in which they are employed and the liability of the Sponsor with 
respect to financial loss due to personal injury and other damage that may arise as a result of the 
carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for subjects participating in this study to be insured against financial loss 
due to personal injury caused by the pharmaceutical product being tested or by medical steps taken 
in the course of the study.  
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. 
An investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with the Sponsor in advance. The terms of publication are governed by the agreements executed 
by the different parties involved in the realization of the study. 

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Dulz, S., Wagenfeld L., Nickel, M., Richard, G., Schwarz, R., Bartsch, U., Kohlschütter, A., 
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13 APPENDICES 
13.1 Appendix 1: Dietary Guidelines for people taking Miglustat (Updated May 2013) 
 
Can miglustat cause gastrointestinal disturbances? 
Diarrhea, gas, bloating, abdominal pain or discomfort, nausea and vomiting are symptoms often reported 
by people taking miglustat. These symptoms are usually mild or moderate and generally decrease over time. 
Side effects are the worst in the first weeks/months of being on the drug and usually get better after about 
3 months. 
 
What is the cause of these symptoms? 
Miglustat stops the intestinal enzymes that break down disaccharides (mainly sucrose, maltose, and to a 
lesser amount lactose) from working. These disaccharides (sugars) are not digested and absorbed properly, 
and stay in the gut. This can cause diarrhea. These sugars are also “food” for the bacteria in your gut and 
are fermented, producing gas. This also means your body doesn’t absorb these sugars and you aren’t getting 
the calories from them. 
 
What can I do to minimize these symptoms? 
• Take miglustat separately from meals (e.g. 2 hours before or after meals)  
• Start dietary changes at least 3 days (up to 2 weeks) before you start taking miglustat 
• Consider gradually increasing your dose (as recommended by your doctor) 
• Eat a diet low in disaccharides (sucrose, maltose, and to a lesser extent lactose) 
 
**Miglustat absorption is not affected if you have diarrhea as it is rapidly absorbed in the gut after it is 
taken 
 
What is a disaccharide? 
Disaccharides are two monosaccharides (single sugars) joined together. 
Examples of disaccharides: 
-Sucrose (table sugar) is made up of glucose and fructose joined together. 
-Maltose is glucose and glucose joined together. 
-Lactose (or milk sugar) is a galactose and glucose joined together. 
 
What is a low disaccharide diet? 
It is a diet low in sucrose, maltose, and lactose. 
Reduce disaccharides to <5g per meal. Look at the sugars on the nutrition label and the ingredient list to 
get an idea of how much disaccharide is in a food. 
Avoid eating foods high in disaccharides (sucrose and maltose)  
Desserts: cookies/biscuits, cakes, pies, puddings, custard, ice cream, sweetened yogurt 
Certain fruits: bananas, dates, peaches, apricots, pineapples, mangos, tangerines, dried fruits 
Additives/condiments: molasses, sugar, chocolate, jam, marmalade, honey, Nutella, sugar-based syrup 
 
Avoid high-carbohydrate drinks such as naturally sweetened soft-drinks, sweetened fruit juices, and 
alcohol-containing drinks (beer/wine). Fructose containing food and fruit drinks, and artificially sweetened 
soft drinks may be consumed. 
 
Reduce dairy intake (milk, cream, yogurt, cream cheese) 
-Lactose-free and soy based products can be used to replace milk and yogurt 
-Unsweetened and/or soy based yogurts allowed 
-Ensure you are meeting your calcium and Vitamin D requirements from diet and/or supplements 

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Reduce intake of starchy foods as the body naturally produces maltose (a disaccharide) as it digests foods 
such as bread, breakfast cereals, legumes, potatoes, corn, rice, beans, pasta and other grains. 
-Avoid large servings starchy foods at one time 
-Spread out your intake of starchy foods over the day 
 
If GI symptoms continue, intake of starchy foods may need to be more severely reduced, and then slowly 
re-introduced one-by-one over several weeks/months. 
 
Will I always have to be this strict with my diet? 
As your gut adapts to miglustat therapy and symptoms improve, you may be able to slowly re-introduce 
foods back into the diet. This would be done slowly and would be based on your tolerance. 
 
What about eating out/special occasions? 
For parties or social occasions where it is hard to avoid high disaccharide foods (e.g. birthday cake) consider 
taking Imodium. Imodium increases the amount of time that food remains in the gut, improving 
carbohydrate digestion and absorption. This may limit diarrhea and abdominal pain. 
 
Will I lose weight? 
Ideally we do not want you to lose weight on miglustat (assuming you are at a healthy weight to start with). 
It is very important that you maintain an adequate calorie intake while taking miglustat. 
If you are getting less calories from carbohydrates, then you will need to get these calories from protein and 
fats. 
Protein Sources: non-breaded meat/fish, eggs, tofu, nuts and seeds 
Fat Sources: oils, margarine, and avocado 
You may need to snack more often. 
Monitor your weight regularly (e.g. at least once a month). Let your doctor, nurse or dietitian know if you 
are losing weight. 
 
Can probiotics help with my symptoms? 
Probiotics (e.g. live cultures in yogurt) may help. There has not been a lot of research done about this. 
Taking probiotics, which deliver helpful bacteria to the gut, might help with symptoms while on miglustat. 
Probiotics that break down disaccharides seem to be helpful. One study showed Tilactase and Lactobacillus 
reuteri improved symptoms related to eating lactose people who were lactose intolerant. 
 
References: 
1. Belmatoug, N. et al. Gastrointestinal disturbances and their management in miglustat treated 
patients. JIMD (2011) 34:991-1001. 
2. Helping yourself with healthy choices – Zavesca. 
 

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13.2 Appendix 2: Unified Batten Disease Rating Scale 
 

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13.3 Appendix 3: Seizure Diary 
 
 
 
 
 

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13.4 Appendix 4: Vineland Adaptive Behavior Scales Scoring Sheet, Third Edition 
 
 
 
 
 

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13.5 Appendix 5: Lumbar Puncture/CSF Collection 
This procedure is done for the collection of CSF for biomarker and miglustat concentration 
analysis. It will be done on an annual basis under sedation in conjunction with other evaluations. 
The lumbar puncture will be performed by a provider credentialed by the NIH CC for this 
procedure. 
The participant will be taken to a procedure room and placed in the left lateral position on a 
stretcher, bed or examination table. A member of the Anesthesia team will monitor sedated patients 
constantly throughout the procedure. A local anesthetic (lidocaine dose as appropriate) will be 
administered in the skin and underlying tissue above the chosen interspace. A small spinal needle 
will be inserted under sterile conditions into the lumbar spinal sac. Approximately 10 mL of CSF 
will be collected, and the volume will be reduced proportionally for children under 4 years of age.  
For participants who can cooperate, the lumbar puncture may be done awake, with anxiolytics if 
needed. Local anesthesia will be used.  
CSF Biomarkers 
CSF will be collected for analysis of biomarkers. Applicable technologies include but are not 
limited to proteomics, lipidomics, expression analysis, gene/exome/genome/transcriptome 
sequencing, metabolomics, and multi-analytes profiling. 
 
 
 

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13.6 
Appendix 6: Contraception Guidance 
Male participants   
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following    
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in Table 13-1when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal 
intercourse or use a male condom during each episode of penile penetration    
Refrain from donating sperm for the duration of the study and for 30 days after the last dose of 
study treatment. 
Female participants  
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in  Table 13-1. 
  
Table 13-1 Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used.  
Sexual abstinence  
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 treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, two highly effective methods of contraception should be 
utilized during the treatment period and for at least 30 days, after the last dose of study treatment  

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COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant 
 
The Investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to male 
participants who receive Batten-1. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within [24 hours] of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
  
Female participants who become pregnant: 
 
Continuation of study intervention may only be allowed if either of the following criteria is met: 
The study intervention has an approved label that indicates it can be used safely in pregnant 
females 
OR 
All of the following apply: 
The participant has a high mortality disease 
The Investigator determines the participant is benefitting from study participation and there is no 
other reasonable treatment for her. 
The Sponsor and the relevant IRB/IEC give written approval 
The participant gives signed informed consent. 
The Investigator agrees to monitor the outcome of the pregnancy and the status of the participant 
and her offspring. 
The protocol is amended to allow such participation on a case-by-case basis, if such participation 
is not already addressed in the protocol. 
Under exceptional circumstances (see related instructional text), the continuation of study 
intervention can be considered. 
  
The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a participant’s 
pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the participant and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
  
Any pregnancy complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

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A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at >22 
weeks gestational age) is always considered to be an SAE and will be reported as such. 
  
Any post-study pregnancy related SAE considered reasonably related to the study intervention by 
the Investigator will be reported to the Sponsor as described in Section 7.1.1.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
 
 
 

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13.7 Appendix 7: Extract of Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 
 
 
 
 
 

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13.8 Appendix 8: Plan for miglustat administration 
Enrolled participants will be contacted by the study team and will have their visit scheduled 
according to the schedule of events listed in the protocol to occur either at home or at the local 
health center. Once the visit is scheduled at home, adequate quantities of the miglustat IP will be 
dispensed from the central pharmacy and shipped directly to the patient’s home to arrive on the 
day of the scheduled visit.  
 
All IP shipments will be temperature controlled and monitored to prevent any temperature 
excursions while IP is in transit. The assigned home nurse will meet with the participant at the 
proposed home setting and will complete all assessments per the study protocol. Completed 
assessments will be relayed to the PI and study team. The PI will then determine the appropriate 
dosage based on the completed assessments and will communicate that order to the pharmacist 
and home health nurse.  
- 
Regarding the miglustat oral dosing, the PI will verify the dosage prior to administration 
and relay that order back to the study team, to provide guidance to the pharmacist and home 
health nurse on how much IP should be administered.  
- 
The nurse will provide IP accountability for the miglustat by counting how much miglustat 
is left following the completion of each visit.