Clinical trial NCT04958642
Conditions: Niemann-Pick Disease, Type C
Keywords: Niemann-Pick Type C1 (NPC1) Disease neurologic disease gross motor dysfunction fine motor dysfunction dysphagia swallowing problems cognitive dysfunction gait abnormalities pediatrics
Sponsor: Mandos LLC
Start date: 2015-12-23; Completion date: 2022-04-11
Enrollment: 66 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Due to different study designs, the sponsor separated Part C into this separate registration (NCT04958642), leaving Parts A/B in NCT02534844. The trial's final results for the primary outcome measure of Adverse Events (AE) will be reported here.

This study is to evaluate how safe and effective adrabetadex is for participants with Niemann-Pick Type C1 (NPC1) disease who experience neurologic symptoms (listed under Keywords).

In Parts A/B (NCT02534844), two out of every 3 participants will receive the study drug. The third participant will receive 1 to 2 small needle pricks at the location where the IT injection is normally made (sham control).

In Part C, all participants will receive study drug.

Detailed description:
Participants in Part C will receive adrabetadex until the investigator considers adrabetadex to no longer be beneficial to the participant, or the development program is discontinued.

Arms: arm 1: All participants receive their prescribed dose of adrabetadex. Dose is allowed to be adjusted down to a minimum of 400 milligrams (mg) or up to a maximum of 900 mg, at the investigator's discretion.
Interventions: intervention 1: Adrabetadex
Intervention descriptions: intervention 1: Mallinckrodt test formulation, administered intrathecal (IT) via lumbar puncture (LP) infusion.

Protocol documents:
Prot_000.pdf: 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company 
Clinical Research 
Protocol Amendment 15.0 
A Phase 2b/3 Prospective, Randomized, Double-blind, Sham-controlled Trial 
of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic 
Manifestations of Niemann-Pick Type C1 (NPC1) Disease 
Protocol Number: 
VTS301 
Version Number: 
Amendment 15.0 
Version Date: 
23 June 2021 
Investigational Product: 
VTS-270 (specific and well-characterized mixture of 
2-hydroxypropyl-β-cyclodextrin [HP-β-CD]) 
IND Number: 
 
EudraCT Number: 
 
Development Phase: 
2b/3 
Sponsor: 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company 
90 Washington Valley Road 
Bedminster, NJ 07921 
Co-Principal Investigator: 
Name:
 Telephone: 
 
Fax: 
 
E-mail: 
Co-Principal Investigator 
Name: 
 Telephone: 
 
Fax: 
 
E-mail: 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document may not be 
disclosed unless federal or state law or regulations require such disclosure. Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who have a need to know, with the 
obligation not to further disseminate this information. 
NCT #: NCT04958642


Protocol Amendment 15.0 
 
VTS-301 
Page 2  
CONFIDENTIAL AND PROPRIETARY 
PROTOCOL AMENDMENT 15.0 CHANGES 
 
The objective of this amendment is reinforce the need for the investigator to assess whether 
subjects treated with intrathecal adrabetadex for NPC1 is benefiting from treatment, to review 
and discuss the risk-benefit assessment of the treatment with those subjects who are benefiting 
from treatment, and to document this discussion in the subject’s medical record. For subjects 
continuing in this study after 21 June 2021, the investigator must assess whether the subject is 
benefiting from treatment with adrabetadex. For those subjects who appear to benefit from 
treatment, the investigator must review with them the risks associated with intrathecal 
adrabetadex, including hearing loss, and the data from the randomized, controlled trial that 
demonstrated no significant differences between patients treated with adrabetadex and sham-
treated subjects on any efficacy measures. Subjects must be discontinued from the study if the 
investigator does not consider them to be benefiting from treatment and/or they do not 
understand the risks associated with adrabetadex, including hearing loss. 
 
A summary of changes (SOC) for Amendment 15 is provided below.  
SUMMARY OF CHANGES FOR AMENDMENT 15.0 
 
1. For subjects continuing in the study after 21 June 2021, the investigator must assess whether 
the subject is benefiting from treatment with intrathecal adrabetadex. 
2. For those subjects who appear to benefit from treatment, the investigator must review with 
them the risks associated with adrabetadex, including hearing loss, and the data from the 
randomized, controlled trial that demonstrated no significant differences between subjects 
treated with adrabetadex and sham-treated subjects on any efficacy measures. 
3. After 21 June 2021, subjects must be discontinued from the study if the investigator either 
does not consider them to be benefiting from treatment and/or they do not understand the 
risks associated with adrabetadex, including hearing loss. 
4. This discussion should be documented in the subject’s medical record and only those 
subjects (or legally authorized representative) who have demonstrated an understanding of 
the risk/benefit of adrabetadex treatment should be permitted to continue in the study. 
The relevant sections of protocol Amendment 15.0 where the above changes may apply, either in 
whole or in part, are provided in the Study Synopsis, Duration of Subject Participation and 
Duration of Study; Section 7.1, Risk/Benefit Assessment; Section 15.1, Evaluations by Visit - 
Part C; and Section 17.1, Early Discontinurion.  
In addition, text changes were made throughout the document to correct residual minor errors of 
grammar, style or abbreviation(s). These minor text changes were not considered substantive. 
 


Protocol Amendment 15.0 
 
VTS-301 
Page 3  
CONFIDENTIAL AND PROPRIETARY 
SIGNATURE OF AGREEMENT FOR APPROVAL OF PROTOCOL 
AMENDMENT 15 
 
 
 
 
 
Refer to the e-signature page. 
 
Approved: 
 
Date: 
 
 
 
 
Mallinckrodt Pharmaceuticals 
 
 
 
 
 
 
 
 
 


Protocol Amendment 15.0 
 
VTS-301 
Page 4  
CONFIDENTIAL AND PROPRIETARY 
1. 
INVESTIGATOR PROTOCOL AGREEMENT 
I have read the protocol specified below. In my formal capacity as investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and providing 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company with complete and timely information, as 
outlined in the protocol. It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures required 
to carry out the study in accordance with accepted Good Clinical Practice principles and to abide 
by the terms of this protocol. 
 
Protocol Number: VTS301 Amendment 15.0 
 
Protocol Title: A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham-Controlled Trial of 
VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of 
Niemann-Pick Type C1 (NPC1) Disease 
 
Protocol Date: 23 June 2021 
 
 
 
 
Investigator Signature 
Date 
Print Name and Title 


Protocol Amendment 15.0 
 
VTS-301 
Page 5  
CONFIDENTIAL AND PROPRIETARY 
2. 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT 15.0 CHANGES..............................................................................2 
SIGNATURE OF AGREEMENT FOR APPROVAL OF PROTOCOL ........................................3 
1. 
INVESTIGATOR PROTOCOL AGREEMENT .........................................................4 
2. 
TABLE OF CONTENTS .............................................................................................5 
3. 
LIST OF TABLES ......................................................................................................11 
4. 
LIST OF ABBREVIATIONS.....................................................................................12 
5. 
PROTOCOL SYNOPSIS ...........................................................................................15 
6. 
BACKGROUND ........................................................................................................22 
6.1. 
NPC1 Disease .............................................................................................................22 
6.2. 
VTS-270 (A Unique Mixture of 2-hydroxypropyl-beta-cyclodextrin [HP-β-
CD]) ............................................................................................................................22 
6.3. 
Overview of Nonclinical Studies ................................................................................23 
6.3.1. 
Overview of Nonclinical Toxicology Studies ............................................................24 
6.4. 
Overview of Clinical Studies ......................................................................................25 
6.4.1. 
NIH Natural History Study .........................................................................................25 
6.4.2. 
Phase 1/2a Study 13-CH-0001 ....................................................................................25 
6.4.2.1. 
Phase 1 Study - Safety Evaluation ..............................................................................26 
6.4.3. 
VTS-270–Related Ototoxicity ....................................................................................27 
6.4.4. 
Rush University iIND Studies ....................................................................................27 
6.4.5. 
Efficacy Based on Comparison Data from Subjects Treated with VTS-270 
with Comparable Subjects in the Natural History Study ............................................27 
6.5. 
Dose Rationale ............................................................................................................27 
7. 
STUDY RATIONALE ...............................................................................................28 
7.1. 
Risk/Benefit Assessment ............................................................................................29 
7.2. 
Sham Procedure Rationale ..........................................................................................30 
7.3. 
Rationale for Administration of VTS-270 via Spinal Intrathecal Access Port 
System.........................................................................................................................31 
8. 
STUDY OBJECTIVES ..............................................................................................31 
8.1. 
Primary Objectives .....................................................................................................31 
8.1.1. 
Part C ..........................................................................................................................31 
8.2. 
Secondary Objectives .................................................................................................31 
8.2.1. 
Part C ..........................................................................................................................31 


Protocol Amendment 15.0 
 
VTS-301 
Page 6  
CONFIDENTIAL AND PROPRIETARY 
8.3. 
Exploratory Objectives ...............................................................................................32 
8.3.1. 
Part C ..........................................................................................................................32 
9. 
INVESTIGATIONAL PLAN .....................................................................................32 
9.1. 
Study Design ...............................................................................................................32 
9.2. 
Dose Reduction ...........................................................................................................32 
9.3. 
Dose Re-escalation .....................................................................................................33 
9.4. 
Rescue Option .............................................................................................................33 
10. 
CRITERIA FOR EVALUATION ..............................................................................34 
10.1. 
Part C (Including Substudies) Endpoints ....................................................................34 
10.1.1. 
Primary Endpoints in Part C .......................................................................................34 
10.1.2. 
Secondary Endpoints in Part C ...................................................................................34 
11. 
SUBJECT SELECTION .............................................................................................35 
11.1. 
Study Population .........................................................................................................35 
11.2. 
Inclusion Criteria Part C .............................................................................................35 
11.3. 
Criteria for Part C European Site-specific Device Safety and Tolerability 
Substudy .....................................................................................................................36 
11.3.1. 
Inclusion Criteria for European Site-specific Device Safety and Tolerability 
Substudy .....................................................................................................................36 
11.3.2. 
Exclusion Criteria for European Site-specific Device Safety and Tolerability 
Substudy .....................................................................................................................36 
11.4. 
Inclusion Criteria for European Site-specific Device PK Substudy ...........................38 
12. 
CONCOMITANT MEDICATIONS ..........................................................................38 
12.1. 
NPC Treatment-related Medications ..........................................................................38 
12.2. 
Allowed Medications and Treatments ........................................................................38 
12.3. 
Prohibited Medications and Treatments .....................................................................39 
13. 
STUDY TREATMENTS............................................................................................39 
13.1. 
Method of Assigning Subjects to Treatment Groups .................................................39 
13.1.1. 
Part C ..........................................................................................................................39 
13.1.1.1. 
Part C: European Site-specific Device Safety and Tolerability Substudy ..................39 
13.1.1.2. 
Part C: European Site-specific Device PK Substudy .................................................39 
13.2. 
Blinding ......................................................................................................................39 
13.2.1. 
Parts A and B ..............................................................................................................39 
13.2.2. 
Part C ..........................................................................................................................39 


Protocol Amendment 15.0 
 
VTS-301 
Page 7  
CONFIDENTIAL AND PROPRIETARY 
13.3. 
Formulation of Test and Control Products .................................................................40 
13.3.1. 
Formulation of Test Product .......................................................................................40 
13.3.2. 
Formulation of Control Product ..................................................................................40 
13.3.3. 
Packaging and Labeling ..............................................................................................40 
13.4. 
Supply of Study Drug at the Site ................................................................................41 
13.4.1. 
Dosage/Dosage Regimen ............................................................................................41 
13.4.2. 
Dispensing ..................................................................................................................42 
13.4.3. 
VTS-270 Administration by Lumbar Puncture and Sham Lumbar Puncture .............42 
13.4.4. 
Study Drug Administration in the European Site-specific Device Substudies...........43 
13.5. 
Storage ........................................................................................................................44 
13.6. 
Study Drug Accountability .........................................................................................45 
13.7. 
Investigational Device (for European Site-specific Device Substudies) ....................45 
13.7.1. 
Investigational Device Handling ................................................................................45 
13.7.2. 
Investigational Device Implantation ...........................................................................45 
13.7.3. 
Investigational Device Removal .................................................................................45 
13.7.4. 
Investigational Device Accountability .......................................................................46 
13.7.5. 
Investigational Device Handling and Disposal ...........................................................46 
13.8. 
Measures of Treatment Compliance ...........................................................................46 
14. 
STUDY PROCEDURES AND GUIDELINES..........................................................47 
14.1. 
Overview of Study Procedures ...................................................................................47 
14.2. 
Clinical Assessments ..................................................................................................47 
14.2.1. 
Concomitant Medications ...........................................................................................47 
14.2.2. 
Demographics .............................................................................................................47 
14.2.3. 
Medical History ..........................................................................................................47 
14.2.4. 
Adverse Events ...........................................................................................................47 
14.2.5. 
Physical Examination .................................................................................................48 
14.2.6. 
Wound Check and Examination of Port Site and Catheter Track for 
European Site-specific Device Subjects .....................................................................48 
14.2.7. 
Vital Signs ..................................................................................................................49 
14.2.8. 
Intracranial Pressure Measurement for European Site-specific Device 
Subjects .......................................................................................................................49 
14.2.9. 
Clinical Laboratory Measurements.............................................................................50 
14.2.9.1. 
Hematology .................................................................................................................50 


Protocol Amendment 15.0 
 
VTS-301 
Page 8  
CONFIDENTIAL AND PROPRIETARY 
14.2.9.2. 
Genetic Analysis – Day 0 ...........................................................................................50 
14.2.9.3. 
Blood Chemistry Profile .............................................................................................50 
14.2.9.4. 
Pregnancy Test ............................................................................................................51 
14.2.9.5. 
Urinalysis ....................................................................................................................51 
14.2.9.6. 
Cerebrospinal Fluid for Routine Clinical Laboratory Tests in Subjects With 
Intrathecal Access Device ...........................................................................................51 
14.2.9.7. 
Collection, Handling, and Storage of Samples for Clinical Laboratory Tests ...........52 
14.2.10. 
Plasma and CSF VTS-270 Concentrations .................................................................52 
14.2.11. 
CSF, Urine, and Plasma Biomarker Assays ...............................................................52 
14.2.12. 
Electrocardiogram .......................................................................................................53 
14.3. 
Audiologic Evaluation ................................................................................................53 
14.3.1. 
Audiologic Testing .....................................................................................................53 
14.3.2. 
Auditory Brainstem Response ....................................................................................53 
14.4. 
Blinded Clinician Clinical Global Impression of Change (Clinician-CGIC) .............53 
14.5. 
Blinded NPC Clinical Severity Score Rating .............................................................54 
14.6. 
Neurological Examination ..........................................................................................54 
14.7. 
Caregiver Clinical Global Impression of Change (Caregiver-CGIC) ........................55 
14.8. 
TUG Test and 9-Hole Peg Test ..................................................................................55 
14.9. 
EQ-5D-3L Quality of Life Assessment ......................................................................55 
15. 
EVALUATIONS BY VISIT ......................................................................................55 
15.1. 
Part C ..........................................................................................................................55 
16. 
ADVERSE EVENT REPORTING AND DOCUMENTATION ...............................56 
16.1. 
Adverse Events ...........................................................................................................56 
16.1.1. 
Definitions ..................................................................................................................56 
16.1.1.1. 
Adverse Event .............................................................................................................56 
16.1.1.2. 
Suspected Adverse Reaction .......................................................................................56 
16.1.1.3. 
Adverse Reaction ........................................................................................................57 
16.1.1.4. 
Unexpected Adverse Event/Unexpected Suspected Adverse Reaction ......................57 
16.1.1.5. 
Serious and Unexpected Suspected Adverse Reaction ...............................................57 
16.1.2. 
Adverse Event Severity ..............................................................................................57 
16.1.3. 
Adverse Event Relationship to Study Drug ................................................................58 
16.1.4. 
Adverse Events of Special Interest .............................................................................58 
16.1.4.1. 
Clinically Significant Hearing Loss ............................................................................58 


Protocol Amendment 15.0 
 
VTS-301 
Page 9  
CONFIDENTIAL AND PROPRIETARY 
16.1.5. 
Adverse Event Relationship to Investigational Device ..............................................59 
16.1.6. 
Adverse Device and Intrathecal Effects of Special Interest .......................................59 
16.1.7. 
Actions for Potential Device Deficiency ....................................................................60 
16.2. 
Serious Adverse Event ................................................................................................60 
16.2.1. 
Serious Adverse Event Reporting ...............................................................................61 
16.3. 
Medical Monitoring ....................................................................................................61 
17. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .............................61 
17.1. 
Early Discontinuation .................................................................................................61 
17.2. 
Replacement of Subjects .............................................................................................62 
17.3. 
Protocol Violations .....................................................................................................62 
18. 
DOSE SELECTION COMMITTEE AND DATA MONITORING 
COMMITTEE .............................................................................................................62 
19. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................63 
19.1. 
Analysis Populations ..................................................................................................63 
19.1.1. 
Intent-to-Treat Population ..........................................................................................63 
19.1.2. 
Modified Intent-to-Treat .............................................................................................63 
19.1.3. 
Per Protocol Population ..............................................................................................63 
19.1.4. 
Safety Population ........................................................................................................63 
19.1.5. 
European Site-specific Safety Population ..................................................................64 
19.1.6. 
European Site-specific Device Pharmacokinetic Population .....................................64 
19.2. 
Demographic and Baseline Characteristics ................................................................64 
19.3. 
Analysis of Pharmacokinetic Endpoints .....................................................................64 
19.4. 
Interim Analysis ..........................................................................................................64 
19.5. 
Sample Size and Randomization ................................................................................64 
19.6. 
Stratification ...............................................................................................................65 
20. 
DATA COLLECTION, RETENTION, AND MONITORING .................................65 
20.1. 
Data Collection Instruments .......................................................................................65 
20.2. 
Data Management Procedures ....................................................................................65 
20.3. 
Data Quality Control and Reporting ...........................................................................66 
21. 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ..............66 
21.1. 
Protocol Amendments ................................................................................................66 
21.2. 
Institutional Review Boards and Independent Ethics Committees.............................66 
21.3. 
Informed Consent Form ..............................................................................................67 


Protocol Amendment 15.0 
 
VTS-301 
Page 10  
CONFIDENTIAL AND PROPRIETARY 
21.4. 
Publications .................................................................................................................67 
21.5. 
Investigator Responsibilities .......................................................................................68 
21.6. 
Archival of Data .........................................................................................................68 
21.7. 
Availability and Retention of Investigational Records ...............................................68 
21.8. 
Monitoring ..................................................................................................................69 
21.9. 
Subject Confidentiality ...............................................................................................69 
22. 
REFERENCES ...........................................................................................................69 
23. 
APPENDICES ............................................................................................................72 
APPENDIX 1. STUDY PARTS A AND B SCHEDULE OF ASSESSMENTS .......................73 
APPENDIX 2. STUDY PART C SCHEDULE OF ASSESSMENTS .......................................79 
 


Protocol Amendment 15.0 
 
VTS-301 
Page 11  
CONFIDENTIAL AND PROPRIETARY 
3. 
LIST OF TABLES 
Table 1: 
Summary Dosing and Therapeutic Effectiveness Data ..............................................28 
Table 2: 
Phase 2b/3 3-Part Study Design .................................................................................33 
Table 3: 
VTS-270 Dose, Injection Volume, and Concentration ...............................................43 
Table 4: 
AE Severity Grading ...................................................................................................58 
Table 5: 
AE Relationship to Study Drug ..................................................................................58 
Table 6: 
Distinguishing VTS-270 from NPC1 Disease Induced Hearing Loss ........................59 
Table 7: 
Adverse Relationship to Investigational Device.........................................................59 
Table 8: 
Study Parts A and B Schedule of Assessments – Screening through Week 26 .........73 
Table 9: 
Study Parts A and B Schedule of Assessments – Week 28 through Week 54 ...........76 
Table 10: Study Part C Schedule of Assessments – Screening through Week 28 ......................79 
Table 11: Study Part C Schedule of Assessments – Week 30 through Week 52 .......................82 
Table 12: Study Part C Schedule of Assessments – Week 54 through Week 182 .....................84 
Table 13: Study Part C Schedule of Assessments – Beyond Week 182 Visit Number 92 .........86 
Table 14: Study Part C Schedule of Assessments – End of Study and Follow-up .....................87 
Table 15: Part C European Site-specific Device Safety and Tolerability Substudy 
Schedule of Assessments ............................................................................................88 
 


Protocol Amendment 15.0 
 
VTS-301 
Page 12  
CONFIDENTIAL AND PROPRIETARY 
4. 
LIST OF ABBREVIATIONS 
Abbreviations 
Description of Abbreviations 
24(S)-HC 
24-(S) hydroxycholesterol 
ABR 
Auditory brainstem response 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-versus-time curve 
AUC0-last 
Area under the concentration-versus-time curve from 0 to the last 
measurable time point 
AUC0-inf 
Area under the concentration-versus-time curve from time 0 extrapolated 
to infinity 
BAER 
Brain stem auditory evoked response 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CL/F 
Oral clearance 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DPOAE 
Distortion product otoacoustic emission(s) 
DS 
Degree of substitution 
DSC 
Dose Selection Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ET 
Early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HP-β-CD  
2-hydroxypropyl-β-cyclodextrin 


Protocol Amendment 15.0 
 
VTS-301 
Page 13  
CONFIDENTIAL AND PROPRIETARY 
Abbreviations 
Description of Abbreviations 
IC 
Intracisternal 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICP 
Intracranial pressure 
ICV 
Intracerebroventricular(ly) 
IEC 
Independent Ethics Committee 
iIND 
Investigator-initiated Investigational New Drug Application 
IRB 
Institutional Review Board 
IT 
Intrathecal 
ITT 
Intent-to-treat 
IV 
Intravenous 
LE/LY 
Late endosomal/lysosomal 
LP 
Lumbar puncture 
mITT 
Modified intent-to-treat 
NCATS 
National Center for Advancing Translational Sciences 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NPC 
Niemann-Pick type C 
NPC1 
Niemann-Pick type C1 (phenotype) 
NPC1 
Niemann-Pick type C1 cat phenotype 
Npc1 or Npc1-/- 
Niemann-Pick type C1 mouse phenotype 
NPC-SS 
NPC Severity Scale 
PIR 
Product Incident Report 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
PT 
Prothrombin time 
PTA 
Pure tone audiometry 
QoL 
Quality of life 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCr 
Serum creatinine 
SOP 
Standard operating procedure 
SUSAR 
Serious and unexpected suspected adverse reaction 
t½ 
Apparent half-life 
Tmax 
Time to maximum concentration 
TUG 
Timed up and go 


Protocol Amendment 15.0 
 
VTS-301 
Page 14  
CONFIDENTIAL AND PROPRIETARY 
Abbreviations 
Description of Abbreviations 
ULN 
Upper limit of normal 
US 
United States 


Protocol Amendment 15.0 
 
VTS-301 
Page 15  
CONFIDENTIAL AND PROPRIETARY 
5. 
PROTOCOL SYNOPSIS 
Title 
A Phase 2b/3 Prospective, Randomized, Double-blind, Sham-controlled Trial of VTS-270 (2-
hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann-Pick 
Type C1 (NPC1) Disease 
Sponsor 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company 
90 Washington Valley Road 
Bedminster, NJ 07921 
Number of Sites 
Approximately 24 sites worldwide 
Study Design 
This is a multicenter, multinational, prospective, randomized, double-blind, sham-controlled, 
3-part, efficacy and safety trial of VTS-270 administered by the lumbar intrathecal (IT) route 
every 2 weeks, with a planned enrollment of approximately 51 subjects (in Parts A and B) 
with Niemann-Pick type C1 (NPC1) disease. The study will be conducted in 3 parts: Parts A, 
B, and C. 
Part A evaluated 3 different dose levels of VTS-270 versus sham control, administered as 
4 lumbar IT injections every 2 weeks, to determine the dose level for Parts B and C. A total of 
12 subjects were enrolled and have completed Part A. 
Part B evaluated the safety and efficacy of the dose selected from Part A, 900 mg, compared 
with sham control in approximately 51 subjects, including the 12 subjects from Part A. 
Subjects received treatment with VTS-270 for up to 52 weeks (inclusive of Part A). Subjects 
who elected not to continue with Part C had 26 weeks of follow-up.  All subjects have 
completed Part B. 
Part C will be an open-label extension phase of the study. Subjects who complete Part B, 
meet the criteria for dose reduction for a second time, or meet the rescue therapy criteria after 
6 months of participation in Part B are eligible to participate in Part C. Subjects who are 
currently active in the National Institutes of Health (NIH) phase 1 study 
(Protocol 13-CH 0001) will also be eligible to participate upon completion of their 
participation in the phase 1 study. Additionally, subjects who have received prior written 
authorization from Vtesse to enroll directly into Part C are eligible to participate. Parts A and 
B subjects and NIH phase 1/2a subjects who transition into Part C will receive treatment with 
VTS-270 until the investigator considers VTS-270 to no longer be beneficial to the subject, or 
the development program is discontinued. The development program for VTS270 has been 
discontinued and Part C of the study is being terminated by the Sponsor. 
A European site-specific substudy was conducted as part of the Part C study. This substudy 
was designed to assess the safety and tolerability of the B. Braun Celsite® Spinal Access Port 
System (hereafter generally referred to as the “device”) for the administration of VTS-270 
every 2 weeks. The device is CE marked in Europe and consists of a subdermal access port 
connected to a catheter that is positioned in the lumbar IT space. Given that VTS-270 does 
not penetrate the blood-brain barrier and requires IT administration, the ability to administer 
VTS-270 via the device will obviate the need for biweekly lumbar punctures (LPs), as well as 
anesthesia, thereby removing a significant burden for subjects and site personnel. In this 
device safety and tolerability substudy, approximately 6 eligible Part C subjects who have 
received at least 3 lumbar IT doses (900 mg VTS-270) in Part C will undergo baseline 
assessments approximately 3 days prior to implantation of the device (same day as their last 
administration of VTS-270 via LP). The device will be implanted in the hospital, and the 
subject will remain in the hospital for 2 additional days post implantation. During the 3-day 
confinement period (Day 1 surgery, Days 2 and 3), subjects will be given intravenous (IV) 
antibiotics, which are part of the routine implantation procedure.  
Subjects entering the European site-specific device safety and tolerability substudy will 
continue on their Part C schedule of assessments but will have additional device safety 


Protocol Amendment 15.0 
 
VTS-301 
Page 16  
CONFIDENTIAL AND PROPRIETARY 
evaluations. After a minimum of 2 weeks after placement of the device and confirmation of 
catheter patency, subjects will receive their VTS-270 dose via device infusion. Dosing will 
continue every 2 weeks for a total of 9 doses via the device. Specific evaluations will be 
conducted during the treatment period to assess device safety. These visits, designated Visit 
D1 through Visit D9, will occur at the same time as the subject’s Part C schedule. Where 
there is duplication of assessments with the Part C schedule, only 1 assessment will be 
conducted. Following 9 device infusions of VTS-270 and the specific device safety 
assessments conducted during the treatment period, subjects will either enter the device 
pharmacokinetic (PK) substudy described below or will remain in the main Part C study and 
continue to receive VTS-270 via the device to evaluate its long-term safety and tolerability. 
A European site-specific device PK substudy was planned, but no subjects consented.  
Dose Reduction 
The following are guidelines for which dose reduction on an individual subject basis was 
allowed in Part B: 
Subjects who, in the opinion of the investigator, experienced a drug-related adverse event 
(AE) after any blinded IT treatment that was considered clinically relevant and impactful to 
the subject’s function could have their dose reduced to 600 mg per IT administration for 
subsequent IT dosing intervals following discussion with the unblinded medical monitor. If, 
following dose reduction to 600 mg, a subject continued to experience AEs as described 
above, the subject’s dose could be further reduced to 400 mg per IT administration for 
subsequent dosing intervals following discussion with the unblinded medical monitor.  
If, following dose reduction to 400 mg, a subject continued to experience a drug-related 
clinically relevant AE, the dose was NOT to be reduced further and the subject was to be 
discontinued from Part B of the study, being given the option to transition into Part C at a 
lower dose, based on discussion with the unblinded medical monitor and on a case-by-case 
basis. 
During Part C, the same guidelines apply for dose reduction, with each subject for whom dose 
reduction is considered being individually reviewed with the medical monitor. 
Dose 
Re-Escalation 
Dose re-escalation is not permitted 
Rescue Option 
Not applicable for Part C 
Primary Objective 
Part A: 
The primary study objective in Part A was to select the dose of VTS-270 to be used in Part B 
and Part C. Dose selection criteria included safety and tolerability including a thorough 
audiologic evaluation. Preliminary efficacy data was provided to the Dose Selection 
Committee (DSC) to assist, if necessary, in dose selection. 
Part B: 
The primary study objective in Part B was to evaluate, in a double-blind sham-controlled 
design, the progression of the neurologic manifestations of NPC1 disease following 52 weeks 
of treatment for subjects treated with VTS-270 compared to sham control, using the following 
assessments: 
• 
The Neimann Pick Type C Severity Scale (NPC-SS) composite which consists 
of the sum of 4 components of the NPC-SS: ambulation, fine motor, cognition, 
and swallowing.  
• 
The blinded Clinician-Clinical Global Impression of Change (CGIC). 
Part C: 
The primary study objective in Part C is to evaluate the long-term safety, tolerability, and 
efficacy of VTS270.  
Secondary 
Objectives 
Part A: 
There were no secondary objectives for Part A. 


Protocol Amendment 15.0 
 
VTS-301 
Page 17  
CONFIDENTIAL AND PROPRIETARY 
Part B: 
The secondary objectives for Part B were divided into 2 categories: key secondary objective 
and other secondary objectives. 
The key secondary objective for Part B was to evaluate the progression of the neurologic 
manifestations of NPC1 disease using the total NPC-SS score, excluding the hearing domain 
and auditory brainstem response (ABR) modifier results, following 52 weeks of treatment for 
subjects treated with VTS-270 compared to sham controls and the Caregiver-CGIC. 
Other secondary objectives were to:  
1. Evaluate the safety and tolerability of VTS-270 administered IT via LP every 2 
weeks, compared to sham control.  
2. Assess quality of life (QoL) using the EQ-5D-3L following 52 weeks of 
treatment for subjects treated for 52 weeks with VTS-270 compared to sham 
controls.  
3. Further assess the efficacy of VTS-270 on treating the neurologic symptoms of 
NPC1 by comparing subjects treated for 52 weeks with VTS-270 compared to 
sham control on: 
• Subjects who required rescue following at least 6 months of treatment. 
• The 9 major domains of the NPC-SS.  
• The total NPC-SS score (hearing domain and ABR modifier included). 
• Time to a 1-point increase (worsening) on the NPC-SS composite score. 
• The annualized rate of change (slope) of the NPC-SS composite score. 
• Timed up and go (TUG) test. 
• 9-Hole peg test. 
Part C: 
The secondary study objectives in Part C are to: 
1. Assess the safety and tolerability of the B. Braun Celsite Spinal Access Port 
utilized to administer VTS-270 (device safety and tolerability substudy). 
2. Assess the plasma and cerebrospinal fluid (CSF) PK of VTS-270 concentrations 
in subjects receiving the 900 mg dose of VTS-270 via the B. Braun Celsite 
Spinal Access Port (device PK substudy). 
Exploratory 
Objectives 
Part A: 
There are no exploratory objectives for Part A. 
Part B: 
The exploratory study objectives in Part B are to:  
1. Collect CSF, urine, and plasma samples from the subjects receiving study drug, 
and urine and plasma samples from subjects randomized to sham control, at 
prespecified intervals. Samples will be stored for exploratory biomarker 
analyses. 
2. Further evaluate the efficacy of VTS-270 on treating the neurologic symptoms 
of NPC1 by comparing subjects treated with VTS-270 compared to sham 
control on: 
• The composite NPC-SS in completers.  
• The composite NPC-SS outcome assuming data missing at random using a 
standard multiple imputation model.  
• The composite NPC-SS using a pattern mixture model. 
• Assigning individual subject changes (+1 if improved, 0 if unchanged, or -1 
if worse relative to baseline). 
Part C: 
There are no exploratory objectives for Part C. 


Protocol Amendment 15.0 
 
VTS-301 
Page 18  
CONFIDENTIAL AND PROPRIETARY 
Number of 
Subjects 
Approximately 51 in Parts A and B. 
Part C may enroll more than 51 subjects. 
Approximately 6 in the device safety and tolerability and device PK substudies. 
Subject Selection 
Criteria 
Parts A and B – not applicable as Part A and B are completed. 
Part C – NO NEW SUBJECTS ARE ALLOWED TO ENTER THE STUDY AS OF 
20 JANUARY 2021 
Inclusion Criteria: 
1. Subject has completed Part B, meets the criteria for dose reduction for a second 
time or meets the criteria for the rescue option. 
OR 
2. Subject is a current participant in the NIH phase 1/2a open-label study and:  
a. 
Subject agrees to convert from the dose of VTS-270 currently receiving as a 
subject in the NIH phase 1/2a protocol to the dose chosen for Parts B and C 
of this study, 900 mg. 
b. Subject agrees to convert from the monthly dosing regimen used in the NIH 
phase 1/2a protocol to an every 2-week dosing regimen. 
c. 
In instances where NIH phase 1/2a subjects eligible to enroll into Part C are 
unable to convert from their current NIH phase 1/2a dose or monthly 
regimen, the investigator must receive prior written authorization from the 
sponsor for the subject to enter Part C of the study on an amended dose 
and/or regimen. 
OR 
3. Subject has received prior written authorization from Vtesse to enroll directly 
into Part C. 
4. Females of childbearing potential (not surgically sterile) must use a medically 
acceptable method of contraception and must agree to continue use of this 
method for the duration of the study and for 30 days after participation in the 
study. Acceptable methods of contraception include barrier method with 
spermicide, intrauterine device, steroidal contraceptive in conjunction with a 
barrier method, abstinence, or same-sex partner. 
5. Subject or parent/guardian must provide written informed consent to participate 
in the study. In addition to parental consent, assent to participate must also be 
sought from minor children. 
 
Subject Inclusion Criteria for European Site-specific Device Safety and Tolerability 
Substudy – Not applicable – enrollment in the Device Substudy concluded Aug 2018. 
Subject Exclusion Criteria for the European Site-specific Device Safety and Tolerability 
Substudy – Not applicable - enrollment in the Device Substudy concluded Aug 2018. 
Subject Inclusion Criteria for the European Site-specific Device Pharmacokinetic (PK) 
Substudy – Not applicable – no subject consented to participate in the PK Substudy. 
Test and Control 
Product, Dose, 
and Route of 
Administration 
 
VTS-270 will be provided in appropriately labeled vials, formulated as a 200 mg/mL 
injectable solution. An unblinded pharmacist/designee at each investigational site will be 
responsible for dispensing or preparing the assigned dosage of 900 mg for administration in 
4.5 mL. In the case of dose reduction, the 600 mg dose is administered in 3 mL and the 
400 mg dose is administered in 2 mL. 
VTS-270 Administration via Lumbar Puncture and Sham Lumbar Puncture 
In Part A, VTS-270 administration via LP and sham will be performed every 2 weeks for 
4 administrations. In Part B, VTS-270 administration via LP and sham will be performed 
every 2 weeks for 52 weeks. In Part C, VTS-270 will be administered via LP or the device 


Protocol Amendment 15.0 
 
VTS-301 
Page 19  
CONFIDENTIAL AND PROPRIETARY 
every 2 weeks. Instructions for administration via the device are presented in the following 
subsection. 
The LP and/or sham is to be performed under monitored anesthesia care (conscious sedation) 
with an appropriate oral or IV agent and performed by an unblinded study physician. General 
anesthesia will be allowed on a case-by-case basis, following discussion with the medical 
monitor, in those subjects for whom a medical condition necessitates it. 
Parents/caregivers will not be present in the room during lumbar IT or sham treatment. Thus, 
the subject and the parent will be blinded to treatment, the former a consequence of 
anesthesia. 
The sham procedure will consist of 1 to 2 small needle pricks on the lower back at the 
location where the LP and IT injection is normally made. The needle(s) will break the skin 
but no lumbar puncture or needle insertion will occur. The needle prick(s) will be covered 
with the same bandage that is used to cover the IT injection normally, thus simulating the 
appearance of an IT LP injection. To maintain the blind, a similar type of anesthesia, 
sedation, or minimal sedation (eg, a low dose of an anxiolytic) should be used for the sham 
procedure as for the subject receiving study drug, following institutional procedures. The 
subject will be kept in the procedure room for approximately 30 minutes, simulating the same 
amount of time that subjects administered study drug are kept for administration procedure. 
VTS-270 will be administered as an IT slow bolus (1 to 2 minutes, depending on the volume 
administered) LP injection (maximum rate of administration = 4.5 mL/minute). The volume 
of the injection is determined by the dose group. Prior to the VTS-270 injection, a volume of 
CSF fluid approximately equal to the VTS-270 dose is to be removed. Anesthesia or sedation 
will be used for the IT dosing procedure, following institutional guidelines and procedures. 
All subjects, sham and study drug, are required to lie flat with feet elevated for 30 to 45 
minutes following dosing. For the 3 days following each procedure, subjects in both the sham 
and active treatment groups are to avoid acoustic overstimulation and minimize exposure to 
loud noises, eg, headphones for music or video games. 
Device Administration (European Site-specific Device Safety and Tolerability Substudy, 
Part C) 
VTS-270 administration via the device will be conducted every 2 weeks. There are no 
adjustments for weight or subject age. The device area will be prepared for sterile 
manipulation following standard site procedures. Cerebrospinal fluid will be withdrawn 
through the port of the device. The first 1 mL will be discarded, and then at least 3 mL will be 
collected for clinical laboratory tests (approximately 2 mL) and VTS-270 concentration 
(approximately 1-2 mL). The volume of CSF to be removed should be approximately equal to 
that being administered. VTS-270 will be administered as a slow bolus over 1 to 2 minutes 
with a maximum rate of infusion of 4.5 mL/minute. Non-coring needles adapted for use with 
the device should be used. Normal hypodermic needles will damage the port septum and may 
cause leakage of the system or blockage due to small silicone particles from the septum. 
Subjects are to receive the same dose of VTS-270 administered during Study VTS301 Part C 
by IT LP. 
Following the infusion of VTS-270, the system should be flushed with 1.5 mL of 
preservative-free 0.9% saline solution. For 30 to 45 minutes following dosing, subjects should 
lie flat with feet elevated. 


Protocol Amendment 15.0 
 
VTS-301 
Page 20  
CONFIDENTIAL AND PROPRIETARY 
Duration of 
Subject 
Participation and 
Duration of Study 
Part C 
Part C is an open-label extension. The total duration of subject participation is until the 
investigator considers VTS-270 to no longer be beneficial to the subject, or the development 
program is discontinued. The Sponsor has discontinued the VTS-270 development program 
following determination of a negative benefit/risk balance. Treatment with VTS-270 should 
be discontinued as soon as possible; in consideration of the need to determine a transition 
plan, treatment with VTS-270 will be permitted for up to an additional 9 months (20 October 
2021). The potential extension of treatment is contingent upon reconsent of the subject and 
approval by their applicable IRB/EC and health authority. 
After 21 June 2021, subjects may not continue to receive IT adrabetadex, except for those 
subjects (and legally authorized representatives, as appropriate): 
• 
who appear to be benefiting from intrathecal adrabetadex based on the 
investigator’s assessment, AND 
• 
who are aware of the risks associated with adrabetadex, including hearing loss, 
and understand that no significant differences were seen between patients 
treated with adrabetadex and sham-treated patients on any efficacy measures in 
this randomized, controlled trial. 
Efficacy Evaluations 
Primary Endpoint 
Part B: 
Not applicable, as Part A/B is complete. 
Secondary 
Endpoints 
Part B: 
Not applicable as these analyses are complete. 
Part C: After 20 January 2021, efficacy endpoints for Part C will not be reported. 
• 
The change from baseline to each assessment in a composite outcome that is the 
sum of the ambulation, cognition, fine motor, and swallowing components of 
the NPC-SS. 
• 
The change from baseline to each assessment in total NPC-SS with the hearing 
domain and ABR modifiers removed. 
• 
Proportion of responders (defined as no change or improvement on NPC-SS 
total score with hearing domain and ABR modifiers removed) at each 
assessment. 
• 
Proportion of blinded Clinician-CGIC responders (defined as a score of no 
change, minimally improved, moderately improved, or markedly improved) at 
each assessment compared to baseline. 
• 
Summary of AEs, concomitant medications, physical examinations, audiologic 
examination, and clinical laboratories. 
• 
Change from baseline in the EQ-5D-3L questionnaire at each assessment. 
• 
Change from baseline to each assessment in each of the 9 clinical domains of 
the NPC-SS. 
• 
Change from baseline to each assessment in the total NPC-SS with hearing 
domain and ABR modifier included. 
• 
Time to 1-point increase (worsening) in NPC-SS composite score. 
• 
The composite NPC-SS mean annualized rate of change (slope) from baseline to 
each assessment. 
Other Evaluations 
• 
CSF, urine, and plasma protein (eg, calbindin D) biomarkers. 
• 
CSF and plasma sterol biomarkers. 
• 
Gene and protein expression. 
Safety Evaluations 
• 
AEs. 
• 
Audiologic testing. 


Protocol Amendment 15.0 
 
VTS-301 
Page 21  
CONFIDENTIAL AND PROPRIETARY 
• 
Clinical laboratory tests (hematology, chemistry, coagulation, urinalysis). 
• 
Vital signs. 
• 
Physical and neurological examinations. 
• 
Electrocardiograms (ECGs). 
• 
Wound check/port and catheter track check for device safety and tolerability. 
• 
Intracranial pressure via LP for subjects with device. 
• 
CSF routine laboratory tests for subjects with device. 
Statistics: 
Primary Analysis 
Plan 
Not applicable, Part A/B completed and reported. 
Rationale for 
Number of 
Subjects 
The sample size for this study is approximately 51 subjects in Parts A and B combined. The 
rationale for the sample was based on both practical and statistical considerations. The sample 
size was determined based on the potential number of available subjects for this ultra-rare 
disorder. Based on the comparison of the NIH phase 1 subjects and similar subjects in the 
NIH natural history data set, approximately 51 subjects, 16 on sham and 35 on active 
treatment, will allow for the detection of clinically relevant difference of the sum of the 
4 NPC-SS score domains that make up the composite outcome. The assumptions applied in 
the power calculation provide 79% power to detect a difference between the VTS-270 and 
sham groups by ANCOVA. 


Protocol Amendment 15.0 
 
VTS-301 
Page 22  
CONFIDENTIAL AND PROPRIETARY 
6. 
BACKGROUND 
6.1. 
NPC1 Disease 
Niemann-Pick type C1 (NPC1) disease is a rare, neurodegenerative, inherited, autosomal 
recessive disorder which primarily manifests in children and teenagers. Niemann-Pick type C 
(NPC) disease is characterized by systemic disease (hepatic, splenic, pulmonary) and progressive 
neurologic manifestations including ataxia, dementia, and seizures resulting in early death by the 
age of 20 to 25 years. The prevalence of NPC disease is estimated to be 1 in 150,000 people in 
the United States (US) (Millat 1999) and 1 in 100,000 people in the European Union (EU) 
(Vanier 2010). 
NPC1 disease is a result of mutations in the NPC1 gene whose protein normally functions in 
neurons and other cells to transport unesterified cholesterol and sphingolipids from the late 
endosomal/lysosomal (LE/LY) compartment. Cells have a complex trafficking system to control 
the cellular concentration of cholesterol, sphingolipids, and other lipids. Part of this system is the 
lipid efflux from LE/LY via the action of NPC1, at least in part. In individuals lacking or with 
deficient NPC1, cholesterol, bis-(monoacylglycerol) phosphate, and various sphingolipids 
accumulate to toxic concentrations in lysosomal storage organelles. Most of the evidence 
supports that the primary storage metabolite in NPC1 disease, especially in the peripheral tissues, 
is low-density lipoprotein-derived cholesterol (Rosenbaum & Maxfield 2011). Cholesterol and 
sphingolipids are important lipids in mammalian physiology; however, in excessive 
concentrations, both are toxic to cells resulting in cellular dysfunction and death. The 
neuropathological abnormalities in NPC patients that are caused by this block in cholesterol 
transport include brain atrophy, widespread neuronal cytoplasmic vacuolization, and neuronal 
loss, with the Purkinje cells being the most severely affected. 
6.2. 
VTS-270 (A Unique Mixture of 2-hydroxypropyl-beta-cyclodextrin 
[HP-β-CD]) 
Cyclodextrins (CD), as well as 2-hydroxypropyl-β-cyclodextrins (HP-β-CDs) in general, have 
been used extensively to modulate cholesterol and other lipids’ composition of model and 
biological membranes. Cyclodextrins are also being used extensively to solubilize 
pharmaceuticals, and various regulatory authorities have approved them as delivery agents. 
2-hydroxypropyl-beta-cyclodextrin has been approved for use as an excipient in oral and 
intravenous (IV) pharmaceuticals for many years. VTS-270 is the first unique mixture of 
HP-β-CD being developed as an active pharmaceutical product for a specific disease. 
VTS-270 is a specific and well-characterized mixture of HP-β-CD, a cyclic oligosaccharide with 
a distinctive truncated cone configuration containing 7-cyclo-α-(1,4)-anhydroglucose units with 
hydroxypropyl groups randomly substituted onto the C-2, C-3, and C-5 positions of the 
molecule. The level of hydroxypropylation in VTS-270 is strictly controlled during 
manufacturing, resulting in a drug with a tightly controlled degree of substitution (DS) and a 
defined fingerprint of the different species present in the mixture. This unique fingerprint 
distinguishes VTS-270 from all other commercially available HP-β-CDs. 


Protocol Amendment 15.0 
 
VTS-301 
Page 23  
CONFIDENTIAL AND PROPRIETARY 
All HP-β-CDs are amorphous mixtures of different isomers, characterized by the DS, which 
represents the average substitution of the hydroxyl with propyl groups per HP-β-CD molecule. 
The active drug substance in Vtesse’s investigational drug product (VTS-270) is KLEPTOSE® 
HPB parenteral grade, which has an average DS of 4.34. 
The average DS and unique substitution fingerprint are critical quality attributes of the drug for 
safety and efficacy. Scientists at the National Center for Advancing Translational Sciences 
(NCATS) have demonstrated that the fingerprint pattern of different substituted species and the 
average DS of methylated betacyclodextrin have a dramatic effect on efficacy as measured by 
the ability to clear cholesterol sequestered in NPC cell lines and to restore normal lysosomal 
function and structure (Rosenbaum 2010). An extensive nonclinical safety and efficacy package 
has been generated specifically for VTS-270 to demonstrate that this unique version of HP-β-CD 
is suitable for intrathecal (IT) dosing in pediatric patients during clinical trials. 
The therapeutic potential of HP-β-CD was discovered in 2009 when HP-β-CD, injected 
systemically to Npc1-/- mice beginning at either postnatal day 7 or 21 and continuing every other 
day, delayed onset of clinical symptoms, reduced intraneuronal cholesterol and 
glycosphingolipid storage, reduced markers of neurodegeneration, and increased animal survival 
(Davidson 2009). HP-β-CD enters cells by the endocytic pathway and is delivered to the LE/LY 
storage organelles where unesterified cholesterol accumulates in NPC deficiency. HP-β-CD 
replaces the function of NPC1 protein and promotes transport of the accumulated unesterified 
cholesterol to the endoplasmic reticulum for esterification by acetyl CoA:acyl transferase and 
subsequent efflux (Rosenbaum & Maxfield 2011; Abi-Mosleh 2009). While the precise 
mechanism of HP-β-CD action to bypass or replace NPC1 function is not defined, HP-β-CD 
normalizes intracellular cholesterol trafficking by binding the hydrophobic moieties of 
cholesterol and other lipids. 
6.3. 
Overview of Nonclinical Studies 
Though multiple cellular processes may play a role in the pathogenesis of NPC1, including 
alterations in autophagy and sphingolipid homeostasis, impaired cholesterol mobilization from 
the lysosomal compartment is most likely the primary result of loss of NPC1 function and thus 
the main cause of the signs and symptoms in NPC1. Experiments have been conducted in vitro 
as well as in vivo in mouse and feline models of NPC1 and in humans that demonstrate the 
effects of HP-β-CD treatment on NPC1 deficiency. It has been shown that HP-β-CD works from 
inside endocytic organelles to reduce cholesterol storage and accumulation (Rosenbaum 2010), 
and that a portion of the cholesterol liberated from lysosomes is transferred to the endoplasmic 
reticulum for regulation of cholesterol homeostatic responses (Abi-Mosleh 2009). In vivo studies 
in animal models of NPC1 and in patients with NPC1 have shown that this redistribution of 
cholesterol modulates multiple pathways and improves NPC1 symptoms, including increasing 
lifespan (Tortelli 2014; Sidhu 2015; Maarup 2015). 
Following its endocytosis into the lysosome, the cellular/molecular mechanism of HP-β-CD 
activity in the treatment of NPC disease is not known, but 3 potential mechanisms have been 
postulated. 
The mouse and cat models of NPC disease are naturally occurring and genetically similar to the 
human disease (Walkley & Suzuki 2004). Recent studies in these 2 models have shown that 
administration of the drug either directly into the lateral ventricle (intracerebroventricularly 


Protocol Amendment 15.0 
 
VTS-301 
Page 24  
CONFIDENTIAL AND PROPRIETARY 
[ICV]) of mice or IT injection at the cerebellomedullary cistern of cats, or central nervous system 
(CNS) administration in combination with systemic treatment in cats and mice, greatly extends 
the lifespan of the animals and prevents or delays neurological symptoms (Aqul 2011; Vite 2015; 
Study Nos. Einstein-Mouse-001; Einstein-Mouse-002; Einstein-Mouse-003; 804000). 
In studies conducted in the naturally occurring NPC1 cat (Vite 2008), investigators recognized a 
dose-dependent increase in hearing threshold associated with therapy as determined by brain 
stem auditory evoked response (BAER) testing. To further assess the effect of HP-β-CD on 
hearing threshold, normal cats were administered the drug subcutaneously (SC) at either 
4000 mg/kg or 8000 mg/kg body weight, or IT at a dose of 4000 mg/kg brain weight. HP-β-CD 
caused a significant increase in hearing threshold following 1 dose of 8000 mg/kg SC or 120 mg 
IT and the effect was maintained for at least 12 weeks. Repeated weekly SC administration of 
4000 mg/kg HP-β-CD resulted in a similar increase in hearing threshold. These studies are the 
first to describe a specific negative effect of HP-β-CD on the auditory system and suggest the 
need for auditory testing in subjects receiving similar doses of HP-β-CD (Ward 2010). 
The safety of Kleptose HPB (VTS-270) has been demonstrated by nonclinical toxicology studies 
conducted to support the use of Kleptose HPB as a pharmaceutical excipient by Janssen 
Pharmaceutical Research (Janssen Drug Master File 9428) and with additional toxicology studies 
in cats and juvenile dogs conducted by the National Institutes of Health (NIH) Therapeutics for 
Rare and Neglected Diseases and collaborators to further support its use as an active drug 
product for the treatment of NPC disease. Kleptose HPB is the active ingredient in VTS-270. 
VTS-270 has been safe and well tolerated in NPC cats treated every 2 weeks via the IT route. 
VTS-270 has also been administered IT in the United States in a NIH phase 1/2a study (13-CH-
0001) and under investigator-initiated Investigational New Drug applications (iINDs), and is 
currently being administered IT in a global phase 2b/3 study (VTS301; the study described in 
this protocol). 
6.3.1. 
Overview of Nonclinical Toxicology Studies 
The pharmacological properties of HP-β-CD have been extensively studied in Npc1-/- mice and 
NPC1 cats. The pharmacokinetic (PK) properties have been studied in rats, dogs, Npc1-/- mice, 
and NPC1 cats. The safety of HP-β-CD was evaluated in a comprehensive toxicology program 
conducted by Janssen Research Foundation (Janssen) to support its use as a pharmaceutical 
excipient. Nonclinical toxicology studies included single and repeat-dose toxicity studies, in 
vitro and in vivo genotoxicity assays, carcinogenicity studies, reproductive and developmental 
toxicity (Segment I, II, and III) studies, and special toxicity (local tolerance and mechanistic 
toxicity) studies. HP-β-CD has been approved for use as an excipient in oral and IV 
pharmaceuticals for over a decade. Vtesse has obtained the rights to reference the Roquette 
Freres Type IV Drug Master File No. 9420 for HP-β-CD, the drug substance. HP-β-CD is being 
developed for the treatment of NPC1, a lethal, autosomal recessive, lysosomal storage disorder 
characterized by neurodegeneration in early childhood and death in adolescence. Since ICV 
administration was the intended route for clinical use, canine repeat-dose toxicity studies of 
6 months were initiated. Clinical ICV administration using an Ommaya reservoir resulted in 
bacterial infections and therefore administration was shifted to IT delivery with testing of IT 
delivery of HP-β-CD in NPC1 mutant cats. Further details of these nonclinical studies are 
presented in the Investigator’s Brochure. 


Protocol Amendment 15.0 
 
VTS-301 
Page 25  
CONFIDENTIAL AND PROPRIETARY 
6.4. 
Overview of Clinical Studies 
6.4.1. 
NIH Natural History Study 
A natural history study is being conducted by the Eunice Kennedy Shriver National Institute of 
Child Health and Human Development (NICHD) in Bethesda, MD, entitled “Evaluation of 
Biochemical Markers and Clinical Investigation of Niemann-Pick Disease, Type C”. This study 
is ongoing and has enrolled 97 subjects with NPC disease as of November 2016 
(NCT00344331). Disease progression is being tracked using the NPC Severity Scale (NPC-SS). 
Planned assessments in this study include disease severity, neuropsychiatric, ophthalmological, 
audiological, speech, and language pathology evaluations. Planned laboratory evaluations 
include cholesterol metabolite measurements in blood, urine, and cerebrospinal fluid (CSF). 
Review of the data collected from 2006 to August 2014 has shown that the mean age at first 
symptoms and diagnosis was 3.8 and 9.2 years, respectively. 
6.4.2. 
Phase 1/2a Study 13-CH-0001 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company, in concert with its development partner 
at the NIH/NICHD, has recently completed a phase 1/2a, open-label, single-center, ascending, 
multiple-dose, cohort dose-escalation study of VTS-270 in 14 subjects with NPC1 disease 
(NCT01747135). The study was designed to characterize the feasibility, safety, tolerability, PK, 
and activity of VTS-270 administered monthly via lumbar injection to subjects with NPC1. 
Subjects with confirmed NPC1 disease have received monthly lumbar IT injections of VTS-270. 
This study applied safety data to guide dose escalation and plasma 24-S hydroxycholesterol 
(24[S]-HC) concentrations to potentially identify an effective dose of VTS-270. 
The primary objectives of this study were: 
• To assess the safety and tolerability of IT administration of VTS-270 with NPC1 
disease. 
• To examine plasma PK of VTS-270 after IT administration. 
• To determine a biochemically active dose of VTS-270 as assessed by changes in 
plasma 24(S)-HC concentration. 
Secondary objectives of this study were: 
• To evaluate the use of candidate plasma and CSF biomarkers. 
• To perform an exploratory evaluation of clinical outcome measures for possible use 
in further clinical development. 
Since October 2013, 14 subjects, aged 4 to 23 years, enrolled in dosing cohorts of 3 subjects each 
and received VTS-270 doses ranging from 50 to 1200 mg monthly. The first 3 enrolled subjects 
received 50 mg ICV via an Ommaya reservoir. However, due to complications associated with 
the Ommaya device implantation procedure (ie, Propionibacterium acnes infections), subsequent 
subjects received doses ranging from 200 mg to 1200 mg monthly via the IT (lumbar) route. 


Protocol Amendment 15.0 
 
VTS-301 
Page 26  
CONFIDENTIAL AND PROPRIETARY 
6.4.2.1. 
Phase 1 Study - Safety Evaluation 
Adverse Events Observed with ICV Administration 
All adverse events (AEs) observed after ICV administration were considered unlikely to be 
related to study drug and included Common Terminology Criteria for Adverse Events (CTCAE) 
grade 1 AEs and 3 serious adverse events (SAEs). The SAEs involved the removal of the 
Ommaya reservoirs in 2 subjects in Cohort 1 due to P. acnes colonization/infection and a false 
positive CSF gram stain in 1 subject, which resulted in increased subject and parent anxiety and 
their request to remove the Ommaya reservoir. In the investigator’s opinion, the complications 
leading to removal of the Ommaya reservoir were protocol related, not drug related. 
Adverse Events Observed After ICV and IT Administration 
Seven subjects have received 1200 mg IT, the highest dose tested. 
Eleven subjects have received 900 mg IT, 9 subjects have received 600 mg IT, 7 subjects have 
received 400 mg IT, 9 subjects have received 300 mg IT, 8 subjects have received 200 mg IT, 
and 3 subjects have received 50 mg IT. All but 1 subject experienced at least 1 AE after IT 
administration. All AEs observed after ICV administration were considered unlikely to be related 
to study drug and included CTCAE grade 1 AEs and 3 SAEs. 
All of the SAEs for ICV treatment were considered to be Ommaya related, not study-drug 
related. No deaths have been reported with VTS-270 administration. As of September 2015, 
there were 2 SAEs (Subject # 
 status epilepticus; Subject # 
 emesis and 
bloody stool) reported that were considered possibly related to VTS-270 in subjects administered 
study drug IT. 
The most common AEs experienced by subjects involved the ear and labyrinth systems. 
Sensorineural hearing loss was reported in 57% (8/14 subjects) and tinnitus in 21% 
(3/14 subjects). Other AEs occurring in 2 or more subjects included headache, post lumbar 
puncture (LP) 57% (8/14 subjects); emesis 50% (7/14 subjects); elevated liver enzymes—pre and 
post drug 36% (5/14 subjects); fatigue after IT administration 29% (4/14 subjects); seizure, 
change in pattern or frequency 29% (4/14 subjects); fever 21% (3/14 subjects); tingling hands 
14% (2/14 subjects); proteinuria 14% (2/14 subjects); urobilinogen 14% (2/14 subjects); 
discomfort at LP site 21% (3/14 subjects); and fecal incontinence 14% (2/14 subjects). Except 
for sensorineural hearing loss and aspiration event during anesthesia, all of the most frequently 
occurring AEs previously mentioned were grade 1 or grade 2, as were most of the AEs reported 
during the study. Of the 8 reported AEs of sensorineural hearing loss on audiometry, 3 AEs were 
grade 1, 1 AE was grade 2, and 4 AEs were grade 3, none of which were considered to be a 
clinical change in hearing. 
Results of assessments of ambulation, ataxia, posture, gait, and swallowing have been largely 
unchanged at the doses of VTS-270 administered to date, in some cases with greater than a year 
of treatment on VTS-270. Preliminary analysis of the biomarker 24(S)-HC, an indicator of target 
engagement, has shown only modest increases with VTS-270 dose escalation. 


Protocol Amendment 15.0 
 
VTS-301 
Page 27  
CONFIDENTIAL AND PROPRIETARY 
6.4.3. 
VTS-270–Related Ototoxicity 
Ototoxicity, an expected AE based on the feline model, was observed in the NIH phase 1/2a 
study (13-CH-0001) at doses of 200 mg and higher, as assessed by tonometric audiometry. These 
data track with murine and feline NPC models that show a dose-dependent hearing loss with 
VTS270 treatment; however, variable susceptibility has been seen, which is common in 
otopathology, and which suggests a number of factors may influence the ototoxic properties of 
VTS-270. 
Additionally, the degree of recovery of ototoxicity between monthly IT treatments is unclear, 
and although data are limited, subjects have demonstrated partial, and in some cases, complete 
recovery on pure tone audiometry (PTA). Additionally, it should be noted that the interpretation 
of ototoxicity is confounded by the fact that hearing loss occurs naturally in the progression of 
NPC disease. Based on this, there is an expectation that some degree of ototoxicity may occur in 
subjects receiving VTS-270 with uncertain reversibility. 
The hearing loss associated with VTS-270 is complex. In a phase 1 study, mid- to 
high-frequency hearing loss was documented in all participants (Ory 2017). The mechanism of 
hearing loss is not fully understood; however, based on preclinical data and our experience, it is 
possible that dose or duration of dosing may result in greater hearing changes. 
6.4.4. 
Rush University iIND Studies 
Approximately 23 subjects are being treated under an iIND at Rush University. These subjects 
have received VTS-270 doses ranging from 200 mg to 750 mg IT every 2 weeks. With the 
exception of hearing loss in 1 subject who had the VTS-270 dose de-escalated, no treatment-
related severe or serious AEs were reported. 
6.4.5. 
Efficacy Based on Comparison Data from Subjects Treated with VTS-270 with 
Comparable Subjects in the Natural History Study 
To assess the effect of VTS-270 in NPC patients, the rate of change in the NPC-SS and its major 
domains was compared in a data set of subjects in the NIH phase 1/2a study with comparable age 
in the natural history study. Results of the latest data analysis are summarized below. 
An effect of adrabetadex above that seen with miglustat cannot be demonstrated in a post-hoc 
comparison subsetted by baseline miglustat use. 
6.5. 
Dose Rationale 
In Part A, the dose-finding portion of this study, VTS-270 in a fixed-dose regimen at 900 mg, 
1200 mg, or 1800 mg was administered to 3 subjects each by IT administration every 2 weeks 
for 4 dosing cycles. After the last subject in Part A received 4 IT infusions at the randomized 
dose level or sham including the 2 weeks observation following the 4th treatment, an independent 
Dose Selection Committee (DSC) reviewed the safety and efficacy data for dose selection. The 
dose of 900 mg was selected for Parts B and C based on evaluation of the safety, audiometric, 
and preliminary efficacy data of the 4 cycles of each of 3 doses tested in Part A. The fixed-dose 
regimen in Part A was chosen to allow for similar exposure and comparable safety and efficacy 
assessment across the study population. 


Protocol Amendment 15.0 
 
VTS-301 
Page 28  
CONFIDENTIAL AND PROPRIETARY 
The doses initially chosen for evaluation in Part A were based on the therapeutically effective 
ranges identified in the naturally occurring NPC1 mutant cat model (intracisternal [IC] dosing) 
and on preliminary clinical data from the open-label iIND and NIH phase 1/2a clinical study (IT 
dosing). 
Because the drug is administered directly into the CNS compartment, dosing is based on brain 
weight (mg VTS-270/kg brain weight). Brain weight in humans is similar from approximately 
4 years of age (1200 g) through adulthood (1400 g) so there is no dose adjustment based on age 
or body size. Summary dosing and therapeutic effectiveness data from the NPC1 mutant cat 
model and preliminary clinical data are shown in Table 1. 
Table 1: 
Summary Dosing and Therapeutic Effectiveness Data 
NPC1 Mutant Cat 
30 g Brain Weight 
NPC Child 
1200 g Brain Weight 
HP-β-CD IC 
(mg) 
HP-β-CD IC 
(mg/kg) Brain 
HP-β-CD IC 
(mg/mL) CSF 
Purkinje Cell 
Survival 
Delay of Ataxia 
Otoxicity 
HP-β-CD IT 
(mg) 
HP-β-CD IT 
(mg/kg) Brain 
HP-β-CD IT 
(mg/mL) CSF 
Otoxicity 
3.8 
127 
0.9 
+ 
+ 
- 
 
 
 
 
 
 
 
 
 
 
200 
166 
1.5 
- 
7.5 
250 
1.8 
NT 
+ 
- 
300 
250 
2.2 
+ 
 
 
 
 
 
 
400 
333 
2.9 
+ 
15 
500 
3.7 
NT 
++ 
- 
600 
500 
4.4 
+ 
 
 
 
 
 
 
900 
750 
6.5 
+ 
30 
1000 
7.5 
++ 
+++ 
++ 
1200 
1000 
8.7 
+ 
 
 
 
 
 
 
1800 
1500 
13.0 
 
Maximum Feasible Dose in Humans: 
2000 
1666 
14.5 
 
60 
2000 
15 
NT 
++++ 
+++ 
2400 
2000 
 
 
120 
4000 
30 
++ 
+++++ 
+++ 
4800 
4000 
 
 
CSF = cerebrospinal fluid; HP-β-CD = 2-hydroxypropyl-β-cyclodextrin; IC = intracisternal; IT = intrathecal; NPC = Niemann-
Pick type C; NT = not tested. 
7. 
STUDY RATIONALE 
At present, no therapies are approved for use in the United States for patients with NPC1 disease. 
Miglustat (ZAVESCA®), an imino sugar, has been approved for the treatment of patients with 
NPC1 disease in many countries outside the United States, including many countries in Europe. 
The Food and Drug Administration (FDA) did not approve miglustat for the treatment of NPC1 
in the United States; however, miglustat was approved by the FDA for a subset of patients with 
Gaucher’s disease. To help address this significant unmet medical need, researchers have 


Protocol Amendment 15.0 
 
VTS-301 
Page 29  
CONFIDENTIAL AND PROPRIETARY 
identified the cholesterol-sequestering agent HP-β-CD as a potential treatment for patients with 
NPC1 disease.  
In naturally occurring nonclinical models of NPC1 disease in the mouse and cat, HP-β-CD has 
been found to: 
• Mobilize excess cellular cholesterol caused by the metabolic deficiency as 
demonstrated in both in vitro and in vivo models (Liu 2010; Ramirez 2010; Aqul 
2011). 
• Delay onset of signs and symptoms and prolong survival by ~ 100% in the mouse 
Npc1 model (Ramirez 2010). 
• Prolong survival by ~ 8-fold, decrease Purkinje cell loss, and improve gait in the cat 
NPC1 model (Vite 2017). 
On the basis of these findings, HP-β-CD has entered clinical evaluation in an NIH phase 1/2a 
study (13-CH-0001) to evaluate the safety of multiple escalating doses. This pivotal phase 2b/3 
efficacy trial in subjects with NPC1 disease is designed to formally evaluate the efficacy of 
HP-β-CD (VTS-270) for the management of the neurologic manifestations of NPC1 disease. 
7.1. 
Risk/Benefit Assessment 
Niemann-Pick type C1 is a fatal disorder with both systemic and CNS signs and symptoms. 
Currently, no treatment has been shown to alter the course of the disease in a clinically 
meaningful manner in subjects with NPC1 disease. Although age of onset varies, patients 
typically develop progressive cerebellar dysfunction, hearing loss, and motor and cognitive 
deterioration with death typically occurring during adolescence. 
2-hydroxypropyl-β-cyclodextrin  administered IT into the CSF has shown effectiveness in the 
naturally occurring mouse and cat models of NPC1. Importantly, it decreased cerebellar neuronal 
loss, delaying or preventing the development of the neurologic signs and symptoms of the 
disease. In the cat, there was an 8-fold prolongation of survival. Efficacy was associated with 
dose-related and irreversible ototoxicity at the highest and maximally efficacious dose tested. 
There are several ongoing independent investigations in which subjects with NPC1 are receiving 
VTS-270 (under iIND). 
In the Phase 1/2a study (Study 13-CH-0001), an effect of adrabetadex above that seen with 
miglustat cannot be demonstrated in a post-hoc comparison of the NPC-SS sub-setted by 
baseline miglustat use. 
Analysis of data from Part A/B of this study shows no benefit of adrabetadex on the pre-
specified co-primary endpoints.  A post-hoc analysis evaluating the effect of miglustat use 
showed that subjects receiving miglustat (with or without adrabetadex) show evidence of disease 
stabilization but subjects receiving adrabetadex without miglustat show disease worsening 
comparable to sham subjects not on miglustat.  
Vtesse has been provided data from 3 subjects being treated under an iIND at Rush University 
Medical Center who have been receiving IT VTS-270 every 2 weeks, the dosing regimen used in 
the NPC1 mutant cat model that was shown to improve neurologic symptoms and improve 


Protocol Amendment 15.0 
 
VTS-301 
Page 30  
CONFIDENTIAL AND PROPRIETARY 
survival. It is important to note that this regimen is different from that employed in the NIH 
phase 1/2a study, where subjects are dosed once a month. 
In the proposed study, it is expected that subjects may experience some degree of nonreversible 
hearing loss; how much of this hearing loss may be attributable to NPC1 disease progression, 
which occurs in approximately 64% of subjects, versus study drug toxicity is not ascertainable at 
the present time. At this stage of clinical development, apart from animal model data and 
uncontrolled clinical reports, there is at present only a theoretical benefit and a known risk of 
ototoxicity in those subjects randomized to study drug. However, given the fatal and irreversible 
nature of NPC1, the continued clinical evaluation of efficacy, despite potential drug-related 
ototoxicity and in the absence of other known dose-limiting or SAEs, is supported, only in those 
subjects (or legally authorized representative): 
• who appear to be benefiting from IT adrabetadex based on the investigator’s 
assessment, AND  
• who are aware of the risks associated with adrabetadex, including hearing loss, and 
understand that no significant differences were seen between patients treated with 
adrabetadex and sham-treated patients on any efficacy measures in this randomized, 
controlled trial. 
7.2. 
Sham Procedure Rationale 
The sham procedure control group for this pivotal study was carefully considered over the 
alternatives (ie, unblinded concurrent non-intervention control, historical control, or a blinded 
placebo control). The sham procedure control (monitored anesthesia care [conscious sedation] or 
if medically necessary, general anesthesia, and 1 to 2 skin needle pricks) minimizes both undue 
risk to the NPC1 subjects and the potential for bias. Because only the IT injection staff would be 
unblinded to treatment assignment, the assessment of the safety and efficacy of VTS-270 by the 
investigator, outcomes raters, and all other site staff is unbiased and no different than if the trial 
were fully placebo-controlled, but without taking the risks inherent in performing lumbar IT 
placebo injections every 2 weeks. 
Subjects enrolled in the VTS301 study were randomly assigned in a 3:1 ratio (in Study Part A) or 
a 2:1 ratio (in Study Part B) to receive either IT administered VTS-270 or a sham control 
procedure. The intention of the sham procedure control group was to provide the most unbiased 
assessment of the efficacy and safety of VTS-270 in the intended population of patients with 
NPC1 disease in this phase 2b/3 pivotal study. 
The sham procedure for this study specifically consisted of 1 to 2 needle skin pricks at the same 
site where a lumbar puncture would occur; the needle(s) were not inserted and no LP was 
performed in sham control subjects. In order to ensure that the sponsor, the investigator, key 
members of the investigator’s staff involved in assessments of efficacy and safety, and the 
subject’s parents/caregivers remained fully blinded to the treatment assignment, a separate 
treatment team was tasked with conducting the IT administration of VTS-270 or sham control 
procedures. This treatment team consisted of a specialist who was credentialed and experienced 
in performing IT injections in pediatric patients (ie, an anesthesiologist, neurologist, pediatric 
oncologist, interventional neuroradiologist, etc.) and an assistant (ie, nursing staff to monitor 
safety and help maintain sterile field). Besides their role on a treatment team, these individuals 


Protocol Amendment 15.0 
 
VTS-301 
Page 31  
CONFIDENTIAL AND PROPRIETARY 
were not involved in any study-specific clinical evaluations, including AE assessments; however, 
physicians in this role could serve as the treating physician/clinician. In this role, the treating 
physician/clinician was the primary point of contact for the subject and family for their overall 
medical care throughout the course of the trial. However, if the treating physician/clinician was 
the IT/sham administrator, a separate blinded clinician at the site (eg, physician, physician 
assistant, nurse practitioner) was responsible for querying and assessing any AEs. The procedure 
(sham procedure or IT injection) was performed in a separate procedure room away from the key 
study staff involved in efficacy and safety assessments and without the parents/caregivers 
present. 
7.3. 
Rationale for Administration of VTS-270 via Spinal Intrathecal 
Access Port System 
Given that VTS-270 does not penetrate the blood-brain barrier and requires IT administration, 
the ability to administer VTS-270 via a spinal IT access port system will obviate the need for 
biweekly LPs, as well as anesthesia, thereby removing a significant burden for subjects and site 
personnel. Part C of the study includes a substudy to assess the safety and tolerability of the 
B. Braun Celsite Spinal Access Port System, which is CE marked in the European Union, for the 
administration of VTS-270 every 2 weeks. An additional substudy of Part C will evaluate the PK 
of VTS-270 administered using the B. Braun Celsite Spinal Access Port System (hereafter 
generally referred to as the “device”). 
8. 
STUDY OBJECTIVES 
8.1. 
Primary Objectives 
8.1.1. 
Part C 
The primary study objective in Part C is to evaluate the long-term safety, tolerability, and 
efficacy of VTS-270. Following a determination of a negative benefit/risk balance on 20 January 
2021, the objective for Part C has been changed to evaluate only longer-term safety and 
tolerability. 
8.2. 
Secondary Objectives 
8.2.1. 
Part C 
The secondary study objectives in Part C are to: 
1. Assess the safety and tolerability of the B. Braun Celsite Spinal Access Port utilized 
to administer VTS-270 (device safety and tolerability substudy). 
2. Assess the plasma and CSF PK of VTS-270 and trough HP-β-CD concentration in 
subjects receiving the 900 mg dose of VTS-270 via the B. Braun Celsite Spinal 
Access Port (device PK substudy). 


Protocol Amendment 15.0 
 
VTS-301 
Page 32  
CONFIDENTIAL AND PROPRIETARY 
8.3. 
Exploratory Objectives 
8.3.1. 
Part C 
There are no exploratory objectives in Part C. 
9. 
INVESTIGATIONAL PLAN 
9.1. 
Study Design 
This is a multicenter, multinational, prospective, randomized, double-blind, sham-controlled, 
3-part, efficacy and safety trial of VTS-270, administered IT every 2 weeks, with a planned 
enrollment of approximately 51 subjects (in Parts A and B) with NPC1 disease. The study is 
being conducted in 3 parts: 
• Part A evaluated 3 different dose levels of VTS-270 versus sham to determine the 
dose level for Parts B and C of the study. A total of 12 subjects were enrolled and 
have completed Part A. 
• Part B evaluated the safety and efficacy of the VTS-270 dose selected from Part A, 
900 mg, compared with sham control in approximately 51 subjects including the 
12 subjects from Part A. Subjects received treatment with VTS-270 for up to 
52 weeks (inclusive of Part A). 
• Part C will be an open-label extension phase of the study for those subjects who 
qualify; additionally: 
− A European site-specific substudy of the safety and tolerability of the device was 
conducted in subjects who met the eligibility criteria to have a device implanted 
for VTS-270 infusion. Device implantations were terminated in August 2018 
following reports of the catheter tip migrating from the IT space in some subjects. 
− A European site-specific substudy of plasma and CSF PK of VTS-270 
administered via the device was planned but not conducted under Part C, as no 
subjects consented. 
The VTS270 development program has been terminated by the sponsor. No new subjects are 
permitted to enroll in the study. 
9.2. 
Dose Reduction 
As established by the DSC, a dose reduction regimen was available in Part B through which, 
under specific circumstances and after discussion with the unblinded medical monitor, an 
investigator could be allowed to reduce the dose for an individual study subject. Subjects who, in 
the opinion of the investigator, experienced a drug-related AE after any blinded IT treatment that 
was considered clinically relevant and impactful to the subject’s function could have their dose 
of study drug reduced. 
If a subject required dose reduction due to an AE meeting the above description, the dose was to 
be initially reduced from 900 mg to 600 mg per lumbar IT administration. If, following dose 


Protocol Amendment 15.0 
 
VTS-301 
Page 33  
CONFIDENTIAL AND PROPRIETARY 
reduction to 600 mg, a subject continued to experience an AE as described above, the subject’s 
dose could be further reduced to 400 mg per lumbar IT administration. Following dose reduction 
to 400 mg, if a subject continued to experience AE(s) as described above, the dose was NOT to 
be reduced further, and the subject was to be discontinued from Part B of the study, being given 
the option to transition into Part C at a lower dose, based on discussion with the unblinded 
medical monitor and on a case-by-case basis. 
Once the dose of VTS-270 had been reduced for a given subject in Part B, the dose could not be 
subsequently increased back to the dose selected for Part B (900 mg). In addition, dose reduction 
on an individual subject basis was separate from the Data Monitoring Committee (DMC) review 
of all subject safety data, which could result in dose reduction for all subjects enrolled in the 
trial. 
The same guidelines apply for dose reduction in Part C, except that study drug will be open-label 
(not blinded) and the frequency of dosing may also be reduced. Each subject for whom dose 
reduction or dose frequency change is considered will be individually reviewed with the medical 
monitor. 
9.3. 
Dose Re-escalation 
Dose re-escalation is not permitted as of 20 January 2021. 
9.4. 
Rescue Option 
The rescue option was only applicable to Part B. 
Please see Table 2 for overall study design, and refer to Section 23 for the Schedule of 
Assessments. 
Table 2: 
Phase 2b/3 3-Part Study Design 
 
Part A 
Part B 
Part C 
Treatment 
Dose 
N 
DSC 
Assessment 
Dose 
N 
Total 
Dose 
N 
Total 
VTS-270 
900 mg 
3 
Final Dose 
Selection 
900 mga 
26 
35 
900 mg 
biweekly, or 
lower dose with 
possible reduced 
frequency 
51 + up 
to 14 
NIH 
phase 1 
51-65? 
1200 mg 
3 
1800 mg 
3 
Sham 
Sham 
Control 
3 
Sham 
Control 
13 
16 
 
Total 
12 
39 
51 
a Subjects who received VTS-270 in Part A will continue on the selected Part B dose, and subjects who received 
sham in Part A will remain on sham for a total of 12 months.  
DSC = dose selection committee; NIH = National Institutes of Health.
 


Protocol Amendment 15.0 
 
VTS-301 
Page 34  
CONFIDENTIAL AND PROPRIETARY 
10. 
CRITERIA FOR EVALUATION 
10.1. 
Part C (Including Substudies) Endpoints 
10.1.1. 
Primary Endpoints in Part C 
As of 20 January 2021 no efficacy analyses will be performed. 
• The change from baseline to each assessment in a composite outcome that is the sum 
of the ambulation, cognition, fine motor, and swallowing components of the NPC-SS. 
• The change from baseline to each assessment in total NPC-SS with the hearing 
domain and auditory brainstem response (ABR) modifiers removed. 
• Proportion of responders (defined as no change or improvement on NPC-SS total 
score with hearing domain and ABR modifiers removed) at each assessment. 
• Proportion of Blinded Clinician-Clinical Global Impression of Change (CGIC) 
(defined as a score of no change, minimally improved, moderately improved, or 
markedly improved) at each assessment compared to baseline. 
• Summary of AEs, concomitant medications, physical examinations, audiologic 
examination, and clinical laboratories. 
• Change from baseline in the EQ-5D-3L questionnaire at each assessment. 
• Change from baseline to each assessment in each of the 9 clinical domains of the 
NPC-SS. 
• Change from baseline to each assessment in the total NPC-SS with hearing domain 
and ABR modifier included. 
• Time to 1-point increase (worsening) in NPC-SS composite score. 
• The composite NPC-SS mean annualized rate of change (slope) from baseline to each 
assessment. 
10.1.2. 
Secondary Endpoints in Part C 
Secondary endpoints in Part C will be evaluated for the device safety and tolerability substudy 
for the first 9 port infusions: 
• Summary of wound check, examination of port site and catheter track at access port 
infusion visits. 
• Intracranial pressure (ICP) via LP. 
• Summary of plasma and CSF pharmacokinetic parameters following a single dose of 
VTS-270. 


Protocol Amendment 15.0 
 
VTS-301 
Page 35  
CONFIDENTIAL AND PROPRIETARY 
11. 
SUBJECT SELECTION 
11.1. 
Study Population 
Subjects with a diagnosis of NPC disease who meet the inclusion and exclusion criteria will be 
eligible for participation in this study. 
Eligibility criteria for Part A/Part B are not applicable as these parts have been completed. 
As of 20 January 2021, no new subjects can be enrolled. 
11.2. 
Inclusion Criteria Part C 
No new subjects may be enrolled in the study. 
1. Subject has completed Part B, meets the criteria for dose reduction for a second time 
(see Section 9.2), or meets the criteria for the rescue option (see Section 9.4). 
OR 
2. Subject is a current participant in the NIH phase 1/2a open-label study and: 
a. 
Subject agrees to convert from the dose of VTS-270 currently receiving as a 
subject in the NIH phase 1/2a protocol to the dose chosen for Parts B and C of 
this study, 900 mg; 
b. 
Subject agrees to convert from the monthly dosing regimen used in the NIH 
phase 1/2a protocol to an every 2 weeks dosing regimen; 
c. 
In instances where NIH phase 1/2a subjects eligible to enroll into Part C are 
unable to convert from their current NIH phase 1/2a dose or monthly regimen, 
the investigator must receive prior written authorization from the sponsor for the 
subject to enter Part C of the study on an amended dose and/or regimen. 
OR 
3. Subject has received prior written authorization from Vtesse to enroll directly into 
Part C. 
4. Females of childbearing potential (not surgically sterile) must use a medically 
acceptable method of contraception and must agree to continue use of this method for 
the duration of the study and for 30 days after participation in the study. Acceptable 
methods of contraception include barrier method with spermicide, intrauterine device, 
steroidal contraceptive in conjunction with a barrier method, abstinence, or same-sex 
partner. 
5. Subject or parent/guardian must provide written informed consent to participate in the 
study. In addition to parental consent, assent to participate must also be sought from 
minor children. 


Protocol Amendment 15.0 
 
VTS-301 
Page 36  
CONFIDENTIAL AND PROPRIETARY 
11.3. 
Criteria for Part C European Site-specific Device Safety and 
Tolerability Substudy 
This European site-specific VTS301 substudy investigated the safety and tolerability of the 
spinal IT access device in approximately 6 subjects who were currently enrolled in VTS301 
Part C. 
11.3.1. 
Inclusion Criteria for European Site-specific Device Safety and Tolerability 
Substudy 
NOTE: Enrollment in the device substudy was terminated in August 2018. 
A subject must have met all of the following inclusion criteria to be eligible to enroll in the 
substudy: 
1. Subject must be enrolled in Study VTS301 Part C. 
2. Subject must have received a minimum of 3 doses of VTS-270 (900 mg each) in Part 
C of Protocol VTS301 (frequency of every 2 weeks) and be on a stable dose to be 
eligible for device placement.  
3. Subject or parent/guardian must provide written informed consent to participate in the 
study. In addition to parental consent, assent to participate must also be sought from 
minor children. 
4. Females of childbearing potential (not surgically sterile) must use a medically 
acceptable method of contraception and must agree to continue use of this method for 
the duration of the study and for 30 days after participation in the study. Acceptable 
methods of contraception include barrier method with spermicide, intrauterine device, 
steroidal contraceptive in conjunction with a barrier method, abstinence, or same-sex 
partner. 
5. Subject or caregiver must possess the ability, in the judgment of the investigator, to 
understand and comply with protocol requirements, including clinical outcome 
measurements and instructions, for the entire duration of the study. 
6. Caregiver, parent, guardian, or responsible adult must be able and willing to 
accompany the subject to study visits. 
11.3.2. 
Exclusion Criteria for European Site-specific Device Safety and Tolerability 
Substudy 
The presence of any of the following excluded a subject from substudy enrollment: 
1. Musculoskeletal/spinal abnormality or other anatomic abnormality identified by 
symptoms, history, physical/neurological examination, and/or imaging studies that 
would impact placement and patency of the device (port and catheter). 
2. Skin infection in the lumbar or abdominal region within 3 months prior to device 
placement. 


Protocol Amendment 15.0 
 
VTS-301 
Page 37  
CONFIDENTIAL AND PROPRIETARY 
3. Subjects who, in the opinion of the investigator, are unable to comply with the 
protocol or have disease severity or medical conditions that would potentially 
increase the risk of participation or confound study results. 
4. Subjects with suspected or confirmed infection of the CNS or any systemic infection. 
5. Absolute neutrophil count less than 1.5 × 109/L. 
6. Platelet count less than 100 × 109/L. 
7. Activated partial thromboplastin time (aPTT) or prothrombin time (PT) greater than 
1.5 times the upper limit of normal (ULN) or known history of a bleeding disorder. 
8. Requirement for anticoagulation therapy. 
9. Evidence of obstructive hydrocephalus or normal pressure hydrocephalus based on 
symptoms, history, and physical/neurological examination, or elevated ICP (opening 
ICP > 25.0 cm H2O). 
10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 4 
times the ULN, or total bilirubin greater than 2 times ULN. 
11. Hemoglobin more than 2 standard deviations below normal for age and gender. 
12. Estimated glomerular filtration rate (eGFR) less than 60 mL/minute/1.73 m2 
calculated using the modified Schwartz formula (2009) for subjects aged 4 through 17 
years or using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula for subjects aged 18 years and older. 
13. Active pulmonary disease, oxygen requirement, or clinically significant history of 
decreased blood oxygen saturation, pulmonary therapy, or requiring active suction. 
14. Hypersensitivity to any materials contained in the device port or catheter. 
15. Subjects with a CNS shunt. 
16. Prior radiation therapy to the area for device placement. 
17. Expected need for magnetic resonance imaging during participation in the study, with 
exception of the following allowable conditions for safe scanning immediately after 
device placement: 
a. Static magnetic field of 3 Tesla and 1.5 Tesla; 
b. Maximum spatial gradient magnetic field of 710 Gauss/cm or less; 
c. Maximum whole body averaged specific absorption rate of 2.9 W/kg for 
15 minutes of scanning. 


Protocol Amendment 15.0 
 
VTS-301 
Page 38  
CONFIDENTIAL AND PROPRIETARY 
11.4. 
Inclusion Criteria for European Site-specific Device PK Substudy 
The European site-specific device PK substudy will investigate plasma and CSF PK of VTS-270 
administered via the IT access device. A subject must meet the following inclusion criteria to be 
eligible to enroll in the device PK substudy: 
1. Subject has completed the device safety and tolerability substudy and received 
9 consecutive doses of 900 mg VTS-270 via the device. 
OR 
2. After 6 subjects have completed the device safety and tolerability substudy, subjects 
in Part C who are receiving a stable dose of 900 mg VTS-270 via LP and are eligible 
for implantation of the device per the above eligibility criteria for the device safety 
and tolerability substudy. 
3. Subject or parent/guardian must provide written informed consent to participate in the 
study. In addition to parental consent, assent to participate must also be sought from 
minor children. 
12. 
CONCOMITANT MEDICATIONS 
All subjects should be maintained on the same medications throughout Parts A and B of the 
study, as medically feasible. 
12.1. 
NPC Treatment-related Medications 
• Allowed NPC treatment-related medications 
− Miglustat (ie, ZAVESCA or generic) maintained at a constant dose (dose 
adjustments for weight or as medically necessary are permitted). 
• Prohibited NPC treatment-related medications 
− Any other investigational treatment for NPC including, for example, vorinostat or 
arimoclomol. 
12.2. 
Allowed Medications and Treatments 
• Age-appropriate multivitamins. 
• Other required chronic medications as prescribed by a physician should be 
maintained at a constant dose throughout the study (dose adjustments for weight or as 
medically necessary are permitted). 
• Short-term course of other medication for treatment of eg, otitis, urinary tract 
infection, pain, upper respiratory infection. 


Protocol Amendment 15.0 
 
VTS-301 
Page 39  
CONFIDENTIAL AND PROPRIETARY 
12.3. 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be considered 
a protocol violation: 
• Nonprescription supplements (Section 11.2), which must be discontinued at least 
1 month before screening and not used for the 12-month duration of the trial. 
• Any other investigational or non-approved therapies. 
13. 
STUDY TREATMENTS 
13.1. 
Method of Assigning Subjects to Treatment Groups 
13.1.1. 
Part C 
All subjects will be assigned to receive VTS-270 at the dose level and frequency used in Part B 
of the study (900 mg every 2 weeks), unless otherwise allowed by the sponsor on an individual 
subject basis. Subjects who have prior written authorization from Vtesse to enroll directly into 
Part C will be assigned to receive 900 mg VTS-270 every 2 weeks, unless otherwise indicated by 
the sponsor on an individual subject basis. 
13.1.1.1. Part C: European Site-specific Device Safety and Tolerability Substudy 
Approximately 6 subjects meeting eligibility criteria for the device safety and tolerability 
substudy were assigned to receive VTS-270 at the dose level and frequency used in Part B of the 
study (900 mg every 2 weeks). 
13.1.1.2. Part C: European Site-specific Device PK Substudy 
All subjects in the device PK substudy will receive 900 mg VTS-270 every 2 weeks via the 
device. 
13.2. 
Blinding 
13.2.1. 
Parts A and B 
Part A and Part B were blinded. 
13.2.2. 
Part C 
Part C is open label. There will be no blinding. Since there is no blinding for subjects in Part C, 
sedation for lumbar IT drug administration is not required and should be used only if in the 
judgment of the treating clinician it is medically warranted. 
The substudies of Part C (device safety and tolerability substudy and device PK substudy) will 
also be open label. There will be no blinding. 


Protocol Amendment 15.0 
 
VTS-301 
Page 40  
CONFIDENTIAL AND PROPRIETARY 
13.3. 
Formulation of Test and Control Products 
VTS-270 will be provided in appropriately labeled vials, formulated as a 200 mg/mL injectable 
solution. An unblinded pharmacist/designee at each investigational site will be responsible for 
dispensing or preparing the assigned dosage undiluted (the 900 mg dose will be administered in 
4.5 mL, the 600 mg dose will be administered in 3 mL, and the 400 mg dose will be administered 
in 2 mL). 
13.3.1. 
Formulation of Test Product 
The formulation and filling of VTS-270 involves dissolving the Active Pharmaceutical 
Ingredient in water for injection, adding sodium chloride to 0.9% w/v and adjusting the pH if 
necessary with 0.01N sodium hydroxide, and bringing to the final volume with water for 
injection. The product is a clear, colorless solution that is free from visible foreign matter. The 
product is then sterile filtered into vials (5 mL fill with a 1 mL overfill) and autoclaved. The final 
formulation and fill process will be transferred to a third party contract manufacturer for future 
commercial manufacturing. This will be carried out under a formal technology transfer protocol 
and product comparability will be assessed. 
13.3.2. 
Formulation of Control Product 
There is no control product in this study. 
13.3.3. 
Packaging and Labeling 
Preparation, packaging, and labeling of all study medications will be in accordance with standard 
operating procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable 
local laws/regulations. All investigational medication used in this study will be prepared, 
packaged, and labeled under the responsibility of Vtesse and their designees. 
Labeling of the study drug will be in accordance with GMP, Manufacture of Investigational 
Medicinal Products, and local legislation. During the study, the study drug will not at any time 
be handed out to the subjects. The designated study personnel will be responsible for the 
handling and administration of the study drug during the study. 
The labels on the outer package (carton) containing vials will include the following minimum 
information: 
1. Study number. 
2. Name of the responsible investigator/site number. 
3. Number of vials containing 2-hydroxypropyl-β-cyclodextrin solution (VTS-270). 
4. Volume of study drug in each vial. 
5. Dosage and route of administration according to special instructions. 
6. Storage conditions. 
7. Expiry date. 
8. Caution statement: For clinical trial use only. 


Protocol Amendment 15.0 
 
VTS-301 
Page 41  
CONFIDENTIAL AND PROPRIETARY 
9. Sponsor name, address, and phone number. 
10. Manufactured by name. 
11. Kit number. 
12. Batch number. 
The labels on the vials containing 2-hydroxypropyl-β-cyclodextrin (VTS-270) will include the 
following minimum information: 
1. Study number. 
2. Sponsor name and address. 
3. Manufactured by name. 
4. Subject number. 
5. Investigator (site) number. 
6. Administration route. 
7. Single-use vial. 
8. Volume of study drug in each vial. 
9. Batch number. 
10. 2-hydroxypropyl-β-cyclodextrin solution for injection. 
11. Caution statement: For clinical trial use only. 
The packaging will consist of 8 mL Type I white glass vial filled with 6 mL of VTS-270 (5 mL 
fill with a 1 mL overfill), 20 mm FIOLAX stopper, and plastic white flip-off caps coated with 
FluroTec. 
13.4. 
Supply of Study Drug at the Site 
The sponsor (or designee) will ship study drug to the investigational sites. The initial study drug 
shipment will be shipped after site activation (ie, all required regulatory documentation has been 
received by the sponsor and a contract has been executed). Subsequent study drug shipments will 
be made after site request for resupply. 
13.4.1. 
Dosage/Dosage Regimen 
VTS-270 will be provided in labeled 8 mL Type I glass vials, formulated as a 200 mg/mL 
injectable solution (5 mL fill with a 1 mL overfill). The assigned dosage will be administered per 
the following: 
• 900 mg dose will be administered in 4.5 mL. 
• 600 mg dose will administered in 3 mL (if dose reduction required and authorized). 
• 400 mg will be administered in 2 mL (if dose reduction required and authorized). 
All doses are administered undiluted. Other doses less than 900 mg will also be administered 
undiluted. VTS-270 administration via LP and sham will be conducted every 2 weeks under 


Protocol Amendment 15.0 
 
VTS-301 
Page 42  
CONFIDENTIAL AND PROPRIETARY 
monitored anesthesia care (conscious sedation) or if medically necessary, general anesthesia, for 
52 weeks in Parts A and B. Subjects in Part C will receive VTS-270 until the investigator 
considers VTS-270 to no longer be beneficial to the subject, or the development program is 
discontinued. There are no adjustments for weight or subject age. 
The VTS270 development program has been terminated by the Sponsor following a 
determination of a negative benefit / risk balance. Although the Sponsor recommends 
discontinuing treatment with VTS270 as soon as possible, treatment for up to an additional 
9 months (20 October 2021) will be permitted to allow for transition planning. This continuation 
of treatment is contingent upon subject re-consent and approval by the applicable IRB/EC and 
health authority. 
13.4.2. 
Dispensing 
An unblinded pharmacist/designee at each investigational site will be responsible for preparing 
the assigned dosage undiluted in a sterile environment (eg, under a laminar airflow hood or other 
clean room environment). Alternatively, the unblinded pharmacist/designee may dispense the 
assigned dosage undiluted for subsequent preparation by the IT administrator within the sterile 
field of the LP procedure room. 
13.4.3. 
VTS-270 Administration by Lumbar Puncture and Sham Lumbar Puncture 
VTS-270 will be provided in appropriately labeled vials (8 mL Type I white glass vial filled with 
6 mL of VTS-270, 20 mm FIOLAX stopper, and plastic white flip-off caps coated with 
FluroTec, or similar vial) formulated as a 200 mg/mL injectable solution. A pharmacist/designee 
at each investigational site will be responsible for preparing the assigned dose undiluted (ie, a 
900 mg dose will be administered in 4.5 mL, a 600 mg dose will be administered in 3 mL, and a 
400 mg dose will be administered in 2 mL). Study drug should be stored between 15 and 30°C, 
inclusive. 
The IT dosing via LP or sham procedure will be conducted by dedicated study personnel who are 
unblinded to treatment group; this cannot involve any of the blinded key study site personnel 
responsible for the blinded efficacy ratings or AEs. Besides their role on a treatment team, these 
individuals will not be involved in any study-specific clinical evaluations, including AE 
assessments. Note that in those instances in which the IT/sham administrator is also serving as 
the treating physician/clinician for the subject and family, being responsible for their overall 
medical care throughout the course of the trial, a separate, blinded clinician at the site (eg, 
physician, physician assistant, nurse practitioner) will be responsible for querying and assessing 
AEs. The IT injection or sham procedure will be performed in a dedicated room and the key 
study personnel and the parents/caretakers will not be present during the procedure to ensure 
blinding. 
For subjects randomized to drug treatment, VTS-270 will be administered as an IT slow bolus 
(1 to 2 minutes, depending on the volume administered) LP injection (maximum rate of 
administration = 4.5 mL/minute). The volume of the injection is determined by the dose group 
(Table 3). Prior to the VTS-270 injection, a volume of CSF approximately equal to the VTS-270 
dose is to be removed. Anesthesia or sedation will be used for the IT dosing procedure, following 
institutional guidelines and procedures. Subjects will be required, if possible, to lie flat for 30 to 
45 minutes following dosing with feet elevated. 


Protocol Amendment 15.0 
 
VTS-301 
Page 43  
CONFIDENTIAL AND PROPRIETARY 
Table 3: 
VTS-270 Dose, Injection Volume, and Concentration 
Dose Group 
Injection Volume 
Concentration (mg/mL) 
900 mg 
4.5 mL 
200 
600 mg 
3.0 mL 
200 
400 mg 
2.0 mL 
200 
For subjects randomized to the sham procedure control group, the sham procedure will consist of 
1 to 2 small needle pricks on the lower back at the location where the LP and IT injection is 
normally made. The needle(s) will break the skin but no LP or needle insertion will occur. The 
needle prick(s) will be covered with the same bandage that is used to cover the IT injection 
normally, thus simulating the appearance of an IT LP injection. Anesthesia or sedation is used 
for the IT dosing procedure in VTS-270 treated subjects, in order to maintain the blind, a similar 
type of anesthesia, sedation, or minimal sedation (ie, a low dose of an anxiolytic) should be used 
for the sham procedure, following institutional procedures. The study subject will be kept in the 
procedure room for approximately 30 minutes, simulating the same amount of time that subjects 
administered study drug are kept for administration procedure. All subjects, sham and study 
drug, are required, if possible, to lie flat with feet elevated for 30 to 45 minutes following dosing. 
For the 3 days following each procedure, subjects in both the sham and drug-treatment groups 
are to avoid acoustic overstimulation and minimize exposure to loud noises, eg, headphones for 
music or video games. 
For additional details, refer to the Study Manual. 
13.4.4. 
Study Drug Administration in the European Site-specific Device Substudies 
The Celsite Spinal Access Port System should be accessed only by personnel experienced in the 
technical and clinical aspects of access ports. 
The port should only be accessed using the non-coring Huber needles. Utilizing a standard 
needle will cause serious damage to the port and will require the system to be surgically 
explanted. 
The port site and catheter track must be inspected prior to study drug administration. If abnormal 
swelling or redness is noted around the port or along the catheter site and infection is suspected, 
study drug should not be administered and appropriate evaluation of the device and catheter track 
should be undertaken to rule out malfunction or infection. 
Subjects/caregivers participating in the European site-specific device substudies (safety and 
tolerability and/or PK) should report any of the following findings to the investigator as soon as 
possible: 
• Significant changes in lower limb function (eg, muscle weakness, numbness). 
• Significant changes in bladder or bowel control (eg, incontinence, inability to void). 
• Severe back pain or sciatica. 
• Persistent headache and/or stiff neck associated with fever. 


Protocol Amendment 15.0 
 
VTS-301 
Page 44  
CONFIDENTIAL AND PROPRIETARY 
VTS-270 administration via the device will be conducted every 2 weeks. There are no 
adjustments for weight or subject age. The access port area will be prepared for sterile 
manipulation following standard site procedures. Cerebrospinal fluid will be withdrawn through 
the port. The first 1 mL will be discarded, and then a volume of CSF approximately equal to that 
being administered (including study drug and a 1.5 mL flush with preservative-free- 0.9% saline 
solution) will be withdrawn. The volume of the study drug infusion is determined by the dose 
(Section 13.4). Subjects will receive the same dose of VTS-270 administered during Part C via 
LP. VTS-270 will be administered as a slow bolus over 1 to 2 minutes with a maximum rate of 
infusion of 4.5 mL/minute. Noncoring needles adapted for use with Celsite Spinal Access Port 
System should be used. Normal hypodermic needles will damage the port septum and may cause 
leakage of the system or blockage due to small silicone particles from the septum.  
Following the infusion of VTS-270, the system should be flushed with 1.5 mL of 
preservative-free 0.9% saline solution. Heparin should not be used in an IT access port. If 
resistance to infusion is noted at any time during administration of VTS-270 or during the flush, 
or if swelling occurs around the port or along the catheter during infusion or flush, device 
malfunction should be suspected and device patency assessed as per Access Port Manual of 
Procedures. 
Additional Procedures for Subjects in the European Site-specific Device PK Substudy 
For subjects in the device PK substudy, paired blood and CSF sampling over time will be 
conducted before and after a single dose administration, which will be the first and only dose in 
the substudy for subjects entering the substudy from the device safety and tolerability substudy 
(Table 15), and the fourth dose for subjects entering the substudy from the main Part C study. 
Just prior to VTS-270 administration, a blood sample (approximately 4 mL) for VTS-270 
concentration and a volume of CSF approximately equal to the volume of VTS-270 to be 
administered (4.5 mL for the 900 mg dose) plus 1.5 mL for flush of the device will be 
withdrawn. The first 1 mL of CSF withdrawn from the port should be discarded. Approximately 
2 mL of the CSF sample will be sent for routine clinical laboratory tests, and approximately 
2.5 mL will be sent for VTS-270 assay. VTS-270 will then be administered via the device as a 
slow bolus over 1 to 2 minutes. Following drug infusion, the device will be flushed with 1.5 mL 
preservative-free 0.9% saline. Blood and CSF samples will then be obtained at 1 hour 
(± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 5 minutes), 6 hours (± 30 minutes), 8 hours 
(± 30 minutes), approximately 24 hours, and approximately 30 hours after infusion. The 30-hour 
time point should be at least 6 hours after the 24-hour time point. See Section 14.2.10 for further 
details on the assessments for PK. 
Anesthesia is not required for administration of VTS-270 via the device; however, as determined 
by the investigator and clinical staff, the clinical site has the option to give topical anesthetic 
agents based on a subject’s condition. 
All subjects should lie flat with feet elevated for 30 to 45 minutes following dosing. 
13.5. 
Storage 
Investigational product should be stored between 15°C and 30°C (59°F and 86°F), inclusive. For 
additional details, refer to the Pharmacy Manual. 


Protocol Amendment 15.0 
 
VTS-301 
Page 45  
CONFIDENTIAL AND PROPRIETARY 
13.6. 
Study Drug Accountability 
Drug supply will be managed by the clinical study center. The study pharmacy/designee is 
responsible for the accountability of the investigational product. This will include documentation 
of receipt, storage, and dispensing of the investigational agent. The pharmacy will return or 
destroy (per instruction of the sponsor) unused investigational drug at the conclusion of the 
study. 
13.7. 
Investigational Device (for European Site-specific Device Substudies) 
13.7.1. 
Investigational Device Handling 
It is the responsibility of the clinical site to ensure that a sufficient stock of port kits is available 
at the appropriate intervals based on subject enrollment. For each subject receiving an IT access 
port, 2 kits that have passed visual inspection are required. A surplus of at least one kit must be 
maintained in inventory at all times. Refer to the sponsor-supplied Access Port System Manual 
of Procedures for ordering, receiving, returning, and presurgical preparation of the device. 
13.7.2. 
Investigational Device Implantation 
The Celsite Spinal Access Port System (port and catheter) will be surgically implanted in 
subjects by personnel experienced in the technical and clinical aspects of access ports. Specific 
procedures for implantation of the device in NPC1 subjects are detailed in the sponsor-supplied 
Access Port Manual of Procedures for the Braun Celsite Access Ports (ST304-20G). The subject 
will begin a 3-day IV course of a fourth-generation cephalosporin antibiotic approximately one 
hour prior to surgery, which will be followed by an 11-day course of oral fourth-generation 
cephalosporin antibiotic (total of 14 days). If cephalosporin cannot be used, the physician will 
administer another appropriate antibiotic. The subject will be under general anesthesia for this 
procedure. Standard hospital procedures for surgery will be followed. An x-ray will be taken 
postoperatively to verify proper implantation of the port and to confirm the catheter was placed 
at the mid-thoracic level. The date the x-ray was taken and subsequently read will be 
documented in the electronic case report form (eCRF). A copy of the x-ray should be stored in 
the subject’s study record. The investigator should take appropriate measures to protect subject 
privacy if the x-ray needs to be transferred outside the facility of origin, such as de-identification 
of the image.  
The subject will remain in the hospital for 3 days, including the day of surgery. Sutures will be 
removed when deemed appropriate by the investigator and may need to be removed by the local 
treating physician. A minimum of 14 days following implantation of the device must elapse 
before it is used for VTS-270 administration. 
13.7.3. 
Investigational Device Removal 
For European site-specific subjects with the device, if the device becomes nonfunctional at any 
time during the study, it will be removed and may be replaced (a flowchart to assess the device 
malfunction is included in the Access Port Manual of Procedures; note that CSF sampling and 
VTS-270 administration can occur via LP injection while the malfunction is being evaluated). If 
the subject discontinues the study early, the device must be removed. See the sponsor-supplied 
Access Port Manual of Procedures for information regarding device removal. Device removal 


Protocol Amendment 15.0 
 
VTS-301 
Page 46  
CONFIDENTIAL AND PROPRIETARY 
and postoperative care will be conducted under standard medical practices, depending on the 
reason for the removal. The procedure for initiating a Product Incident Report (PIR) and return 
of the device is located in the sponsor-supplied Access Port Manual of Procedures. 
Additional reasons for device removal include termination of the adrabetadex (VTS-270) clinical 
development program. 
13.7.4. 
Investigational Device Accountability 
Inventory and accountability records for the investigational devices will be kept by the 
investigator or designee. 
The clinical site is responsible for providing by-subject accountability of the device components 
throughout the clinical study. To facilitate tracking the devices from the time of receipt to time of 
return to the vendor, the sponsor has supplied an Accountability Log. All information should be 
recorded in permanent black ink. Any corrections should be made by a using a single line to 
strike out any text, and the corrections should be initialed and dated by the staff member making 
the corrections. The Accountability Log will be added to the on-site Regulatory Binder and 
entered into the electronic data capture system. Please refer to the sponsor-supplied Access Port 
Manual of Procedures for detailed instructions. 
13.7.5. 
Investigational Device Handling and Disposal 
The Celsite Spinal Access Port System is for single subject use only; do not re-sterilize the 
product or any of the components, and destroy unused items after use. The device and its 
accessories are neither re-usable nor designed to be re-used. Any re-use will compromise the 
performance and safety of the device. 
13.8. 
Measures of Treatment Compliance 
Study drug or sham procedure will be administered at the study site by a study clinician. The 
amount of study drug infused will be recorded and overall treatment compliance will be 
calculated. 
For European site-specific subjects with the Celsite Spinal Access Port System, the device will 
be surgically implanted by a qualified surgeon according to the sponsor-supplied Access Port 
Manual of Procedures which contains additional details beyond the Instructions for Use insert for 
the Braun Celsite Access Ports (ST304-20G). Proper implantation of the port and catheter 
location at the mid-thoracic level will be confirmed by radiograph on the day of implantation and 
as indicated by the investigator to determine device placement and/or integrity during the study. 
Catheter patency will be verified according to the discretion of the site. A qualified staff member 
(MD, nurse practitioner [NP], registered nurse [RN], or physician assistant [PA]) will inspect the 
port site and catheter track at each study visit following implantation for evidence of any 
malfunction or adverse reactions. At device infusion visits, this examination will occur prior to 
and during administration of study drug. 


Protocol Amendment 15.0 
 
VTS-301 
Page 47  
CONFIDENTIAL AND PROPRIETARY 
14. 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for Parts A, 
B, and C (including substudies) of the study is diagrammed in Section 23.  
Prior to conducting any study-related activities, written informed consent must be signed and 
dated by the subject or subject’s legal representative. If appropriate, assent must also be obtained 
prior to conducting any study-related activities. 
Part C European site-specific subjects who are eligible to participate in the device safety and 
tolerability substudy, or in the device PK substudy, will undergo a device baseline visit at the last 
LP IT infusion approximately 3 days prior to device placement. Following completion of the 
device safety and tolerability substudy, subjects will have the option to participate in the device 
PK substudy or will continue in the main Part C study. Following completion of the device PK 
substudy, subjects will continue in the main Part C study. 
14.1. 
Overview of Study Procedures 
See Table 10, Schedule of Assessments for Screening through Week 28. See Table 11, Schedule 
of Assessments for Week 30 through Week 52. See Table 12, Schedule of Assessments for 
Week 54 through Week 182. See Table 13, Schedule of Assessments for Week 183 and beyond. 
See Table 14, Schedule of Assessments for End of Study and Follow-up. 
14.2. 
Clinical Assessments 
14.2.1. 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at each study visit for 
Parts A, B, and C until end of study or early termination (ET), when applicable, as well as the 
follow-up visits. Dose, route, unit frequency of administration, and indication for administration 
and dates of medication will be captured. 
14.2.2. 
Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening for Parts A, 
B, and C. 
14.2.3. 
Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases, will be recorded at Screening for Parts A, B, 
and C. 
14.2.4. 
Adverse Events 
Information regarding occurrence of AEs (including adverse device effects for European site-
specific device subjects) will be captured throughout the study, ET, and follow-up visits 1, 2, and 
3, except at the baseline visit. At device infusion visits, AE assessment will be completed prior to 
and after administration of study drug. Definitions associated with AEs and the procedures for 
reporting them are presented in Sections 16.1 and 16.2. 


Protocol Amendment 15.0 
 
VTS-301 
Page 48  
CONFIDENTIAL AND PROPRIETARY 
14.2.5. 
Physical Examination 
At screening for Parts A, B, and C, a complete physical examination will be performed by either 
the investigator or a subinvestigator who is a physician. Subjects in Part B who do not continue 
into Part C will also undergo a complete physical examination at the Week 54 Follow-up Visit. 
Subjects in Part C will undergo a complete physical examination at ET and Follow-up Visit 1. 
Qualified staff (MD, NP, RN, or PA) may complete the abbreviated physical examination at all 
other visits (Part B: Weeks 24 and 52; Part C: every 6 months). New abnormal findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled 
visit, or earlier if clinically indicated. 
In the European site-specific device safety and tolerability substudy, an abbreviated physical 
examination will be conducted during the device baseline visit, on confinement period Days 2 
and 3, and at the first and ninth device infusion visits (D1 and D9). For subjects in the European 
site-specific device PK substudy who transitioned from the device safety and tolerability 
substudy, an abbreviated physical examination will be conducted at baseline. Subjects who enter 
the device PK substudy from the main Part C study will have an abbreviated physical 
examination at baseline of the substudy and on confinement period Days 2 and 3. 
The abbreviated physical examination includes the following: 
• Skin – general examination of exposed skin. 
• Chest – auscultation and percussion of lungs; auscultation of the heart. 
• Abdomen – palpation and auscultation. 
• Extremities – visual inspection. 
New abnormal skin or physical examination findings associated with the site of port and catheter 
implantation must be documented and followed up by a physician or other qualified staff at the 
next scheduled visit, or earlier if clinically indicated. 
14.2.6. 
Wound Check and Examination of Port Site and Catheter Track for European 
Site-specific Device Subjects 
For European site-specific subjects who have an implanted IT access device, immediately after 
implantation of the device, a qualified staff member (MD, NP, RN, or PA) will examine the port 
site and catheter track for any evidence of malfunction. On the day of the first VTS-270 infusion 
via the device, a qualified staff member will perform a check of the wound, port site, and 
catheter track. At all study visits after implantation of device, a qualified staff member will 
inspect the port site and catheter track for any evidence of infection or malfunction associated 
with the IT port system. This examination will include the following:  
• A directed examination of the following areas: 
− The port abdominal implant site. 
− Surrounding skin along the entire path as well as the vertebral bodies adjacent to 
the catheter. 
• The staff member will examine all of the above areas for any adverse changes such as 
but not limited to: 


Protocol Amendment 15.0 
 
VTS-301 
Page 49  
CONFIDENTIAL AND PROPRIETARY 
− Redness. 
− Tenderness of skin and subcutaneous tissues. 
− Swelling and/or fibrotic reaction.  
− Increased warmth. 
− Effusion or exudate (fluctuance and/or discharge). 
− Poor healing/wound dehiscence. 
At device infusion visits, this examination will occur prior to and during any administration of 
study drug, as well as after study drug administration, during the 30- to 45-minute recovery 
period. If any significant concerns are noted during the examination of the wound, port site, 
and/or catheter track such as abnormal swelling or redness around the port or along the catheter 
site, study drug should not be administered, the sponsor/medical monitor should be notified, and 
an appropriate evaluation of the device and catheter track, including imaging, should be 
undertaken to confirm the device and placement and to assess possible malfunction or infection 
(see Access Port Manual of Procedures). Abnormal port and catheter-related observations and 
the lack of integrity of the device or dislodgement will be reported as device-related AEs. 
If the subject is terminating study participation, the device must be removed (see Section 13.7.3).  
A wound check should be performed at ET and all follow-up visits. 
14.2.7. 
Vital Signs 
Body temperature, blood pressure, pulse, and respirations will be performed after a 5-minute rest 
period at 2 different times during each study visit for Parts A, B, and C (including ET and 
Follow-up Visit 1): 1) prior to LP or sham, and 2) after recovery from LP or sham (every study 
visit). For non-dosing visits, perform and record vital signs including blood pressure following 5-
minute rest in supine position. 
In the European site-specific device safety and tolerability substudy, vital signs will be 
performed at baseline visit for device implantation and confinement period Days 1 through 3 for 
device implantation. At each port infusion visit in the substudy, vital signs will be measured 
before infusion and after a 30- to 45-minute recovery period following VTS-270 infusion. 
For subjects in the European site-specific device PK substudy who transitioned from the device 
safety and tolerability substudy, vital signs will be measured at baseline, before infusion of 
VTS-270 using the device, and after a 30- to 45-minute recovery period following the infusion.  
For subjects in the device PK substudy who transitioned from the main Part C study, vital signs 
will be performed at baseline visit for device implantation and confinement period Days 1 
through 3 for device implantation. At each subsequent port infusion visit, vital signs will be 
measured before infusion and after a 30- to 45-minute recovery period following VTS-270 
infusion. 
14.2.8. 
Intracranial Pressure Measurement for European Site-specific Device Subjects 
For subjects in the European site-specific device safety and tolerability substudy and subjects 
transitioning from Part C of the main study to the device PK substudy, ICP (cm H2O) will be 


Protocol Amendment 15.0 
 
VTS-301 
Page 50  
CONFIDENTIAL AND PROPRIETARY 
measured via LP per standard hospital practice just prior to CSF collection at baseline of device 
implantation.  
14.2.9. 
Clinical Laboratory Measurements 
All clinical laboratory samples obtained will be sent to an outside central laboratory, unless 
stated otherwise. Refer to the Laboratory Manual for detailed instructions. 
14.2.9.1. Hematology 
Blood will be obtained and sent to the central laboratory for a complete blood count 
(hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell 
differential, and platelet count), and coagulation (PT and aPTT) at screening (Parts A, B, and C); 
at Weeks 12 (Part B), 24 (Part B), 26 (Part C), 40 (Part B), and 52 (Parts B and C); and every 
6 months after Week 52 (Part C), including ET. 
In the European site-specific device safety and tolerability substudy, blood will be collected for 
hematology and coagulation at the device baseline visit and at the ninth device infusion visit 
(Visit D9).  
For subjects in the European site-specific device PK substudy, hematology and coagulation 
blood tests will be performed at the baseline visit. 
14.2.9.2. Genetic Analysis – Day 0 
Blood will be obtained and archived for genetic analysis (eg, exome or genome sequencing) and 
other research purposes. 
14.2.9.3. Blood Chemistry Profile 
Blood will be obtained for determination of serum sodium, potassium, chloride, bicarbonate, 
calcium, random glucose, blood urea nitrogen, creatinine, AST, ALT, alkaline phosphatase, total 
bilirubin, direct bilirubin, albumin, and lactate dehydrogenase at Screening (Parts A, B, and C); 
at Weeks 12 (Part B), 24 (Part B), 26 (Part C), 40 (Part B), and 52 (Parts B and C); and every 
6 months after Week 52 in Part C, including ET. 
For subjects in the European site-specific device safety and tolerability study, blood will be 
collected for serum chemistry analyses at the device baseline visit and at the ninth device 
infusion visit (Visit D9). 
For subjects in the European site-specific device PK substudy, blood for clinical chemistry tests 
will be collected at the baseline visit. 
The eGFR will be calculated using either the revised Schwartz equation for subjects 4 through 
17 years of age, or the CKD-EPI equation for subjects 18 years of age or older. The following 
formulas are appropriate when creatinine measurements are obtained using creatinine methods 
that have calibration traceable to an isotope dilution mass spectrometry (IDMS) reference 
measurement procedure. 
The revised Schwartz equation (Schwartz 2009) for subjects 4 through 17 years of age: 
• When serum creatinine (SCr) is reported in mg/dL: GFR (mL/min/1.73 m2) = (0.41 × 
Height in cm) / Creatinine in mg/dL). 


Protocol Amendment 15.0 
 
VTS-301 
Page 51  
CONFIDENTIAL AND PROPRIETARY 
• When SCr is reported in µmol/L: GFR (mL/min/1.73 m2) = (36.2 × Height in cm) / 
Creatinine in µmol/L). 
The CKD-EPI equation (Levey 2009) for subjects 18 through 21 years of age: 
• When SCr is reported in mg/dL: GFR = 141 × min (SCr /κ, 1)α × max(SCr /κ, 1)-1.209 
× 0.993Age × 1.018 [if female] × 1.159 [if black] 
Where, SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α 
is -0.329 for females and -0.411 for males, min indicates the minimum of SCr /κ or 1, 
and max indicates the maximum of SCr /κ or 1. 
• When SCr is reported in µmol/L: 
GFR = 141 × min (SCr /κ, 1)α × max(SCr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
Where SCr is serum creatinine in µmol/L, κ is 61.9 for females and 79.6 for males, α 
is -0.329 for females and -0.411 for males, min indicates the minimum of SCr /κ or 1, 
and max indicates the maximum of SCr /κ or 1. 
The revised Schwartz and the CKD-EPI formulae are less likely to overestimate creatinine 
clearance than the more commonly used Cockcroft-Gault formula, as they take into account the 
reduced body size and muscle mass of individuals in the NPC1 patient population. 
14.2.9.4. Pregnancy Test 
A serum pregnancy test will be obtained from female subjects who are of childbearing potential 
at screening (Parts A, B, and C), at Study Visit 27 (Week 52, Parts B and C), and annually after 
Week 52 (Part C). For subjects who complete Part B but elect not to go into Part C, a urine 
pregnancy test will also be obtained at Follow-up Visit 1 (Week 54, Part B). For subjects in 
Part C, a urine pregnancy test will be obtained after ET at Follow-up Visit 1. 
For female subjects of childbearing potential in the European site-specific device substudies 
(safety and tolerability and/or PK), a serum pregnancy test will be performed at baseline of each 
substudy. 
14.2.9.5. Urinalysis 
Urine will be obtained and sent to the central laboratory for determination of color, specific 
gravity, pH, protein, glucose, ketones, and blood. Urinalysis will be performed at screening 
(Parts A, B, and C); at Week 8 (Part A); at Weeks 12, 24, 40, and Week 52 (Part B); and every 
6 months in Part C. 
14.2.9.6. Cerebrospinal Fluid for Routine Clinical Laboratory Tests in Subjects With 
Intrathecal Access Device  
A CSF sample (at least 2 mL) for routine laboratory tests will be collected at the following time 
points: 
• Port and catheter implantation. 


Protocol Amendment 15.0 
 
VTS-301 
Page 52  
CONFIDENTIAL AND PROPRIETARY 
• Immediately prior to each infusion of study drug through the device (the first 1 mL of 
CSF withdrawn should be discarded); includes infusions through the device in the 
main Part C study after the subject completes the substudy (or substudies). 
• End of study. 
The following parameters will be assessed: 
• Glucose. 
• Protein. 
• Red blood cell count. 
• White blood cell count with differential. 
14.2.9.7. Collection, Handling, and Storage of Samples for Clinical Laboratory Tests 
Procedures for collection, storage, and shipment of blood and CSF will be detailed in a separate 
manual of procedures. 
14.2.10. 
Plasma and CSF VTS-270 Concentrations 
Sampling of CSF for Trough Concentrations of HP-β-CD 
A portion of the CSF sample removed prior to VTS-270 infusion via LP in Parts A and B of the 
study (Section 14.2.11) will be analyzed for trough concentrations of HP-β-CD to assess the 
potential for accumulation with repeated dosing. 
Subjects in the European site-specific device safety and tolerability substudy will have CSF 
samples collected for measurement of trough HP-β-CD concentration prior to the first through 
ninth infusions via the device (Visits D2 through D9). The CSF samples will come from the CSF 
routinely removed prior to administration of VTS-270 (Section 13.4.4). 
In addition, subjects in the device PK substudy who transition from main Part C will have CSF 
samples collected for measurements of trough HP-β-CD concentration prior to the first, second, 
and third device infusions. 
Lastly, subjects continuing in the main Part C study after completing either the European 
site-specific device safety and tolerability substudy or the device PK substudy will have CSF 
samples collected for measurement of trough HP-β-CD concentration just before each 
subsequent infusion of VTS270. 
NOTE: Collection of CSF samples for trough HP-β-CD concentrations will no longer be 
performed. 
Sampling of Blood and CSF for Full VTS-270 PK Profile (Device Subjects Only) 
Not applicable as no subject provided consent for this substudy. 
14.2.11. 
CSF, Urine, and Plasma Biomarker Assays 
Not applicable for Part C. 


Protocol Amendment 15.0 
 
VTS-301 
Page 53  
CONFIDENTIAL AND PROPRIETARY 
14.2.12. 
Electrocardiogram 
A 12-lead ECG will be obtained and interpreted locally (at the investigational sites) for safety 
monitoring at screening (Parts A, B, and C), at Week 52 in Parts B and C, and annually after 
Week 52 in Part C. 
14.3. 
Audiologic Evaluation 
Acoustic reflexes, PTA, and ABRs have been used to date to evaluate abnormalities that have 
been previously reported in NPC subjects (King 2014). 
14.3.1. 
Audiologic Testing 
Audiologic evaluations will be performed at defined intervals throughout the study in all 
subjects. In Part A, assessments will be performed at screening, first visit Study Day 0 (first 
study dose), and Weeks 2, 4, 6, and 8. In Part B, assessments will be performed at screening, and 
prior to dosing at Study Day 0, Weeks 8, 16, 24, 32, 40, 46, and 52. In Part C, assessments will 
be performed at screening and every 6 months thereafter, as well as ET and the follow-up visit. If 
a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, 
unscheduled audiologic evaluation visits will increase in regularity at the discretion of the 
Primary Investigator. 
Audiologic assessments will include: 1) behavioral assessment of pure-tone and speech 
thresholds, and air conduction and bone conduction thresholds, when indicated; 2) word 
recognition ability using test techniques appropriate for age and condition; 3) evaluation of 
middle ear function (tympanometry); and 4) otoacoustic emissions (cochlear function). The 
degree of any hearing loss will be defined by a standard clinical pediatric scale (ie, slight, mild, 
moderate, moderately severe, severe, and profound). 
14.3.2. 
Auditory Brainstem Response 
The ABR will be used to assess functional integrity of the auditory nerve and auditory brainstem 
pathways. A hearing threshold will not be obtained, but the waveform morphology and latencies 
will be evaluated. ABR will be conducted at screening in Parts A, B, and C; at Week 8 for all 
subjects in Part A; at Week 52 in Parts B and C; and annually after Week 52 in Part C, and ET. 
The ABR will not be performed as of 20 January 2021 (implemented in advance of 
amendment 14 as there is a direct impact to subject safety). 
14.4. 
Blinded Clinician Clinical Global Impression of Change (Clinician-
CGIC) 
The Clinician-CGIC is to be conducted by an independent, blinded clinician, trained in 
performing neurological exams. This rater will meet with the subject/caregiver at the first visit 
Study Day 0 (Part A and B) and establish a clinical assessment of the subject based on input 
from both subject and caregiver according to a standardized review of clinical status and 
functionality. This assessment at the baseline visit prior to administration of the subject’s first 
dose of study drug is to allow the rater to establish an overall clinical baseline assessment of the 
subject’s status and functionality. These notes are to be kept separately by the blinded rater and 
segregated from all other data regarding a study subject. 


Protocol Amendment 15.0 
 
VTS-301 
Page 54  
CONFIDENTIAL AND PROPRIETARY 
The Clinician-CGIC will be conducted at the beginning of the following visits prior to all other 
procedures and assessments. After the baseline assessment, the blinded rater will have no access 
or knowledge to treatment assignment, clinical and laboratory AEs, laboratory tests, 
Caregiver-CGIC, timed up and go (TUG) test, 9-hole peg test, quality of life (QoL) assessment, 
or NPC-SS assessment. The Clinician-CGIC evaluated using a 7-point Likert scale ranging from 
1 = marked improvement from screening to 7 = marked worsening from screening, will be 
assessed at Weeks 8, 16, 24, 32, 40, 46, and 52 in Parts A and B, plus at Follow-up Weeks 63 
and 76 in Part B for subjects who elect not to participate in Part C. The rater should refer to their 
baseline assessment notes to make these periodic assessments. The same rater should conduct the 
Clinician-CGIC at all visits for a given subject. Additionally, if a subject is deemed to be 
improved or worsened on the 7-point Likert scale, the blinded rater is to indicate the major factor 
that led to said change in score. 
NOTE: The Clinician-CGIC will no longer be performed. 
14.5. 
Blinded NPC Clinical Severity Score Rating 
Data for the NPC-SS rating will be collected at each site by a trained and blinded clinician 
separate from the centralized blinded rater who conducts the Clinician-CGIC. The trained 
clinician will collect the data using a directed source document to permit consistent collection of 
NPC specific domain information. This information will be provided to a centralized 
independent blinded rater who will analyze all NPC information for all subjects across all sites. 
This rater will be blinded to treatment assignment, clinical and laboratory AEs, laboratory tests, 
Clinician-CGIC and Caregiver-CGIC assessments, TUG and 9-hole peg test results, and the QoL 
assessment. 
The NPC-SS score will be assessed at screening, at Study Day 0, and Weeks 8, 16, 24, 32, 40, 
46, and 52 prior to sham or study drug treatment in Parts A and B, and at Follow-up Weeks 63 
and 76 in Part B for subjects who elect not to participate in Part C.  
For Part C, the NPC-SS score will be assessed every 6 months, ET, and the follow-up visit. All 
efforts will be made to have the same trained clinician complete the NPC-SS Intake Form 
assessment at all visits during Parts A and B of the study for a given subject. 
NOTE: The NPC-SS Intake Form assessment will no longer be performed. 
14.6. 
Neurological Examination 
Neurological exams will be performed by the same independent, blinded clinician who performs 
the Clinician-CGIC. A complete neurological exam will be performed at screening (Parts A, B, 
and C), at Week 52 in Part B, at Week 52 of Part C, and ET in Part C. 
An abbreviated neurological exam comprising assessments of eye movements, coordination, 
gait, and reflexes, will be conducted at Week 24 (Part B), at Week 26 (Part C), and every 
6 months after Week 52 in Part C. 
In Parts A and B, the neurological exams will be videotaped to provide a retrievable, visual 
record of the subjects’ neuromotor status and functional capabilities at the 3 distinct evaluation 
time points (Screening, Week 24, and Week 52). Guidelines for obtaining standardized 
videotaped recordings of the neurological exams are provided in the Study Manual. 


Protocol Amendment 15.0 
 
VTS-301 
Page 55  
CONFIDENTIAL AND PROPRIETARY 
In the European site-specific device safety tolerability substudy in Part C, an abbreviated 
neurological examination will be conducted at the baseline visit and ninth IT device infusion 
visit (Visit D9). Additionally, subjects in the device safety tolerability substudy will follow their 
Part C schedule for abbreviated neurological examination (Week 26 of Part C participation) and 
complete neurological examination (Week 52 of Part C participation). Where there is duplication 
of assessments with the baseline and infusion visits of the safety and tolerability substudy, only 
1 assessment will be conducted. 
For subjects in the European site-specific device PK substudy who transitioned from the device 
safety and tolerability substudy, an abbreviated neurological examination will be conducted at 
the baseline visit. Subjects who enter the European site-specific device PK substudy from the 
main Part C study will have an abbreviated neurological examination at the baseline visit. 
14.7. 
Caregiver Clinical Global Impression of Change (Caregiver-CGIC) 
Not applicable for Part C. 
14.8. 
TUG Test and 9-Hole Peg Test 
Not applicable for Part C. 
14.9. 
EQ-5D-3L Quality of Life Assessment 
The EQ-5D-3L assessment is a self-reported, simple, descriptive system measuring 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
The EQ-5D-3L assessment will be conducted prior to dosing at Study Day 0, and at Weeks 8, 16, 
24, 32, 40, 46, and 52 in Parts A and B. Caregiver proxy assessments will be obtained for all 
subjects. 
For Part C, the EQ-5D-3L assessment will be conducted every 6 months and at ET. 
NOTE: The EQ-5D-3L assessment will no longer be conducted. 
15. 
EVALUATIONS BY VISIT 
The collection period of AEs/SAEs will begin after informed consent is obtained and end after 
procedures for the final study visit have been completed. 
15.1. 
Part C 
For the schedules of assessments, see 
• Table 10 (Part C Schedule of Assessments – Screening through Week 28). 
• Table 11 (Part C Schedule of Assessments – Week 30 through Week 52). 
• Table 12 (Part C Schedule of Assessments – Week 54 through Week 182). 
• Table 13 (Part C Schedule of Assessments – Beyond Week 182 Visit Number 92). 


Protocol Amendment 15.0 
 
VTS-301 
Page 56  
CONFIDENTIAL AND PROPRIETARY 
• Table 14 (Part C Schedule of Assessments – End of Study and Follow-up). 
• Table 15 (Part C European Site-specific Device Safety and Tolerability Substudy 
Schedule of Assessments). 
For patients continuing in the study after 21 June 2021, the investigator must assess whether the 
subject is benefiting from treatment with IT adrabetadex.  For those subjects who appear to 
benefit from treatment, the investigator must review with them the risks associated with 
adrabetadex, including hearing loss, and the data from the randomized, controlled trial that 
demonstrated no significant differences between subjects treated with adrabetadex and sham-
treated patients on any efficacy measures.  This discussion should be documented in the subject’s 
medical record and only those subjects (or legally authorized representative) who have 
demonstrated an understanding of the risk/benefit of adrabetadex treatment should be permitted 
to continue in the study. 
16. 
ADVERSE EVENT REPORTING AND DOCUMENTATION 
Information regarding occurrence of AEs will be captured throughout the study. Duration (start 
and stop dates and times), severity/grade, outcome, treatment and relation to study drug will be 
recorded on the eCRF. 
Safety and tolerability data will be summarized by treatment group. 
Adverse event rates will be coded by body system and Medical Dictionary for Regulatory 
Activities (MedDRA) classification term. Adverse events will be tabulated by treatment group 
and will include the number of subjects for whom the event occurred, the rate of occurrence, and 
the severity and relationship to study drug. 
16.1. 
Adverse Events 
16.1.1. 
Definitions 
16.1.1.1. Adverse Event 
An AE (also known as an “adverse experience”) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related (Code of 
Federal Regulations [CFR] 312.32). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the drug, without any 
judgment about causality (GCP definition). 
16.1.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is an AE for which there is reasonable possibility (ie, evidence to 
suggest a causal relationship between the drug and the AE) that the drug caused the event. 
Suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction (21 CFR 312.32(a)). 


Protocol Amendment 15.0 
 
VTS-301 
Page 57  
CONFIDENTIAL AND PROPRIETARY 
16.1.1.3. Adverse Reaction 
An adverse reaction is defined as any AE caused by a drug. 
16.1.1.4. Unexpected Adverse Event/Unexpected Suspected Adverse Reaction 
An unexpected AE (or unexpected suspected adverse reaction) is any AE or suspected adverse 
reaction that is not listed in the Investigator’s Brochure or is not listed at the specificity or 
severity that has been observed if an Investigator’s Brochure is not required/available, or is not 
consistent with the risk information described in the general investigational plan. This also refers 
to AEs or suspected adverse reactions mentioned in the Investigator’s Brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the investigational product. Such events are to be 
reported to the sponsor’s representative (CTI) within 24 hours. 
16.1.1.5. Serious and Unexpected Suspected Adverse Reaction 
A serious and unexpected suspected adverse reaction (SUSAR) is any SAE related to 
investigational product, the specificity or severity of which is not consistent with those noted in 
the current protocol, Investigator’s Brochure, or product labeling. This also refers to AEs or 
suspected adverse reactions mentioned in the Investigator’s Brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the investigational product. Notify the CTI within 24 hours of 
becoming aware of a SUSAR. 
At each study site, a qualified clinician (eg, physician, physician assistant, nurse practitioner) 
will be specifically designated to assess and follow AEs for the study subjects enrolled in the 
trial. This clinician investigator will probe, via discussion with the subject, for the occurrence of 
AEs during each subject visit and record the information in the site’s source documents. Adverse 
events will be recorded in the subject’s eCRF. Adverse events will be described by duration 
(start and stop dates and times), severity, outcome, treatment and relation to study drug, or if 
unrelated, the cause. 
16.1.2. 
Adverse Event Severity 
The National Cancer Institute-CTCAE Version 4.03 should be used to assess and grade AE 
severity, including laboratory abnormalities judged to be clinically significant. If the experience 
is not covered in the AEs of special interest/hearing loss (Section 16.1.4; Table 6), the guidelines 
shown in Table 4 should be used to grade severity. It should be pointed out that the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious. 


Protocol Amendment 15.0 
 
VTS-301 
Page 58  
CONFIDENTIAL AND PROPRIETARY 
Table 4: 
AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically might 
have caused death if it were more severe. 
16.1.3. 
Adverse Event Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 5. 
Table 5: 
AE Relationship to Study Drug 
Relationship to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to that suspected drug; but that 
could readily have been produced by a number of other factors. 
Unlikely 
An event with a temporal sequence from administration of the drug that makes a 
relationship improbable (but not impossible); underlying disease or other concurrent 
therapies provide plausible explanation. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
16.1.4. 
Adverse Events of Special Interest 
16.1.4.1. Clinically Significant Hearing Loss 
NPC1 disease and VTS-270 are both associated with hearing loss. The severity and site of lesion 
of auditory damage may differ between VTS-270 and NPC1 disease induced hearing loss. As 
shown in Table 6, there are some overlapping sites of lesion (outer hair cells), but some more 


Protocol Amendment 15.0 
 
VTS-301 
Page 59  
CONFIDENTIAL AND PROPRIETARY 
likely only in NPC1 disease. In addition, NPC hearing loss appears to progress more slowly than 
drug induced hearing loss. 
Table 6: 
Distinguishing VTS-270 from NPC1 Disease Induced Hearing Loss 
Site of Lesion 
VTS-270 Toxicity 
NPC1 Disease 
Test(s) to Detect 
Outer hair cells 
Yes 
Yes 
PTA, DPOAE 
Inner hair cells 
Maybe 
Maybe 
PTA, ABR 
Hair cell synapses 
Unknown 
Maybe 
PTA, ABR 
Neuronal dysfunction 
Unknown 
Maybe 
PTA, ABR 
ABR = auditory brainstem responses; DPOAE = distortion product otoacoustic emissions; NPC1 = Niemann-Pick type C1; 
PTA = pure tone audiometry. 
If at any time a subject is reported to have clinically significant hearing loss (CTCAE grade 3 or 
higher), this AE will be reviewed in an open-label manner by the DSC (if occurring during 
Part A). Such individuals will have repeat PTA and distortion product otoacoustic emission 
(DPOAE) testing as part of the hearing loss AE evaluation. 
16.1.5. 
Adverse Event Relationship to Investigational Device 
For European site-specific subjects who have an IT access device, the investigator should assess 
relationship of all AEs to the investigational device based on the information in the Investigator’s 
Brochure, the subject’s medical history, and other interventions that preceded the event. 
Guidelines are included in Table 7. 
Table 7: 
Adverse Relationship to Investigational Device 
Related: 
The AE follows a reasonable temporal sequence following the administration of 
the investigational device. The AE follows a known or expected response pattern 
to the investigational device. 
Not related: 
Sufficient information exists to indicate that the etiology of the AE is unrelated to the 
investigational device. The AE does not follow a reasonable temporal sequence 
following administration of the investigational device, and/or the AE is readily 
explained by the subject’s clinical state and/or other therapies. 
AE = adverse event. 
16.1.6. 
Adverse Device and Intrathecal Effects of Special Interest 
Adverse reactions of special interest are categorized as either device issues or issues associated 
with IT access. A list of potential adverse reactions is included below: 
• Device issues: catheter disconnection, rupture, or fragmentation, erosion of 
portal/catheter through the skin, catheter occlusion, inflammatory/foreign body 
reaction, explanation of the port secondary to inflammatory reaction, fibrin sheath 
formation around catheter tip, hematoma, portal site or subcutaneous tract infection, 
malposition of catheter, or port/catheter migration. 
• Issues associated with IT access: CSF leak, dura mater or epidural vein perforation, 
epidural or IT space infection, sepsis, inadvertent epidural placement, pain on 


Protocol Amendment 15.0 
 
VTS-301 
Page 60  
CONFIDENTIAL AND PROPRIETARY 
injection, spinal cord or nerve injury, spinal cord compression (which could lead to 
paralysis), or spinal headache. 
In addition, subjects/caregivers should report any of the following findings to the investigator as 
soon as possible: 
• Significant changes in lower limb function (eg, muscle weakness, numbness). 
• Significant changes in bladder or bowel control (eg, incontinence, inability to void). 
• Severe back pain or sciatica. 
• Persistent headache and/or stiff neck associated with fever. 
16.1.7. 
Actions for Potential Device Deficiency 
A malfunction is the failure of a device to meet its performance specifications or otherwise 
perform as intended. Performance specifications include all claims made in the labeling for the 
device according to local regulations. Note that a flowchart to assess the device malfunction is 
included in the Access Port Manual of Procedures; CSF sampling and VTS-270 administration 
can occur via LP injection as indicated by the investigator. 
If the device becomes nonfunctional or is found to be deficient at any time during the study, it 
will be placed in quarantine and may be replaced. If any deficiency of the investigational device 
occurs, it must not be used. The responsible site staff member will contact the sponsor study 
monitor or the sponsor study director to initiate a PIR. Upon initiation of a PIR, the site will 
receive a package containing all the necessary items to safely return the quarantined item(s). The 
procedure for placing an item in quarantine and initiating a PIR is described in the sponsor-
supplied Access Port Manual of Procedures. 
16.2. 
Serious Adverse Event 
An AE or suspected adverse reaction is considered ‘serious’ if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening AE. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed. 


Protocol Amendment 15.0 
 
VTS-301 
Page 61  
CONFIDENTIAL AND PROPRIETARY 
16.2.1. 
Serious Adverse Event Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) on an SAE 
Report Form. The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed. 
All SAE Report Forms will be reviewed by the site investigator and sent by fax within 24 hours 
of the site learning of the event. Sites will fax the SAE report to the appropriate CTI SAE fax 
number identified on the SAE Fax cover page. 
The site will notify the CTI of additional information or follow-up to an initial SAE Report as 
soon as relevant information is available. Follow-up information is reported on an SAE Report 
Form. 
In accordance with the SOPs and policies of the local Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the 
IRB/IEC. 
16.3. 
Medical Monitoring 
Please refer to the study Operations Manual for medical monitor contact information. 
17. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
17.1. 
Early Discontinuation 
A subject may be discontinued from study treatment at any time if the subject, the investigator, 
or the sponsor feels that it is not in the subject’s best interest to continue. 
After 21 June 2021, subjects must be discontinued from the study if the investigator does not 
consider them to be benefiting from treatment and/or they do not understand the risks associated 
with adrabetadex, including hearing loss, and that the data from the randomized, controlled trial 
did not demonstrate significant differences between patients treated with adrabetadex and sham-
treated patients on any efficacy measures. 
If a subject is withdrawn from treatment due to an AE, the subject will be followed and treated 
by the investigator until the abnormal parameter or symptom has resolved or stabilized. 
The sponsor has made a determination of a negative benefit/risk balance for adrabetadex. 
Subjects in this study will be allowed to continue treatment until 20 October 2021 to allow time 
for transition planning unless there are additional time restrictions mandated by an IRB/EC or 
health authority. 
Following the last dose of adrabetadex, subjects will be asked to return to the clinic for a 
follow-up safety visit. Procedures for the End of Study (EOS) visit and the safety follow-up visit 
are noted in Table 14. 
Subjects with an implanted device will need to undergo device explanation. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. 


Protocol Amendment 15.0 
 
VTS-301 
Page 62  
CONFIDENTIAL AND PROPRIETARY 
17.2. 
Replacement of Subjects 
Only subjects in Part A who discontinue or are discontinued from the study following 
randomization and did not receive sham/study drug or a subject who discontinued prior to 
receiving all scheduled doses of sham/study drug will be replaced by newly enrolled subjects, 
not to exceed 6 total replacements. 
17.3. 
Protocol Violations 
A protocol violation occurs when the subject or investigator fails to adhere to protocol 
requirements. Major protocol deviations are those that are: 
• Deviations from the required consent procedure. 
• Failure to meet inclusion or exclusion criteria. 
• Wrong treatment or incorrect dose. 
• Failure to follow any other study-specified procedure that, in the opinion of the 
investigator, sponsor, or sponsor representative, impacts the integrity of the trial or 
puts the trials subjects at increased risk. 
All major protocol deviations will be reported to the IRB/IEC as local IRB/IEC regulations 
dictate. 
18. 
DOSE SELECTION COMMITTEE AND DATA MONITORING 
COMMITTEE 
After all subjects in Part A have received 4 IT infusions at the randomized dose levels or sham 
including 2 weeks of observation following the fourth dosing, all safety and efficacy data was 
provided to the DSC. The DSC included 2 neurologists with expertise in NPC1 disease who were 
also allowed to participate, in an unblinded role, in the conduct of the study. The DSC also 
included a physician who was not allowed to be otherwise involved in the conduct of the study. 
The single dose selected for Parts B and C of the study was based on identification of the highest 
dose with acceptable safety and tolerability, including results of audiologic testing, as determined 
by the DSC. All data available through the 8-week time point was evaluated by the DSC in an 
unblinded fashion. These data included information on all AEs and SAEs through 8 weeks. 
Results of efficacy assessments also were provided to the committee. 
If at any time following the second dose of study drug during Part A of the study, a subject was 
reported to have clinically significant hearing loss (CTCAE grade 3 or higher), this was to be 
reviewed in an unblinded manner by the DSC, which could have made recommendations in light 
of other available audiometric data from the study. Such individuals were to have repeat PTA 
and DPOAE testing as part of the hearing loss AE evaluation. Such recommendations could have 
included, for example, continuing on the current dose scheme, decreasing that subject’s dose by 
300 to 600 mg, decreasing all subjects in a specific dose cohort by 300 to 600 mg, discontinuing 
that subject from the study, or discontinuing that dose cohort. 
In Part B, an independent DMC monitored safety in an ongoing basis. This committee consisted 
of a neurologist with expertise in lysosomal storage disease, a second neurologist and a 


Protocol Amendment 15.0 
 
VTS-301 
Page 63  
CONFIDENTIAL AND PROPRIETARY 
statistician, all of whom were not involved in the conduct of the trial. The DMC convened at 
least quarterly during the trial to review the cumulative blinded clinical safety and efficacy data. 
The DMC could make recommendations about continued enrollment based on safety. Data for 
Part B was provided to the DMC in a blinded format. Upon request, individual treatment codes 
could be disclosed to the DMC to assist in the evaluation of safety. If the DMC identified safety 
and tolerability issues, assessed in the context of the efficacy data in Part B, in subjects receiving 
study drug, they could recommend, for example, continuing the study as is, decreasing the 
VTS-270 dose level by 300 mg or 600 mg for all subjects receiving active treatment for the 
remainder of the study, or discontinuation of the study. There were no stopping rules for safety 
or for futility or superiority based on the efficacy data. 
In Part C, an independent DMC will be re-convened to monitor safety on an ongoing basis.  
Details of the re-convened independent DMC constituency and remit can be found in the DMC 
charter. The responsibilities of the Rescue Option Criteria Committee are described in Section 
9.4. 
19. 
STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed statistical analysis plan (SAP) will be 
written describing all analyses that will be performed. The SAP will contain any modifications to 
the analysis plan described below and therefore serves as the overriding document dictating the 
statistical analyses performed. 
19.1. 
Analysis Populations 
19.1.1. 
Intent-to-Treat Population 
The ITT population will include all randomized subjects categorized by their randomized 
treatment assignment. 
19.1.2. 
Modified Intent-to-Treat 
The mITT population will consist of all randomized subjects who received at least one dose of 
VTS-270 infusion or sham control. The primary population for the co-primary efficacy 
assessment will be the mITT. 
19.1.3. 
Per Protocol Population 
The PP population will consist of all randomized subjects who had no major protocol deviation 
that would have had an impact on the primary outcome and who received at least 75% of their 
scheduled VTS-270 IT administrations. The major protocol deviations will be defined prior to 
database lock and unblinding. A blinded review of data will identify which subjects will be 
included in the PP populations prior to unblinding of the data. 
19.1.4. 
Safety Population 
The safety population will consist of all randomized subjects who receive at least 1 dose of 
VTS-270 or sham control. 


Protocol Amendment 15.0 
 
VTS-301 
Page 64  
CONFIDENTIAL AND PROPRIETARY 
19.1.5. 
European Site-specific Safety Population 
The European site-specific safety population will consist of all randomized subjects who receive 
at least 1 dose of VTS-270 via the IT access device. 
19.1.6. 
European Site-specific Device Pharmacokinetic Population 
The PK population will consist of subjects enrolled in the device PK substudy who have received 
at least one dose administration of VTS-270 and have at least one quantifiable concentration 
value post dose. Subjects in the PK population will be used for all PK data summaries. 
19.2. 
Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized by treatment group. 
Information to be summarized includes age in years, gender, race, ethnicity, height, weight, and 
body mass index, miglustat status (Yes/No), NPC-SS score category (10-19, 20+), seizures 
(Yes/No), and baseline NPC-SS total score, NPC-SS total score minus hearing components, and 
NPC-SS composite endpoint score. 
19.3. 
Analysis of Pharmacokinetic Endpoints 
Plasma and CSF PK parameters, AUClast, AUC0-inf, Tmax, Cmax, CL/F, t½, will be derived using 
noncompartmental analysis, if data permit. PK parameters except Tmax will be summarized using 
descriptive statistics (geometric mean, arithmetic mean, standard deviation, coefficient of 
variation, sample size, minimum, maximum, and median). Tmax will be only reported as sample 
size, minimum, maximum, and median. . 
Other PK endpoints will be measured repeatedly over the course of the study and where possible, 
statistical analysis will be performed. With the exception of the CSF measures, outcome data will 
be collected for both groups. The CSF measures will not be collected in the sham group since no 
LPs are done in this group. 
19.4. 
Interim Analysis 
No interim analysis is planned. 
A database lock is planned and will include data from Part A/B subjects who completed the 
double-blind portion of the study (or transitioned early to Part C for rescue), as well as Part C 
data collected up to the data cut-off date will be included in the analysis. All the data up to this 
time point will be reviewed, cleaned, and locked. This interim database lock is the final analysis 
lock for Part A/B data. 
19.5. 
Sample Size and Randomization 
The sample size for this study was approximately 51 subjects in Parts A and B combined. The 
rationale for the sample was based on both practical and statistical considerations. The sample 
size was determined based on the potential number of available subjects for this ultra-rare 
disorder. Based on the comparison of the NIH phase 1 subjects and similar subjects in the NIH 
natural history data set, approximately 51 subjects, 16 on sham and 35 on active treatment, 
would allow for the detection of clinically relevant difference of sum of the 4 NPC-SS score 


Protocol Amendment 15.0 
 
VTS-301 
Page 65  
CONFIDENTIAL AND PROPRIETARY 
domains that make up the composite outcome. The assumptions applied in the power calculation 
provide 79% power to detect a difference between the VTS-270 and sham groups by ANCOVA. 
In Part B, at least 39 eligible subjects were to be randomly assigned to receive either VTS-270 or 
sham in a ratio of 2:1. The randomization was carried out using permuted blocks of size 3 and a 
total of 4 strata defined by miglustat use (yes or no) and baseline total NPC-SS score (10-19 or 
≥ 20). 
19.6. 
Stratification 
The fact that subjects were not stratified in Part A but were stratified in Part B creates a unique 
situation.  In order to understand the effect of stratification, the following stratification groups 
will be used in statistical analyses: 
• Subjects randomized in Part A. 
• Subjects randomized in Part B, miglustat use +, NPC-SS total score ≥ 20. 
• Subjects randomized in Part B, miglustat use -, NPC-SS total score ≥ 20. 
• Subjects randomized in Part B, miglustat use +, NPC-SS total score < 20. 
• Subjects randomized in Part B, miglustat use -, NPC-SS total score < 20. 
20. 
DATA COLLECTION, RETENTION, AND MONITORING 
20.1. 
Data Collection Instruments 
The investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug. An 
electronic data capture system will be used to collect data in this study. 
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific eCRF when the information corresponding to that visit is 
available. Subjects will not be identified by name in the study database or on any study 
documents to be collected by the sponsor (or designee), but will be identified by a site number, 
subject number, and initials. 
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating the eCRF data and create an electronic audit trail. 
The investigator is responsible for all information collected on subjects enrolled in this study. All 
data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the investigator. A copy of the eCRF will remain at the investigator’s site at the 
completion of the study. 
20.2. 
Data Management Procedures 
The data will be entered into a validated database. The data management group will be 
responsible for data processing, in accordance with procedural documentation. Database lock 
will occur once quality assurance procedures have been completed. 


Protocol Amendment 15.0 
 
VTS-301 
Page 66  
CONFIDENTIAL AND PROPRIETARY 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
20.3. 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the electronic data capture system directly. The study database will 
be updated in accordance with the resolved queries. All changes to the study database will be 
documented. 
21. 
ADMINISTRATIVE, ETHICAL, REGULATORY 
CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records will be identified by a coded number and initials only. All study records will be kept in a 
locked file cabinet and code sheets linking a subject’s name to a subject identification number 
will be stored separately in another locked file cabinet. Clinical information will not be released 
without written permission of the subject, except as necessary for monitoring by the applicable 
regulatory authority. The investigator must also comply with all applicable privacy regulations 
(eg, Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
21.1. 
Protocol Amendments 
Any amendment to the protocol will be written by Vtesse LLC, a Mallinckrodt Pharmaceuticals 
Company. Protocol amendments cannot be implemented without prior written IRB/IEC approval 
except as necessary to eliminate immediate safety hazards to subjects. A protocol amendment 
intended to eliminate an apparent immediate hazard to subjects may be implemented 
immediately, provided the IRBs are notified within 5 working days. 
21.2. 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation. Serious adverse experiences regardless of causality 
will be reported to the IRB/IEC in accordance with the SOPs and policies of the IRB/IEC, and 
the investigator will keep the IRB/IEC informed as to the progress of the study. The investigator 
will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning subject 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IEC. The IRB/IEC’s written unconditional approval of the study protocol 
and the informed consent form will be in the possession of the investigator before the study is 


Protocol Amendment 15.0 
 
VTS-301 
Page 67  
CONFIDENTIAL AND PROPRIETARY 
initiated. The IRB/IEC’s unconditional approval statement will be transmitted by the investigator 
to Vtesse LLC, a Mallinckrodt Pharmaceuticals Company or designee prior to the shipment of 
study supplies to the site. This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the subjects 
or when the change(s) involves only logistical or administrative aspects of the study. Such 
modifications will be submitted to the IRB/IEC and written verification that the modification 
was submitted and subsequently approved should be obtained. 
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
SOPs and policies of the IRB; new information that may affect adversely the safety of the 
subjects of the conduct of the study; an annual update and/or request for re-approval; and when 
the study has been completed. 
21.3. 
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25 [a, b], CFR 50.27, 
and CFR Part 56, Subpart A), HIPAA, and local regulations. 
The investigator will prepare the informed consent form (ICF), assent, and HIPAA authorization 
and provide the documents to the sponsor or designee for approval prior to submission to the 
IRB/IEC. The ICF generated by the investigator must be acceptable to the sponsor and be 
approved by the IRB/IEC. The written consent document will embody the elements of informed 
consent as described in the International Conference on Harmonisation and will also comply 
with local regulations. The investigator will send an IRB/IEC-approved copy of the ICF to the 
sponsor (or designee) for the study file. 
A properly executed, written ICF will be obtained from each subject prior to entering the subject 
into the study. Information should be given in both oral and written form and subjects (or their 
legal representatives) must be given ample opportunity to inquire about details of the study. If 
appropriate and required by the local IRB/IEC, assent from the subject will also be obtained. If a 
subject is unable to sign the ICF and the HIPAA authorization, a legal representative may sign 
for the subject. A copy of the signed ICF (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
21.4. 
Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study sponsor 
and participating institutions. The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996. 


Protocol Amendment 15.0 
 
VTS-301 
Page 68  
CONFIDENTIAL AND PROPRIETARY 
21.5. 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in 21 CFR, Parts 50 and 56. 
4. Report to the sponsor or designee any AEs that occur in the course of the study, in 
accordance with 21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with 21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB/IEC approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in 21 CFR Part 312. 
21.6. 
Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained. 
Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database. 
At critical junctures of the protocol (eg, production of interim reports and final reports), data for 
analysis are locked and cleaned per established procedures. 
21.7. 
Availability and Retention of Investigational Records 
The investigator must make study data accessible to the monitor, other authorized representatives 
of the sponsor (or designee), IRB/IEC, and regulatory agency (eg, FDA) inspectors upon request. 
A file for each subject must be maintained that includes the signed informed consent, 
confidentiality commitments (eg, HIPAA), Assent Form, and copies of all source documentation 
related to that subject. The investigator must ensure the reliability and availability of source 
documents from which the information on the eCRF was derived. 


Protocol Amendment 15.0 
 
VTS-301 
Page 69  
CONFIDENTIAL AND PROPRIETARY 
All study documents (subject files, signed informed consent forms, copies of eCRFs, Study File 
Notebook, etc.) must be kept secured for a period of 2 years following marketing of the 
investigational product or for 2 years after centers have been notified that the IND has been 
discontinued. There may be other circumstances for which the sponsor is required to maintain 
study records and, therefore, the sponsor should be contacted prior to removing study records for 
any reason. 
21.8. 
Monitoring 
Monitoring visits will be conducted by representatives of the sponsor according to the US CFR 
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the 
investigator grants permission to the sponsor (or designee) and appropriate regulatory authorities 
to conduct on-site monitoring and/or auditing of all appropriate study documentation. 
21.9. 
Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number, and subject 
initials will identify all study subjects on eCRFs and other documentation submitted to the 
sponsor. Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement. 
22. 
REFERENCES 
Abi-Mosleh L, Infante RE, Radhakrishnan A, Goldstein JL, Brown MS. Cyclodextrin overcomes 
deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C 
cells. Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19316-21. 
Aqul A, Liu B, Ramirez CM, et al. Unesterified cholesterol accumulation in late 
endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export 
from this compartment. J Neurosci. 2011 Jun 22;31(25):9404-13. 
Davidson CD, Ali NF, Micsenyi MC, et al. Chronic cyclodextrin treatment of murine Niemann-
Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease 
progression. PLoS One. 2009 Sep 11;4(9):e6951. 
King KA, Gordon-Salant S, Yanjanin N, et al. Auditory phenotype of Niemann-Pick disease, 
type C1. Ear Hear. 2014 Jan-Feb;35(1):110-7. 
Levey AS, Stevens LA, Schmid CH, et al. CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 
5;150(9):604-12.  
Liu B, Ramirez CM, Miller AM, Repa JJ, Turley SD, Dietschy JM. Cyclodextrin overcomes the 
transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered 
cholesterol as bile acid. J Lipid Res. 2010 May;51(5):933-44. 
Maarup TJ, Chen AH, Porter FD, et al. Intrathecal 2- hydroxypropyl-beta-cyclodextrin in a 
single patient with Niemann-Pick C1. Mol Genet Metab. 2015 Sep-Oct;116(1-2):75-9. 


Protocol Amendment 15.0 
 
VTS-301 
Page 70  
CONFIDENTIAL AND PROPRIETARY 
Millat G, Marçais C, Rafi MA, et al. Niemann-Pick C1 disease: the I1061T substitution is a 
frequent mutant allele in patients of Western European descent and correlates with a classic 
juvenile phenotype. Am J Hum Genet. 1999 Nov;65(5):1321-9. 
Ory DS, Ottinger EA, Farhat NY, et al. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases 
neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-
label, phase 1-2 trial. Lancet. 2017;Aug10 (Epub ahead of print). 
Ramirez CM, Liu B, Taylor AM, et al. Weekly cyclodextrin administration normalizes 
cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly 
prolongs life. Pediatr Res. 2010 Oct;68(4):309-15. 
Rosenbaum AI, Zhang G, Warren JD, Maxfield FR. Endocytosis of beta-cyclodextrins is 
responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc Natl Acad Sci U 
S A. 2010;107(12):5477-82. 
Rosenbaum AI, Maxfield FR. Niemann-Pick type C disease: molecular mechanisms and 
potential therapeutic approaches. J Neurochem. 2011 Mar;116(5):789-95. 
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with 
CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. 
Sidhu R, Jiang H, Farhat NY, et al. A validated LC-MS/MS assay for quantification of 24(S)-
hydroxycholesterol in plasma and cerebrospinal fluid. J Lipid Res. 2015 Jun;56(6):1222-33. 
Study No. 804000: Evaluation of efficacy of intrathecal HP-β-CD on NPC diseased cats. School 
of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA. 21 September 2012. 
Study No. EINSTEIN-MOUSE-001; Intracerebroventricular Administration of 2- 
Hydroxypropyl Beta-Cyclodextrin for Treatment of Niemann-Pick Type C Disease: 4000 mg/kg 
Dose 
Study No. EINSTEIN-MOUSE-002; Intracerebrovascular Administration of 2- Hydroxypropyl 
Beta-Cyclodextrin for Treatment of Niemann-Pick Type C Disease: 8000 mg/kg Dose 
Study No. EINSTEIN-MOUSE-003; Combination Therapy Using Miglustat and 2- 
Hydroxypropyl-β-Cyclodextrin for Treatment of Niemann-Pick Type C Disease 
Tortelli B, Fujiwara H, Bagel JH, et al. Cholesterol homeostatic responses provide biomarkers 
for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1). Hum Mol 
Genet. 2014 Nov 15;23(22):6022-33. 
Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5(16):1-18. 
Vite CH. Personal communication; 17 October 2017. 
Vite CH, Bagel JH, Swain GP, et al. Intracisternal cyclodextrin prevents cerebellar dysfunction 
and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci Transl Med. 2015 Feb 
25;7(276):276ra26. 
Vite CH, Ding W, Bryan C, et al. Clinical, electrophysiological, and serum biochemical 
measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C 
disease. Pediatr Res. 2008 Nov;64(5):544-9. 


Protocol Amendment 15.0 
 
VTS-301 
Page 71  
CONFIDENTIAL AND PROPRIETARY 
Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian 
neurons. Biochim Biophys Acta. 2004 Oct 11;1685(1-3):48-62. 
Ward S, O'Donnell P, Fernandez S, Vite CH. 2-hydroxypropyl-beta-cyclodextrin raises hearing 
threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr Res. 2010 
Jul;68(1):52-6. 
 


Protocol Amendment 15.0 
 
VTS-301 
Page 72  
CONFIDENTIAL AND PROPRIETARY 
23. 
APPENDICES 


Protocol Amendment 15.0 
 
VTS-301 
Page 73  
CONFIDENTIAL AND PROPRIETARY 
APPENDIX 1. STUDY PARTS A AND B SCHEDULE OF ASSESSMENTS 
Table 8: 
Study Parts A and B Schedule of Assessments – Screening through Week 26 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Day 
Day -45 
to Day -1 
0 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
Window (days) 
 
 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
Screening 
1st 
Study 
Dose
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics, medical hxa 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medication history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Collect urineb 
X 
- 
- 
- 
- 
X# 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Pregnancy test 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Physical examc 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
 
Vital signs 
Xd 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Weight 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Neurological examinationf 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Clinical laboratory testingg 
X 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
12-lead ECG 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Audiologic testingh 
X 
X 
X# 
X# 
X# 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
Auditory brainstem response 
X 
- 
- 
- 
- 
X# 
- 
- 
- 
- 
- 
- 
- 
 
- 
NPC Clinical Severity intake 
X 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 


Protocol Amendment 15.0 
 
VTS-301 
Page 74  
CONFIDENTIAL AND PROPRIETARY 
Table 8: 
Study Parts A and B Schedule of Assessments – Screening through Week 26 (Continued) 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Day 
Day -45 
to Day -1 
0 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
Window (days) 
 
 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
Screening 
1st 
Study 
Dose
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
Clinician-CGIC
i and 
Caregiver-CGIC 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
TUG Test 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
9-Hole Peg Test 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
EQ-5D-3L QoL 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
Confirm subject eligibility 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Randomization
j 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Collect plasma biomarker 
samples
k 
- 
X 
- 
- 
- 
X# 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Sham or lumbar puncture 
and study drug 
administration 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect CSF samples(study 
drug subjects only) 
- 
X 
- 
- 
- 
X# 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Collect whole blood for 
genetic testingl 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Adverse eventsm 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
b Urine will be obtained for urinalysis and biomarker testing.  
c Full physical exam at Screening; abbreviated physical exam at all other visits. 
d Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
e A second set of vital signs will be recorded following recovery of sedation from lumbar puncture or sham procedure. 
f Full, videotaped neurological exam at Screening and Week 52; brief, videotaped neurological exam at Week 24. 
g Clinical laboratory tests include chemistry, hematology, and coagulation. 


Protocol Amendment 15.0 
 
VTS-301 
Page 75  
CONFIDENTIAL AND PROPRIETARY 
h If a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, unscheduled audiologic evaluation visits will increase in regularity at the 
discretion of the Primary Investigator. 
i Blinded Clinician to meet with subject and assess overall status and functionality that will form baseline for future Clinician-CGIC assessments. 
j Randomization may occur on or before Study Visit 1, Day 0, after receipt of NPC Clinical Severity Score from central rater to confirm eligibility. 
k Plasma samples for biomarkers should obtained prior to intrathecal or sham treatment. 
l CSF samples for subjects on 900 mg VTS-270 may also be used for trough HP-β-CD measurements.  
m The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
# Part A participants ONLY. 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; hx = history; NPC = Niemann-Pick disease, type C; NPC1 = Niemann-Pick 
disease, type C1; QoL = quality of life; TUG = timed up and go. 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 76  
CONFIDENTIAL AND PROPRIETARY 
Table 9: 
Study Parts A and B Schedule of Assessments – Week 28 through Week 54 
Visit Number 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Follow-upp 
ETq 
Study Day 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
378 
441 
532 
 
Window (days) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) (±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7)
(±7) 
(±7) 
Time Point (Week) 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
63 
76 
 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Xn 
- 
- 
- 
- 
Demographics, medical 
historya 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medication history 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Collect urineb 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
Xc 
- 
- 
- 
Pregnancy test 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Xc 
- 
- 
X 
Physical examd 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
X 
Vital signse,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
- 
- 
X 
Weight 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
Neurological examinationh 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
Clinical laboratory testingi 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
Xj 
12-lead ECG 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
Audiologic testingk 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
Auditory brainstem response 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
X 
- 
- 
- 
X 
NPC Clinical Severity Intake 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
X 
X 
X 
Clinician-CGICl and 
Caregiver-CGIC 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
X 
X 
X 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 77  
CONFIDENTIAL AND PROPRIETARY 
Table 9: 
Study Parts A and B Schedule of Assessments – Week 28 through Week 54 (Continued) 
Visit Number 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Follow-upp 
ETq 
Study Day 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
378 
441 
532 
 
Window (days) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) (±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7)
(±7) 
(±7) 
Time Point (Week) 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
63 
76 
 
TUG Test 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
9-Hole Peg Test 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
EQ-5D-3L QoL 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
Confirm subject eligibility 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Collect plasma biomarker 
samplesm 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
Sham or lumbar puncture and 
study drug administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
- 
- 
- 
- 
Collect CSF samples (study 
drug subjects only)o 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
Xn 
- 
- 
- 
- 
Adverse eventsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
X 
a Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
b Urine will be obtained for urinalysis and biomarker testing.  
c Urine will be collected at Follow-up Visit 1 (Week 54) for pregnancy test. No other tests will be performed with urine. 
d Full physical exam at Screening; abbreviated physical exam at all other visits. 
e Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
f A second set of vital signs will be recorded following recovery of sedation from lumbar puncture or sham procedure. 
g The second set of vital signs will only be recorded for subjects proceeding to Part C following recovery of sedation from lumbar puncture or sham procedure. 
h Full, videotaped neurological exam at Screening and Week 52; brief, videotaped neurological exam at Week 24. 
i Clinical laboratory tests include chemistry, hematology, and coagulation. 
j Clinical laboratory tests include chemistry, hematology, coagulation, urinalysis, and pregnancy. 
k If a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, unscheduled audiologic evaluation visits will increase in regularity at the 
discretion of the Primary Investigator. 
l  Blinded Clinician to meet with subject and assess overall status and functionality that will form baseline for future Clinician-CGIC assessments. 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 78  
CONFIDENTIAL AND PROPRIETARY 
m Plasma samples for biomarkers should obtained prior to intrathecal or sham treatment. 
n To be performed only for subjects proceeding to Part C. 
o CSF samples for subjects on 900 mg VTS-270 may also be used for trough HP-β-CD measurements.  
p Only subjects who will NOT be continuing into Part C, the open-label extension, will complete the Follow-up visits. 
q All subjects who discontinue study treatment will be requested to return to the clinic to complete an Early Termination (ET) visit. 
r The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; ET = early termination; NPC = Niemann-Pick disease, type C; 
NPC1 = Niemann-Pick disease, type C1; QoL = quality of life; TUG = timed up and go. 
 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 79  
CONFIDENTIAL AND PROPRIETARY 
APPENDIX 2. STUDY PART C SCHEDULE OF ASSESSMENTS 
Table 10: 
Study Part C Schedule of Assessments – Screening through Week 28 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Study Day 
Day –45 
to  
Day –1 
0 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
196 
Window (days) 
 
 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
Screena 
1st 
Study 
Dose 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics, medical historyb 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medication history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Collect urinec 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Pregnancy test 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Physical examd 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Vital signs 
X
e 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
Weight 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Neurological examinationg 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Wound check/port site exam for 
IT access port subjectsh 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
(X) 
(X) 
(X) 
Clinical laboratory testingi 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
12-lead ECG 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Audiologic testingj 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Auditory brainstem response 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 80  
CONFIDENTIAL AND PROPRIETARY 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Study Day 
Day –45 
to  
Day –1 
0 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
196 
Window (days) 
 
 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
Screena 
1st 
Study 
Dose 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician-CGIC 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
NPC-SS intake 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
EQ-5D-3L 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Lumbar puncture and study 
drug administration 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IT access port study drug 
administration for IT access 
port subjectsh 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
(X) 
(X) 
(X) 
CSF lab tests and trough 
HP-β-CD for IT access 
device subjectsh 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
(X) 
(X) 
(X) 
Adverse eventsk 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Screening visit is only for subjects newly enrolled at Part C; for subjects continuing from Part B, the Week 52 visit functions as the Screening visit for Part C. 
b Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
c Urine will be obtained for urinalysis only.  
d Full physical exam at Screening; abbreviated physical exam at all other visits. 
e Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
f A second set of vital signs will be recorded following recovery of sedation from lumbar puncture or sham procedure. 
g Full neurological exam at Screening and Week 52; brief, videotaped neurological exam at Week 24. 
h Subjects participating in the European site-specific IT access port safety and tolerability assessment will remain in their Part C schedules and will add additional port-specific 
assessments as detailed in the device-specific schedule of events for the first nine port infusions (Table 15). Where there is duplication of assessments with Part C, only 1 
assessment will be conducted. CSF samples for subjects on 900 mg VTS-270 may also be used for trough HP β CD measurements 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 81  
CONFIDENTIAL AND PROPRIETARY 
i Clinical laboratory tests include chemistry, hematology, and coagulation. 
j If a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, unscheduled audiologic evaluation visits will increase in regularity at the 
discretion of the Primary Investigator. 
k The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; IT = intrathecal; NPC = Niemann-Pick disease, Type C; NPC-SS = NPC 
Severity Scale. 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 82  
CONFIDENTIAL AND PROPRIETARY 
Table 11: 
Study Part C Schedule of Assessments – Week 30 through Week 52 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Study Day 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
Window (days) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52
k 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consenta 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics, medical historyb 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medication history 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Collect urinec 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
Pregnancy test 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,m 
Physical examd 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
Vital signs 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f 
X
e,f,k 
Weight 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Neurological examination 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
Wound check/port site exam for IT access 
port subjectsg 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Clinical laboratory testingh 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
12-lead ECG 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
m 
Audiologic testingi 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
Auditory brainstem response 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,m 
Clinican-CGIC assessment 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
NPC-SS intake 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 
EQ-5D-3L assessment 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X
k,l 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 83  
CONFIDENTIAL AND PROPRIETARY 
Table 11: 
Study Part C Schedule of Assessments – Week 30 through Week 52 (Continued) 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Study Day 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
Window (days) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52
k 
Lumbar puncture and study drug 
administration j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IT access port study drug administration  
for IT access port subjects g 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
CSF lab tests and trough HP-β-CD for 
device subjects g 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Adverse events n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
a Study Visit 1 only. 
b Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
c Urine will be obtained for urinalysis only.  
d Full physical exam at Screening; abbreviated physical exam at all other visits. 
e Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
f A second set of vital signs will be recorded following recovery of sedation from LP procedure. 
g Subjects participating in the European site-specific IT access port safety and tolerability assessment will remain in their Part C schedules and will add additional port-specific 
assessments as detailed in the device-specific schedule of events for the first nine port infusions (Table 15). Where there is duplication of assessments with Part C, only 1 
assessment will be conducted.  
h Clinical laboratory tests include chemistry, hematology, and coagulation. 
i If a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, unscheduled audiologic evaluation visits will increase in regularity at the 
discretion of the Primary Investigator. 
j Subjects who have transitioned from the NIH phase 1 study will continue to receive IT administration of VTS-270 every 2 weeks (or as per authorized amended dosing regimen). 
k All subjects who discontinue study treatment will be requested to return to the clinic to complete an Early Termination (ET) visit comprising these evaluations. 
l After Study Visit 27, record every 6 months thereafter. 
m After Study Visit 27, record annually thereafter. 
n The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; IT = intrathecal; LP = lumbar puncture; NIH = National Institutes of Health 
NPC1 = Niemann-Pick disease, type 1; NPC-SS = NPC Severity Scale. 
 
 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 84  
CONFIDENTIAL AND PROPRIETARY 
Table 12: 
Study Part C Schedule of Assessments – Week 54 through Week 182 
Visit Number 
28-39 
40 
41-52 
53 
54-65 
66 
67-78 
79 
80-91 
92 
Study Day 
378-532 
546 
560-714 
728 
742-896 
910 
924-1078 
1092 
1106-1260 
1274 
Window (days) 
(±7) 
(±7
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point 
Wk 54-76 
(>1 yr to <1.5 yr) 
Wk 
78 
Wk 80-102 
(>1.5 yr to <2 yr) 
Wk 
104 
Wk 106-128 
(>2 yr to <2.5 yr) 
Wk 
130 
Wk 132-154 
(>2.5 yr to <3 yr) 
Wk 156 
(3 yr) 
Wk 158-180 
(>3 yr to<3.5 yr) 
Wk 
182 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Collect urinea 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Pregnancy test 
- 
 
- 
X 
- 
- 
- 
X 
- 
-- 
Physical exam 
(abbreviated) 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Wound check/port site 
and catheter track 
examb 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Vital signsc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
Neurological 
examination 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Clinical laboratory 
testinge 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
12-lead ECG 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
Audiologic testingf 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Lumbar puncture and 
study drug 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IT access port study 
drug administrationb 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
CSF lab tests  
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 85  
CONFIDENTIAL AND PROPRIETARY 
Table 12: 
Study Part C Schedule of Assessments – Week 54 through Week 182 (Continued) 
Visit Number 
28-39 
40 
41-52 
53 
54-65 
66 
67-78 
79 
80-91 
92 
Study Day 
378-532 
546 
560-714 
728 
742-896 
910 
924-1078 
1092 
1106-1260 
1274 
Window (days) 
(±7) 
(±7
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point 
Wk 54-76 
(>1 yr to <1.5 yr) 
Wk 
78 
Wk 80-102 
(>1.5 yr to <2 yr) 
Wk 
104 
Wk 106-128 
(>2 yr to <2.5 yr) 
Wk 
130 
Wk 132-154 
(>2.5 yr to <3 yr) 
Wk 156 
(3 yr) 
Wk 158-180 
(>3 yr to<3.5 yr) 
Wk 
182 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Urine will be obtained for urinalysis only.  
b Subjects participating in the European site-specific IT access port safety and tolerability assessment will remain in their Part C schedules and will add additional port-specific 
assessments as detailed in the device-specific schedule of events for the first nine port infusions (Table 15). Where there is duplication of assessments with Part C, only 1 
assessment will be conducted.  
c Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
d A second set of vital signs will be recorded following recovery of sedation from lumbar puncture procedure.  
e Clinical laboratory tests include chemistry, hematology, and coagulation. 
f If a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, unscheduled audiologic evaluation visits will increase in regularity at the 
discretion of the Primary Investigator. 
CSF = cerebrospinal fluid; ECG = electrocardiogram; IT = intrathecal; NPC = Niemann-Pick disease, type C; NPC-SS = NPC Severity Scale; Wk = week. 
 
 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 86  
CONFIDENTIAL AND PROPRIETARY 
Table 13: 
Study Part C Schedule of Assessments – Beyond Week 182 Visit Number 92 
Visit Number 
93-104, 106-117, 119-130, 132-143 
118 & 144 
105 & 131  
Week 
184-206, 210-232, 236-258, 262-284 
234 & 286 
208 & 260 
Window (days) 
(±7) 
(±7) 
(±7) 
Time Point 
Every 2 weeks except 6 monthly and 
yearly visits 
Every 6 Months from 
Year 4.5 and beyond 
Yearly visit from Year 4 
and beyond 
Study Procedure 
 
 
 
Collect urinea 
- 
X 
X 
Pregnancy test 
- 
- 
X 
Physical exam (abbreviated) 
- 
X 
X 
Wound check/port site and catheter track examb 
X 
X 
X 
Vital signsc,d 
X 
X 
X 
Weight 
- 
- 
X 
Neurological examination 
- 
X 
X 
Clinical laboratory testinge 
- 
X 
X 
12-lead ECG 
- 
- 
X 
Audiologic testingf 
 
X 
X 
Lumbar puncture and study drug administration 
X 
X 
X 
IT access port study drug administrationb 
X 
X 
X 
CSF lab tests  
X 
X 
X 
Adverse events 
X 
X 
X 
Concomitant medications 
X 
X 
X 
a Urine will be obtained for urinalysis only.  
b Subjects participating in the European site-specific IT access port safety and tolerability assessment will remain in their Part C schedules and will add additional port-specific 
assessments as detailed in the device-specific schedule of events for the first nine port infusions (Table 15). Where there is duplication of assessments with Part C, only 1 
assessment will be conducted.  
c Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
d A second set of vital signs will be recorded following recovery of sedation from lumbar puncture procedure.  
e Clinical laboratory tests include chemistry, hematology, and coagulation. 
f If a subject reports an increase in clinically significant hearing loss at any post-baseline assessment, unscheduled audiologic evaluation visits will increase in regularity at the 
discretion of the Primary Investigator. 
CSF = cerebrospinal fluid; ECG = electrocardiogram; IT = intrathecal. 
 
 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 87  
CONFIDENTIAL AND PROPRIETARY 
Table 14: 
Study Part C Schedule of Assessments – End of Study and Follow-up 
Study Day 
End of Study 
Follow-up Visit 
Window (days) 
 
(±7) 
Time Point (Week) 
 
ET + 2W 
Study Procedure 
 
 
Adverse events 
X 
X 
Concomitant medications 
X 
X 
Audiologic testing 
X 
- 
Complete physical exam 
X 
X 
Vital signsa 
X 
X 
Clinical laboratory testingb 
X 
- 
Complete neurological examination 
X 
- 
Urine pregnancy test 
- 
X 
Port device removalc 
X 
- 
Wound check 
X 
X 
a Vital signs, including blood pressure, will be recorded following a 5-minute rest in supine position. 
b Clinical laboratory tests include chemistry, hematology, and coagulation. 
c For subjects with port device, remove device prior to termination. 
ET = early termination; NPC = Niemann-Pick disease, type C; NPC-SS = NPC Severity Scale; W = week. 
 
 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 88  
CONFIDENTIAL AND PROPRIETARY 
Table 15: 
Part C European Site-specific Device Safety and Tolerability Substudy Schedule of Assessments 
Visit Numbera 
 
 
 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
Device Substudy 
Day 
-7 to -3 
1b 
2 to 3 
15 c 
29 
43 
57 
71 
85 
99 
113 
127 or 
ETe 
Window (days) 
 
+3 
NA 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
Study Procedure 
/ Time Point 
Baseline 
Confinement 
Period / 
Surgery 
Device Infusion Visits 
1  
2 
3 
4 
5 
6 
7 
8 
9 
Consent/assent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Eligibility criteria 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics & 
medical history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medication 
history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Adverse eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medicationsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationh 
X 
- 
X 
X 
- 
- 
- 
- 
- 
- 
- 
X 
Neurological 
examinationi 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Clinical lab tests j 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Lumbar puncture 
and study drug 
administrationd 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Intracranial 
pressure 
collection  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 89  
CONFIDENTIAL AND PROPRIETARY 
Table 15: 
Part C European Site-specific Device Safety and Tolerability Substudy Schedule of Assessments (Continued) 
Visit Numbera 
 
 
 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
Device Substudy 
Day 
-7 to -3 
1b 
2 to 3 
15 c 
29 
43 
57 
71 
85 
99 
113 
127 or 
ETe 
Window (days) 
 
+3 
NA 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
Study Procedure 
/ Time Point 
Baseline 
Confinement 
Period / 
Surgery 
Device Infusion Visits 
1  
2 
3 
4 
5 
6 
7 
8 
9 
Serum pregnancy 
test 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
CSF lab tests 
- 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Device 
implantation 
- 
X k,l 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Radiograph of 
device 
placementm 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Wound checkn, o 
- 
X 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Inspect port site 
& catheter trackn 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VTS-270 device 
infusionp 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
AE = adverse event; CSF = cerebrospinal fluid; EOS = end of study; ET = early termination; lab = laboratory; NA = not applicable; PK = pharmacokinetics  
a Subjects will remain in their Part C schedules and will add additional device-specific assessments as detailed in the device-specific schedule of events for the first 9 device 
infusions (D1-D9). Where there is duplication of assessments with Part C, only 1 assessment will be conducted. 
b Implantation surgery will be scheduled as close as possible to the last lumbar puncture (within approximately 3 days).  
c A minimum of 14 days following device implantation must elapse before the device is used for VTS-270 administration. 
d Subjects will also receive last dose of VTS-270 via lumbar puncture per VTS301 protocol. 
e All subjects who complete the VTS301 Part C or discontinue study treatment early should return to the clinic to complete a EOS/ET Visit. If the subject completes the study and 
does not continue to receive VTS-270, the device will be removed; if the subject discontinues from the study early, the device will be removed. Adverse events and concomitant 
medications should be recorded post removal. 
f Concomitant medications and AEs to be collected before and after infusion (through end of visit), where appropriate. 
g Vital signs including pulse rate, blood pressure, respiratory rate, and oral temperature will be recorded following a 5-minute rest in supine position. Vital signs should be 
repeated after the 30- to 45-minute recovery period following VTS-270 infusion. 


Protocol Amendment 15.0 
 
VTS-301 
 
Page 90  
CONFIDENTIAL AND PROPRIETARY 
h An abbreviated physical examination will be performed at baseline, Day 2 and 3 confinement period, and at the first and ninth device infusion visits. 
i An abbreviated neurological examination will be performed at baseline and the ninth device infusion visit. 
j Testing includes hematology, serum chemistry, and coagulation tests. 
k If the device becomes nonfunctional at any time during the study, it will be removed; replacement with a new device requires approval from the sponsor.  
l Procedures for implantation and removal are detailed in the device sponsor-supplied Access Port Manual of Procedures. 
m The investigator may obtain repeat radiographs as indicated during the study to determine device placement and/or integrity. 
n If abnormal swelling or redness is noted around the port or along the catheter site and infection is suspected, study drug should not be administered and appropriate evaluation of 
the device and catheter track should be undertaken to rule out malfunction or infection.  
o Check wound at first infusion visit and until healed. 
p All evaluations on the days of device infusion, including inspection of the port site and catheter track, will occur prior to and during administration of study drug, as well as after 
study drug administration. Following infusion of VTS-270 via the device, all subjects are required, if possible, to lie flat with feet elevated for 30 to 45 minutes. Following the 
recovery, the subject will be reassessed for vital signs, any new AEs, and any new concomitant medications. 
q If an early termination visit is needed, subjects will not be treated with VTS-270 via the device. 
 


Signature Page for VV-CLIN-028279 v1.0
Signature Page for VV-CLIN-028279 v1.0
Approval
24-Jun-2021 23:00:03 GMT+0000

SAP_001.pdf: 
CONFIDENTIAL 
Vtesse, Inc. 
Protocol VTS301 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham-Controlled 
Trial of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with 
Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease 
Statistical Analysis Plan 
Version 1.0 
27 August 2018 
Based on Protocol 
Version 11.0, 
 
24 August 2018 
Prepared by: 
CTI Clinical Trial & Consulting Services 
NCT #NCT02534844




VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page i 
CONFIDENTIAL 
Contents 
1. 
Introduction ............................................................................................................................................... 8 
 
Purpose ......................................................................................................................................................... 8 
 
Timing of analyses ........................................................................................................................................ 9 
2. 
Study objectives ........................................................................................................................................ 10 
 
Part A objectives ......................................................................................................................................... 10 
2.1.1. 
Primary objective ................................................................................................................................ 10 
 
Part B objectives .......................................................................................................................................... 10 
2.2.1. 
Primary objective ................................................................................................................................ 10 
2.2.2. 
Key secondary objectives ................................................................................................................... 10 
2.2.3. 
Other secondary objectives ................................................................................................................ 10 
2.2.4. 
Exploratory objectives ........................................................................................................................ 11 
 
Part C objectives .......................................................................................................................................... 12 
2.3.1. 
Primary objective ................................................................................................................................ 12 
2.3.2. 
Secondary objectives .......................................................................................................................... 12 
3. 
Changes to the planned analyses ............................................................................................................... 12 
4. 
Study description and conduct .................................................................................................................. 13 
 
Study design and randomization ................................................................................................................. 13 
 
Study duration, visits and assessments ....................................................................................................... 16 
 
Eligibility ...................................................................................................................................................... 17 
5. 
Study endpoints ........................................................................................................................................ 17 
 
Part B endpoints .......................................................................................................................................... 17 
5.1.1. 
Co‐primary efficacy endpoints ............................................................................................................ 17 
5.1.2. 
Key secondary endpoints .................................................................................................................... 17 
5.1.3. 
Other secondary endpoints ................................................................................................................ 18 
5.1.4. 
Exploratory endpoints ........................................................................................................................ 18 
 
Part C endpoints .......................................................................................................................................... 19 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page ii 
CONFIDENTIAL 
5.2.1. 
Primary endpoints .............................................................................................................................. 19 
5.2.2. 
Secondary endpoints .......................................................................................................................... 20 
6. 
Analysis populations ................................................................................................................................. 20 
 
Intent‐to‐treat population ........................................................................................................................... 20 
 
Modified intent‐to‐treat population ........................................................................................................... 21 
 
Per protocol population .............................................................................................................................. 21 
 
Safety population ........................................................................................................................................ 21 
 
Part C open‐label population ...................................................................................................................... 21 
 
Device safety and tolerability substudy population .................................................................................... 21 
7. 
Blinded data review meeting ..................................................................................................................... 22 
8. 
General conventions and statistical considerations .................................................................................... 22 
 
Study days ................................................................................................................................................... 23 
 
Baseline ....................................................................................................................................................... 24 
 
Change from baseline ................................................................................................................................. 24 
 
Visit windows .............................................................................................................................................. 24 
 
Sample size determination and power calculation ..................................................................................... 24 
 
Pooling of investigator sites ........................................................................................................................ 26 
 
Stratification ............................................................................................................................................... 26 
 
Safety parameters ....................................................................................................................................... 27 
9. 
Study population summaries ..................................................................................................................... 28 
 
Enrollment ................................................................................................................................................... 28 
 
Subject disposition ...................................................................................................................................... 28 
 
Protocol deviations and violations .............................................................................................................. 28 
 
Demographics and baseline characteristics ................................................................................................ 29 
 
Medical history ............................................................................................................................................ 29 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page iii 
CONFIDENTIAL 
 
NPC disease history ..................................................................................................................................... 29 
10. 
Study drug and other medications ......................................................................................................... 29 
 
Prior and concomitant medications ............................................................................................................ 29 
 
Duration of treatment and exposure to study drug .................................................................................... 30 
11. 
Efficacy analyses ................................................................................................................................... 30 
 
Co‐primary efficacy analyses ...................................................................................................................... 31 
 
Sensitivity analyses for the co‐primary endpoints....................................................................................... 32 
 
Key secondary endpoints and analyses ....................................................................................................... 33 
 
Other secondary endpoints and analyses ................................................................................................... 35 
 
Multiplicity .................................................................................................................................................. 37 
 
Exploratory endpoints and analyses ........................................................................................................... 37 
 
Subgroup analyses ...................................................................................................................................... 38 
12. 
Safety summaries .................................................................................................................................. 39 
 
Adverse events ............................................................................................................................................ 39 
12.1.1. 
Hearing AEs of special interest ........................................................................................................... 39 
12.1.2. 
AE summaries ..................................................................................................................................... 40 
 
Deaths ......................................................................................................................................................... 42 
 
Vital signs .................................................................................................................................................... 42 
 
Physical examination .................................................................................................................................. 42 
 
Laboratory data .......................................................................................................................................... 43 
 
Audiologic evaluation ................................................................................................................................. 43 
 
Auditory brainstem response ...................................................................................................................... 45 
 
Neurological evaluation .............................................................................................................................. 45 
 
12‐lead ECG ................................................................................................................................................. 45 
 
Serum pregnancy .................................................................................................................................... 45 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page iv 
CONFIDENTIAL 
 
Device safety and tolerability substudy .................................................................................................. 45 
13. 
Appendices ........................................................................................................................................... 47 
 
NPC Clinical Severity Scale .......................................................................................................................... 47 
 
Schedule of Assessments ............................................................................................................................. 49 
14. 
References ............................................................................................................................................ 64 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page v 
CONFIDENTIAL 
Exhibits 
Exhibit 1. 
Phase 2b/3 three‐part study design ............................................................................................... 16 
Exhibit 2. 
Study Parts A and B schedule of assessments (Screening through Week 26) ................................... 49 
Exhibit 3. 
Study Parts A and B schedule of assessments (Week 28 through Week 54) ..................................... 52 
Exhibit 4. 
Study Part C schedule of assessments (Screening through Week 28)............................................... 54 
Exhibit 6. 
Study Part C schedule of assessments (Week 30 through Week 52) ................................................ 57 
Exhibit 6. 
Study Part C schedule of assessments (Week 54 through Week 182) .............................................. 59 
Exhibit 7. 
Part C European Site‐specific Device Safety and Tolerability Substudy Schedule of Assessments ..... 61 
 
 
 
 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 6 
CONFIDENTIAL 
Abbreviations 
ABR 
auditory brainstem response 
AC 
air conduction 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BC 
bone conduction 
BCA 
bone conduction average 
CGIC 
Clinical Global Impression of Change 
CMH 
Cochran‐Mantel‐Haenszel 
CSF 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTI 
CTI Clinical Trial and Consulting Services 
dB 
decibel 
DSC 
Dose Selection Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EU 
European Union 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonization   
ICP 
Intracranial pressure 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IT 
intrathecal 
ITT 
intent‐to‐treat 
LP 
lumbar puncture 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent to treat 
MNAR 
missing not at random 
NCI 
National Cancer Institute   
NIH 
National Institutes of Health 
NPC1 
NPC‐SS 
Niemann‐Pick Type C1 
Niemann‐Pick Type C1 Severity Scale 
PP 
per‐protocol 
PT 
preferred term 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 7 
CONFIDENTIAL 
 
 
PTA 
pure tone audiometry   
QoL 
quality of life 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
TUG 
timed up and go test 
WHO 
World Health Organization 
   
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 8 
CONFIDENTIAL 
1. 
Introduction 
Purpose 
Niemann‐Pick type C (NPC) disease is a rare, neurodegenerative, inherited, autosomal 
recessive disorder which primarily manifests in children and teenagers. NPC is characterized 
by systemic disease (hepatic, splenic, pulmonary) and progressive ataxia, dementia and early 
death due to the predominate manifestations of neurological disease.    In subjects diagnosed 
with NPC, cholesterol, bis‐(monoacylglycerol) phosphate, and various sphingolipids 
accumulate to toxic concentrations in lysosomal storage organelles in tissues.    Cholesterol 
and sphingolipids are important lipids in mammalian physiology; however, in excessive 
concentrations both are toxic to cells.    NPC disease is heterogeneous in terms of age of onset, 
signs and symptoms, and disease progression. In the most common form of the disease, 
representing 60‐70% of cases, children between the ages of 6 and 15 years present with 
symptoms such as frequent falls or clumsiness, ataxia, as well as school and behavioural 
problems.    Progressive dysarthria and dysphagia usually present later in the disease, with 
death commonly occurring in the second or third decade of life [1].     
2‐hydroxypropyl‐beta‐cyclodextrin (HP‐β‐CD) is 
 
    All HP‐β‐CD’s are amorphous mixtures of different isomers, characterized 
by the degree of substitution of the hydroxyl with propyl groups. 
 
   
 
    Results from a Phase 1/2a study (13‐CH‐
0001), suggest that treatment with VTS‐270 may result in clinically relevant stabilization or 
delay in progression of NPC disease status.    Thus, the sponsor initiated Study VTS301, A 
Phase 2b/3 Prospective, Randomized, Double‐Blind, Sham‐Controlled Trial of VTS‐270 in 
Subjects with NPC Disease. 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 9 
CONFIDENTIAL 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Version 11.0, 
 of Protocol 
VTS301, dated August 24, 2018.   
The statistical principles applied in the design and planned analyses of this study are 
consistent with the ICH guidelines E9 (Statistical Principles for Clinical Trials) [2].    The key 
elements of the SAP have been discussed with the FDA 
 
 and the European Medicines Agency 
 
 
Timing of analyses 
An interim database lock is planned and will include data from all Part A/B subjects who 
completed the double‐blind portions of the study, as well as Part C data collected up to 30 
March 2018. All the data up to this timepoint will be reviewed, cleaned, and locked. This 
interim database lock is the final analysis lock for Part A/B data. 
The interim database lock therefore includes Part A/B analysis and Part C analysis up to the 
cut‐off date of 30 Mar 2018 and will not have any impact on the continuation of the open‐label 
Part C of the study.   
Additional Part C analyses may be conducted prior to final database lock to provide 
additional information for registration dossiers submitted to Health Authorities 
Final analysis of all Part C subject data will be performed when the VTS‐270 receives 
marketing authorization.   


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 10 
CONFIDENTIAL 
2. 
Study objectives 
Part A objectives 
2.1.1.Primary objective 
The primary objective in Part A is to select the dose of VTS‐270 to be used in Part B and Part C. 
Dose selection criteria include safety and tolerability including a thorough audiologic 
evaluation. Preliminary efficacy data will be provided to the Dose Selection Committee (DSC) 
as well to assist, if necessary, in dose selection.   
Part B objectives 
2.2.1.Primary objective 
The primary study objective in Part B is to evaluate, in a double‐blind sham‐controlled design, 
the progression of the neurologic manifestations of NPC1 disease following 52 weeks of 
treatment for subjects treated with VTS‐270 compared to sham control, as assessed by: 
 
The NPC‐SS composite which consists of the sum of 4 components of the Neimann Pick 
Type C Severity Scale (NPC‐SS): ambulation, fine motor, cognition, and swallowing.   
 
The blinded Clinician‐Global Impression of Change (CGIC) 
2.2.2.Key secondary objectives 
The key secondary objectives for Part B are to evaluate:   
 
The progression of the neurologic manifestations of NPC1 disease using the total NPC‐
SS excluding the hearing domain and auditory brainstem response (ABR) modifier , 
following 52 weeks of treatment for subjects treated with VTS‐270 compared to sham 
controls. 
 
Caregiver CGIC   
2.2.3.Other secondary objectives 
The other secondary objectives for Part B are as follows: 
 
Evaluate the safety and tolerability of VTS‐270 administered IT via LP every 2 weeks, 
for 52 weeks compared to sham control   


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 11 
CONFIDENTIAL 
 
Assess quality of life using the EQ‐5D‐3L following 52 weeks of treatment for subjects 
treated with VTS‐270 compared to sham controls   
 
Further assess the efficacy of VTS‐270 on treating the neurologic symptoms of NPC1 by 
comparing subjects treated for 52 weeks with VTS‐270 compared to sham control on: 
 
Subjects who required rescue following at least 6 months of treatment 
 
The 9 major domains of the NPC‐SS   
 
The total NPC‐SS score (hearing domain and ABR modifier included) 
 
Time to a one point increase (worsening) on the NPC‐SS composite score 
 
The annualized rate of change (slope) of the NPC‐SS composite 
 
Timed up and go (TUG) test 
 
9‐hole peg test 
2.2.4.Exploratory objectives 
The exploratory objectives for Part B are as follows: 
 
Assessment of exploratory biomarkers using cerebrospinal fluid (CSF), urine, and 
plasma samples from the subjects receiving study drug, and urine and plasma samples 
from subjects randomized to sham control.    The analysis methods for the above 
exploratory objectives for biomarker analysis will be defined in a separate plan prior to 
analysis, and the results will be reported separately.   
 
Further evaluation of the efficacy of VTS‐270 on treating the neurologic symptoms of 
NPC1 following 52 weeks of treatment for subjects treated with VTS‐270 compared to 
sham controls on the NPC‐SS composite: 
 
In completers   
 
Assuming data missing at random 
 
Using a pattern mixture model 
 
Assigning individual subject changes (+1 if improved, 0 if unchanged, or ‐1 if worse 
relative to baseline) 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 12 
CONFIDENTIAL 
Part C objectives 
2.3.1.Primary objective 
The primary study objective in Part C is to evaluate the long‐term safety, tolerability, and 
efficacy of VTS‐270. 
2.3.2.Secondary objectives 
 
To evaluate the safety and tolerability of the B. Braun Celsite Spinal Access Port 
utilized to administer VTS‐270 (device safety and tolerability substudy). 
 
To assess the plasma and CSF PK of VTS‐270 and trough HP‐‐CD concentration in 
subjects receiving the 900 mg dose of VTS‐270 via the B. Braun Celsite Spinal Access 
Port (device PK substudy).   
The analysis methods for the device PK substudy will be defined in a separate plan prior to 
analysis, and the results will be reported separately.   
3. 
Changes to the planned analyses 
The statistical methods described in this SAP take precedence over the methods described in 
the protocol.    The following is a list of changes to the analyses described in the protocol. 
Changes to supplementary analyses: 
There will be no supplementary analyses.    The following supplementary analyses described 
in the protocol have been changed to key secondary endpoints: 
 
Proportion of responders (defined as no change or improvement) on the NPC‐SS total 
score, with the hearing domain and ABR modifiers removed, at Week 52 
 
Proportion of Clinician CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 
Changes to key secondary endpoint analyses: 
The list of key secondary endpoints in the protocol has been changed to the following: 
 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 13 
CONFIDENTIAL 
 
Proportion of Clinician CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 
 
Change from baseline to Week 52 in the NPC‐SS total score with the hearing domain 
and ABR modifiers removed 
 
Proportion of responders (defined as no change or improvement) on the NPC‐SS total 
score, with the hearing domain and ABR modifiers removed, at Week 52 
Changes to other secondary endpoints: 
The following key secondary endpoint described in the protocol has been changed to the first 
other secondary endpoint: 
 
Proportion of Caregiver CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 
Changes to exploratory endpoints: 
The following exploratory endpoints have been added to the SAP: 
 
Proportion of subjects that are responders (defined as a score of 0 or +1) on each domain 
(ambulation, cognition, fine motor, swallowing) of the NPC‐SS composite. 
 
Cross‐tabulation analysis of Clinician CGIC responders (defined as a score of no 
change, minimally improved, moderately improved, or markedly improved) and 
individual NPC‐SS composite domain responders (defined as no change or 
improvement) at Week 52. 
4. 
Study description and conduct 
Study design and randomization 
This is a multicenter, multinational, prospective, randomized, double‐blind, sham‐controlled, 
3‐part efficacy and safety trial of VTS‐270, administered IT every 2 weeks, with a planned 
enrollment of approximately 51 subjects (in Parts A and B) with NPC1 disease. The study is 
being conducted in 3 parts. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 14 
CONFIDENTIAL 
Part A: 
In Part A, 12 subjects were randomly assigned to 1 of 4 study arms (1:1:1:1), and received 
either 1 of 3 dose levels of VTS‐270 (900 mg, 1200 mg, or 1800 mg per IT via LP) or sham LP.   
Each subject received a total of 4 lumbar IT injections or sham (once every 2 weeks). 
After all the subjects in Part A received the 4 IT infusions at the randomized dose levels or 
sham LP, including 2 weeks of observation following the fourth assigned treatment, all safety 
and efficacy data were reviewed by an independent unblinded dose selection committee 
(DSC) composed of 2 neurologists with expertise in NPC1 disease and a physician who was 
not involved in the conduct of the study as a sponsor representative. Evaluation of hearing 
loss across the different doses was included as part of the dose selection process.    The goal of 
the DSC was to select the highest dose with acceptable safety and tolerability to be 
administered in Parts B and C of the study.    Until this dose was selected, the subjects in Part 
A continued in their assigned groups for infusion or sham procedure.    The data cut‐off for 
Part A was when the last of the 12 subjects had completed 8 weeks of the study following 
randomization. 
Part B: 
Following dose selection in Part A, approximately 39 additional subjects were to be enrolled 
and randomized 2:1 to receive either study drug at the dose level chosen in Part A (900 mg) or 
sham.    Study drug lumbar IT infusion or sham procedure occurred every 2 weeks for a total 
of 52 weeks of treatment. 

Subjects from Part A who are on sham continued on sham for the duration of Part B;

Subjects who received the selected dose in Part A continued on that dose for the duration
of Part B;

Subjects on either of the two VTS‐270 doses not selected from Part A converted to the
selected dose from Part A for the duration of Part B.
Total duration of subject participation in Parts A and/or B inclusive was approximately 58 
weeks, to include the screening period of up to 45 days (maximum) and 52 weeks of IT 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 15 
CONFIDENTIAL 
injections or sham control procedures given every 2 weeks.    An additional 26 weeks of post‐
treatment follow‐up was included for any subject who elects not to participate in Part C for a 
total of 84 weeks. 
Rescue option: Subjects enrolled in Part B who manifested significant disease progression 
according to predefined clinical criteria after treatment of 26 weeks or more in Part B had the 
option to enter Part C. The predefined criteria for worsening are: 1) change of 1 level or more 
on all 4 of the NPC‐SS components of ambulation, cognition, fine motor, and swallowing and 
2) a worsening of 2 or more points on the blinded Clinician‐CGIC. Subjects who met criteria 
for predefined worsening returned 2 weeks later for confirmation of their status. At that time, 
the NPC‐SS and blinded Clinician‐CGIC assessments were repeated. If a subject still met 
criteria for predefined worsening, the subject could enter the open‐label extension study or to 
withdraw from the program. The subjects confirmed to have predefined worsening were not 
be informed of their assigned treatment in Part B in order to maintain blinding. 
Part C:   
Part C is an open‐label extension phase of the study for those subjects who qualify: 
 
Subjects who complete Part B, meet the criteria for dose reduction for a second time (i.e., 
subjects who do not tolerate 400 mg), or participated in Part B for at least 6 months and 
meet the rescue therapy criteria are eligible to participate in Part C. 
 
Subjects enrolled in the National Institutes of Health (NIH) Phase 1/2a study (13‐CH‐
0001) will also be eligible to participate upon completion of their participation in the 
phase 1/2a study.   
 
Subjects who have received prior written authorization from Vtesse to enroll directly into 
Part C are eligible to participate. 
Part A, Part B and NIH phase 1/2a subjects who transition into Part C will receive treatment 
with VTS‐270 for up to 3.5 years or until the investigator considers VTS‐270 to no longer be 
beneficial to the subject, VTS‐270 receives marketing authorization, or the development 
program is discontinued.   


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 16 
CONFIDENTIAL 
Further details about Parts A, B, and C can be found in the Protocol. 
Device Safety and Tolerability Substudy: 
A substudy investigation of the safety and tolerability of the intrathecal port B. Braun Celsite 
IT Access Port System is being conducted in approximately 6 subjects in European sites who 
meet the eligibility criteria to have the device implanted for VTS‐270 infusion. These subjects 
will remain in Part C of VTS301. 
Exhibit 1 displays the overall study design.   
Exhibit 1. Phase 2b/3 three-part study design 
 
Part A 
Part B 
Part C 
Treatment 
Dose 
N 
DSC 
Assessment 
Dose 
N 
Total 
Dose 
N 
Total 
VTS‐270 
900 mg 
3 
Final Dose 
Selection 
900 mg1 
26 
35 
900 mg biweekly, 
or lower dose with 
possible reduced 
frequency 
51 + up 
to 14 
NIH 
phase 1 
Up to 
65 
 
1200 mg 
3 
 
 
 
1800 mg 
3 
 
 
Sham 
Sham 
control 
3 
 
Sham 
control 
13 
16 
 
 
 
 
Total 
12 
 
 
39 
51 
 
 
 
DSC = dose selection committee; NIH = National Institutes of Health
 
1 Subjects who receive VTS‐270 in Part A will continue on the selected Part B dose, and subjects who receive sham 
in Part A will remain on sham for a total of 12 months.   
Study duration, visits and assessments 
Total duration of subject participation in Parts A and/or B was approximately 58 weeks, which 
included the screening period of 45 days, and 52 weeks of IT injections or sham control 
procedures to be given every 2 weeks.    Study visits coincided with study drug administration 
every 2 weeks.    An additional 26 weeks of post‐treatment follow‐up was included for any 
subject who elects not to participate in Part C for a total of 182 weeks.    Assessments of 
adverse events, vital signs and concomitant medications occur throughout Part C with study 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 17 
CONFIDENTIAL 
drug administration visits, but many other assessments were conducted only every 6 months.   
Schedules of assessments are presented in Appendix 13.2. 
Eligibility 
Male or female subjects between 4 and 21 years of age who met all study inclusion and no 
exclusion criteria at screening were eligible to enter the study. Eligible subjects were 
randomized in Part A in a 1:1:1:1 ratio to receive 900 mg, 1200 mg, or 1800 mg VTS‐270, or 
sham. In Part B, subjects were randomized in a 2:1 ratio to receive 900 mg VTS‐270 or sham.   
The specific inclusion/exclusion criteria for each study part can be found in Protocol Section 
10.   
5. 
Study endpoints 
Part B endpoints 
5.1.1.Co‐primary efficacy endpoints 
The co‐primary efficacy endpoints are as follows: 
 
Change from baseline in NPC‐SS composite score at Week 52 in the group treated with 
VTS‐270 vs. the sham control group.   
 
The Blinded Clinician CGIC at Week 52 in the group treated with VTS‐270 vs. the sham 
control group. 
5.1.2.Key secondary endpoints 
The key secondary endpoints for Part B include: 
 
Proportion of Clinician CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 in the group 
treated with VTS‐270 vs. the sham control group. 
 
Change from baseline to Week 52 in the NPC‐SS total score, with the hearing domain 
and ABR modifiers removed, in the group treated with VTS‐270 vs. the sham control 
group. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 18 
CONFIDENTIAL 
 
Proportion of responders (defined as no change or improvement) on the NPC‐SS total 
score, with the hearing domain and ABR modifiers removed, at Week 52 in the group 
treated with VTS‐270 vs. the sham control group. 
5.1.3.Other secondary endpoints 
The other (non‐key) secondary endpoints for Part B include: 
 
Proportion of Caregiver CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 in the group 
treated with VTS‐270 vs. the sham control group. 
 
Change from baseline in the EQ‐5D‐3L questionnaire at Week 52 in the group treated 
with VTS‐270 vs. the sham control group. 
 
Percentage of subjects in each group, treated for at least 6 months, who qualified for the 
rescue option in the group treated with VTS‐270 vs. the sham control group. 
 
Change from baseline to Week 52 in each of the 9 clinical domains of the NPC‐SS in the 
group treated with VTS‐270 vs. the sham control group. 
 
Change from baseline to Week 52 in the total NPC‐SS with hearing domain and ABR 
modifier included in the group treated with VTS‐270 vs. the sham control group. 
 
Time to one point increase (worsening) in NPC‐SS composite score in the group treated 
with VTS‐270 vs. the sham control group. 
 
The composite NPC‐SS mean annualized rate of change (slope) from baseline to Week 
52 in the group treated with VTS‐270 vs. the sham control group. 
 
Change from baseline in the TUG test at Week 52 in the group treated with VTS‐270 vs. 
the sham control group. 
 
Change from baseline in the 9‐hole peg test at Week 52 in the group treated with VTS‐
270 vs. the sham control group. 
5.1.4.Exploratory endpoints 
The following exploratory analyses will be performed for Part B: 
 
Change from baseline to Week 52 in the composite NPC‐SS outcome based on a 
completers analysis.   


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 19 
CONFIDENTIAL 
 
Change from baseline to Week 52 in the composite NPC‐SS outcome assuming data 
missing at random (MAR) using a standard multiple imputation. 
 
Change from baseline to Week 52 in the composite NPC‐SS outcome performed using a 
pattern mixture model. 
 
Summary of individual subject changes on NPC‐SS composite domains (assigning +1 if 
improved, 0 if unchanged, or ‐1 if worse relative to baseline) 
 
Proportion of subjects that are responders (defined as a score of 0 or +1) on each domain 
(ambulation, cognition, fine motor, swallowing) of the NPC‐SS composite. 
 
Cross‐tabulation analysis of Clinician CGIC responders (defined as a score of no 
change, minimally improved, moderately improved, or markedly improved) and 
individual NPC‐SS composite domain responders (defined as no change or 
improvement) at Week 52. 
Part C endpoints 
5.2.1.Primary endpoints 
The following endpoints will be assessed during Part C at Weeks 26, 52, 78, 104, 130, 156, 182, 
and End of Study: 
 
Change from baseline to each assessment in a composite outcome that is the sum of the 
ambulation, cognition, fine motor, and swallowing components of the NPC‐SS 
 
The change from baseline to each assessment in total NPC‐SS with the hearing domain 
and ABR modifiers removed in the VTS‐270/VTS‐270 group vs. the sham control/VTS‐
270 group. 
 
Proportion of responders (defined as no change or improvement on NPC‐SS total score 
with hearing domain and ABR modifiers removed) at each assessment 
 
The Blinded Clinician‐CGIC at each assessment compared to baseline 
 
Summary of adverse events, concomitant medications, physical examinations, 
audiologic examination, and clinical laboratories in the VTS‐270/VTS‐270 group vs. the 
sham control/VTS‐270 group. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 20 
CONFIDENTIAL 
 
Change from baseline in the EQ‐5D‐3L questionnaire at each assessment in the VTS‐
270/VTS‐270 group vs. the sham control/VTS‐270 group. 
 
Change from baseline to each assessment in each of the 9 clinical domains of the NPC‐
SS in the VTS‐270/VTS‐270 group vs. the sham control/VTS‐270 group. 
 
Change from baseline to each assessment in the total NPC‐SS with hearing domain and 
ABR modifier included in the VTS‐270/VTS‐270 group vs. the sham control/VTS‐270 
group.   
 
Time to one point increase (worsening) in NPC‐SS composite score in the VTS‐270/VTS‐
270 group vs. the sham control/VTS‐270 group. 
 
The composite NPC‐SS mean annualized rate of change (slope) from baseline to each 
assessment in the VTS‐270/VTS‐270 group vs. the sham control/VTS‐270 group. 
 
Proportion of responders (defined as no change or improvement on NPC‐SS composite 
domains) at each assessment 
5.2.2.Secondary endpoints 
The following secondary endpoints for Part C will be evaluated for the device safety and 
tolerability substudy for the first nine port infusions: 
 
Summary of wound check, examination of port site and catheter track at access port 
infusion visits 
 
Intracranial pressure (ICP) via LP 
6. 
Analysis populations 
Intent‐to‐treat population 
The intent‐to‐treat (ITT) population will include all randomized subjects in Parts A and B 
categorized by their randomized treatment assignment.   


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 21 
CONFIDENTIAL 
Modified intent‐to‐treat population 
The modified intent‐to‐treat (mITT) population will consist of all randomized subjects in Parts 
A and B who received at least one dose of 900 mg of VTS‐270 infusion or sham control.    The 
mITT will be analyzed by the planned treatment group.   
The primary population for all efficacy assessments will be the mITT population.   
Per protocol population 
The per‐protocol (PP) population will consist of all randomized subjects in Parts A and B who 
have no major protocol deviations that would impact evaluation of the primary outcome and 
who received at least 75% of their scheduled VTS‐270 IT administrations or sham procedures. 
The major protocol deviations will be defined prior to database lock and unblinding. 
A blinded review of data will identify which subjects will be included in the PP populations 
prior to unblinding of the data. Section 7 provides the details for this meeting. 
Safety population 
The safety population will consist of all randomized subjects who receive at least one dose of 
VTS‐270 or sham control.    The safety population will be analyzed by the actual treatment 
group.     
Part C open‐label population 
The Part C open‐label population will consists of all subjects who receive at least one dose of 
VTS‐270 during Part C. 
Device safety and tolerability substudy population   
The device safety and tolerability substudy population will consist of all subjects who receive 
at least one dose of VTS‐270 via the IT access device in Part C. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 22 
CONFIDENTIAL 
7. 
Blinded data review meeting                                                               
A blinded data review meeting will be held prior to locking the database and breaking the 
blind. The purpose is to assign subjects to populations based on the above definitions. 
Allocation of subjects to populations and all decisions made during this meeting will be 
documented in the meeting minutes. 
The following listings will be provided for the meeting and will follow definitions of the ITT, 
mITT and safety populations: 
 
eligibility of all subjects 
 
demographic and other baseline data 
 
medical history 
 
prior and concomitant medications 
 
post‐treatment efficacy assessments completed or not 
To define the PP population, a listing of protocol deviations will be provided. 
Missing data, visit windows, and subject withdrawals may be reviewed. Further ad hoc 
listings may be provided as required. 
No further definition of populations will be made after the blind data review meeting. 
8. 
General conventions and statistical considerations 
Descriptive and inferential statistics will be used to summarize results. Standard descriptive 
statistics, such as tabulations by clinically relevant discretizations, the mean, median, standard 
deviation, quartiles, minimum, and maximum, will be calculated for continuous variables. For 
discrete variables, descriptive analyses will be based on numbers of subjects and related 
percentages.     
In order to control for interpretability issues that could arise from pooling Part A subjects 
(randomized 3:1 treatment: sham) with the Part B subjects (randomized 2:1 treatment: sham), 
and to keep the integrity of the randomization, all table presentations will display results in 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 23 
CONFIDENTIAL 
two ways.    First, the results will be presented by overall treatment group (one column per 
treatment group), similar to that shown below:   
Overall 
Sham 
(N=X) 
n (%) 
Overall 
Treatment 
(N=X) 
n (%) 
 
Total 
(N=XX) 
n (%) 
 
 
 
P‐VALUE 
 
Second, the results will be presented by treatment group, stratified by Part A vs. Part B.    The 
layout will be presented similar to that shown below: 
Part A 
Sham 
(N=X) 
n (%) 
Part A 
Treatment 
(N=X) 
n (%) 
Part B 
Sham 
(N=XX) 
n (%) 
Part B 
Treatment 
(N=XX) 
n (%) 
 
Additionally, all formal statistical analyses will be stratified by whether subjects were 
randomized into Part A vs. randomized into Part B.     
For Part C, all table presentations will display results by path of entry (e.g., Part A/B Sham, 
Part A/B Treatment, Part C) and overall.     
In addition to tabular summaries, all relevant electronic case report form (eCRF) data and 
external lab data will be provided in by‐subject listings.    All data listings, summaries, figures, 
and statistical analyses will be generated using SAS Version 9.4 or higher [3]. 
Study days 
For the purpose of the analysis, the reference time (time zero) is defined as the start date/time 
of study drug administration for all purposes, except for the age and concomitant medication 
where time zero is the time when Informed Consent was granted. Randomization may occur 
on or before Study Visit 1 (Day 0).    Protocol‐defined Day 0 is the calendar date of the first 
administration of the study drug.    Study day will be calculated relative to first administration 
of the study drug. Specifically: 
Study day = date of visit/test/procedure – first dose date + 1. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 24 
CONFIDENTIAL 
Statistical analyses will be performed using study day as defined above.    Protocol study day = 
Study day if study day < 0; or (Study day – 1) if Study day ≥ 0. All data listings will be based 
on the Study day as defined above. 
Baseline 
The baseline value for all NPC‐SS related endpoints will be based on the assessment 
performed at screening.    The baseline value for all other study assessments including but not 
limited to vital signs, clinical outcome and disease progression measures, and concomitant 
medications is defined as the last non‐missing value prior to the first dose, unless otherwise 
specified.   
 
Change from baseline 
Change from baseline in a measurement is calculated as: 
Change = measurement at post‐baseline visit – measurement at baseline. 
Annualized rate of change (Slope) = 365.25 *((measurement at post‐baseline visit – 
measurement at baseline)/(date of post‐baseline visit – date of baseline visit + 1)). 
Visit windows 
The visit windows around the bi‐weekly visits will range from +/‐ 3 days through Week 10, 
and +/‐ 7 days through Week 52. Data will be summarized based on the eCRF (Study Visit) in 
which it was collected.    Data collected as an unscheduled visit will be re‐assigned to a Study 
Visit based on the SAP visit windows specified.    If a subject has multiple values of the same 
efficacy data within a visit, the worst case data will be used.    If a subject has multiple values 
of the same safety data within a visit, the average of the multiple records will be used.    Data 
from all assessments will be listed. 
 
Sample size determination and power calculation 
The sample size for this study is approximately 51 subjects in Parts A and B combined. The 
rationale for the sample was based on both clinical and statistical considerations.    Based on 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 25 
CONFIDENTIAL 
the comparison of the NIH phase 1 subjects and similar subjects in the NIH natural history 
dataset, approximately 51 subjects: 16 on sham and 35 on active treatment will allow for the 
detection of a clinically relevant difference of the sum of the 4 NPC‐SS domains that make up 
the composite outcome.   
The power calculation was based on the primary endpoint, defined as the change from 
baseline at week 52 in the VTS‐270 group compared to the sham group in the composite 
outcome that is the sum of the ambulation, cognition, fine motor, and swallowing scores of the 
NPC‐SS. This outcome ranges between 0 and 20 at each assessment.    Positive values for this 
change indicate a decline in function whereas negative values indicate improvement.    The 
assumptions for the calculation of the power are as follows: 
 
The VTS‐270 group has an average increase in value over 52 weeks ranging from 0 
points to 0.2 points. Taking the greatest decline of this range, the estimate of (composite 
outcome at week 52) – (composite outcome at baseline) = 0.2 
 
The sham group has an average increase in value over 52 weeks ranging from 1.6 points 
to 1.9 points. Taking the least decline of this range, the estimate of (composite outcome 
at week 52) – (composite outcome at baseline) = 1.6. 
 
A common standard deviation of 1.64. 
 
The sample size in the VTS‐270 group is 35 and the sample size in the sham group is 16. 
 
Two‐sided alpha = 0.05. 
Based on these assumptions, an analysis of covariance (ANCOVA) will have 79% power to 
detect a statistically significant difference between the VTS‐270 and sham groups.     
Three additional subjects above the planned sample size were enrolled into the study, such 
that there were 54 subjects randomized.    Assuming a 5‐10% drop out rate, the number of 
completers could range from 48‐51.    Thus, the power of the trial, based on the parameters 
above, could range from 76% if 48 subjects complete to 79% if 51 subjects complete. 
Six different scenarios are presented in Table 1. These are various differences based on an 
assumed average increase of 0 to 0.2 points in the composite outcome in the VTS‐270 group 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 26 
CONFIDENTIAL 
over a 12‐month period and an average increase in the composite outcome ranging from 1.6 to 
1.9 points in the sham group. Thus, the difference in the change from baseline to 52 weeks for 
the two groups ranges from 1.4 to 1.9 (this is based on 1.6 – 0.2 and 1.9 – 0).    In general, the 
study is well‐powered to detect differences that are similar to those that were observed 
between the Phase 1/2a and natural history study with the power for the scenarios presented 
below ranging from 0.79 to 0.96.   
 
Table 1. Estimated power for the VTS301 protocol where VTS-270 group is assumed to increase 0 
to 0.2 points over 1 year 
Estimated difference in change from baseline 
for the VTS‐270 group compared to sham 
 
Estimated power   
1.9 points 
0.96 
1.8 points 
0.94 
1.7 points 
0.91 
1.6 points 
0.88 
1.5 points 
0.84 
1.4 points 
0.79 
 
No formal power calculation was performed for clinician CGIC. 
Pooling of investigator sites 
Analyses will not be stratified by site since the study has many investigative sites (20) relative 
to the anticipated number of randomized subjects (51) as NPC is an ultra‐rare orphan disorder. 
All sites use the same protocol, entry criteria, data collection methods, and endpoints and are 
monitored to verify compliance with the protocol. The NPC‐SS will be assessed and scored 
centrally for all subjects across sites, and this blinded centralized scoring will be used for all 
NPC‐SS efficacy analyses. According to Meinert (1986), these criteria justify pooling results 
across centers [4]. 
Stratification 
Although randomization in Part B is stratified by miglustat use and baseline NPC‐SS level to 
ensure balance across the 2 treatment groups, the statistical analyses will not be stratified 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 27 
CONFIDENTIAL 
based on these variables.    The number of subjects in any one stratum may be too small to 
make any meaningful comparative inferences.     
All formal statistical analyses will be stratified by whether the subject entered the study in Part 
A or entered in Part B. 
In order to understand the effects of stratification, the following stratification groups will be 
used as sensitivity analyses: 
 
Subjects randomized in Part A 
 
Subjects randomized in Part B, miglustat use +, NPC‐SS total score ≥ 20 
 
Subjects randomized in Part B, miglustat use ‐, NPC‐SS total score ≥ 20 
 
Subjects randomized in Part B, miglustat use +, NPC‐SS total score < 20 
 
Subjects randomized in Part B, miglustat use ‐, NPC‐SS total score < 20 
Safety parameters 
All safety summaries will present data by study part.    Summaries will present adverse 
events, including those related to the study treatment and administration procedure.    Serious 
adverse events will be summarized similarly and include narratives as well.    Clinical 
laboratory, vital sign and ECG values and changes from baseline will be summarized by 
treatment group and time point.    Physical examination abnormal results will be listed and 
summarized.    Results of several audiologic evaluations and ABR will be summarized and 
presented. 
In addition to the above assessments, the following safety evaluations will be conducted for 
the device safety and tolerability substudy in Part C: 
 
Wound check, examination of port site and catheter track at access port infusion visits 
 
Intracranial pressure (ICP) via LP 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 28 
CONFIDENTIAL 
9. 
Study population summaries 
Enrollment 
Enrollment will be summarized by treatment group. A table will present the number and 
percentages of subjects in each stratum by treatment group. A listing of screen fail subjects 
with reason for screen fail will be provided. 
Subject disposition 
The disposition of subjects (number randomized but did not receive study drug, number 
randomized and received all study drug procedures, number randomized but who did not 
receive all study drug procedures) will be tabulated by study part and treatment group and 
presented in a CONSORT diagram. All possible reasons for not receiving all study drug 
procedures will be summarized by study part and treatment group. 
Listings will present time to and reason for discontinuation or withdrawal by study part, 
treatment group and subject.   
The analysis population table will summarize the number and percent of subjects in the 
following populations: 
 
ITT 
 
mITT (primary population for efficacy assessments) 
 
Per Protocol   
 
Safety Population. 
Protocol deviations and violations 
Protocol deviations from monitoring reports and other relevant sources will be tabulated by 
type of protocol deviation (whether the deviation is major or minor) using the ITT population 
by study part and treatment group. Listings will present all protocol deviations and violations 
by study part, treatment group and subject. Any violation of the inclusion/exclusion criteria 
will be reported in accordance with the policy and procedures of the IEC/IRBs at participating 
study sites.   


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 29 
CONFIDENTIAL 
Demographics and baseline characteristics 
Subject demographics and baseline characteristics will be summarized by study part and 
treatment group using the ITT and mITT populations, if there is a difference between the 
populations. Information to be summarized includes age in years, gender, race, ethnicity, 
weight, miglustat status (Yes/No), NPC‐SS Score category (10‐19, 20+), duration of 
neurological symptoms at baseline (years), duration of neurological symptoms at baseline (<4 
years, 4‐8 years, >8 years), seizures (Yes/No), and baseline NPC‐SS total score, NPC‐SS total 
score minus hearing components and NPC‐SS composite endpoint score.   
Medical history 
Relevant medical history, including history of current disease, pertinent respiratory history, 
and information regarding underlying diseases will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA, version 18.0).    Medical history will be summarized by 
system organ class (SOC) and preferred term (PT) by study part and treatment group using 
the mITT population. All medical history data will also be listed. 
NPC disease history 
NPC disease history, including occurrence of NPC related medical conditions or procedures 
(yes or no), medication used to treat NPC or symptoms associated with NPC (yes or no), and 
family history of NPC (yes or no) will be summarized by study part and treatment group 
using the mITT population.     
10. 
Study drug and other medications 
Prior and concomitant medications 
All concomitant medications collected from screening through the end of the study will be 
classified by drug class and PT according to the World Health Organization (WHO) Drug 
Dictionary. Prior medications are any medications taken prior to the first dose of study 
medication (i.e., start date and end date occurs before the first study medication dose date).   
If the medication start date is completely missing, then the medication will be considered as 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 30 
CONFIDENTIAL 
concomitant unless it can be determined that the medication end date occurred prior to the 
first dose of study medication. If the medication start date is partially missing and the partial 
date is not sufficient to determine if the medication was taken after the first dose of study 
medication, then the medication will be considered concomitant for the study unless it can be 
ruled out by the partial date and/or medication end date.     
The number and percent of safety subjects using concomitant medications will be tabulated by 
drug class, study part and treatment group. All prior and concomitant medications will be 
listed. 
Duration of treatment and exposure to study drug 
Duration of treatment will be defined as the length of time from first dose of study 
administration to date of discontinuation from the study treatment within each study part 
(Part A/B combined and Part C).    That is, (Date of last dose during study part treatment 
period – Date of first dose of study drug during study part + 1 day).    Exposure to VTS‐270 
will be calculated as the total dose (mg) received during the study part (Part A/B combined or 
Part C).    Standard descriptive statistics will be used to summarize duration and exposure by 
study part and treatment group using the safety analysis set.   
Compliance to study medication will be calculated as 100 × (number of times a subject 
received study medication)/(Expected number of times a subject was to receive study 
medication per the protocol schedule while participating in the trial). Compliance will be 
calculated separately for each study part (A/B combined and C).    All dosing information will 
be listed by study part, treatment group and subject ID. Study drug administration over time 
will be summarized in a listing showing VTS‐270 dose at each scheduled clinic visit and/or IT 
administration. 
11. 
Efficacy analyses 
The statistical methods described below apply to the analyses performed for Part B.    All Part 
C data will only be listed and summarized. 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 31 
CONFIDENTIAL 
Co‐primary efficacy analyses 
The co‐primary efficacy endpoints are as follows: 
 
Change from baseline in NPC‐SS composite score at Week 52 in the group treated with 
VTS‐270 vs. the sham control group 
 
The Blinded Clinician CGIC at Week 52 in the group treated with VTS‐270 vs. the sham 
control group 
The NPC‐SS composite score is the sum of the ambulation, cognition, fine motor, and 
swallowing domains of the NPC‐SS.    This outcome ranges in value from 0 to 20 points at each 
assessment. Measurements at baseline, each post‐baseline measurement through Week 52, and 
change from baseline for each measurement through Week 52 will be summarized 
descriptively.    For the co‐primary efficacy analysis, any missing Week 52 assessments will be 
imputed.    Subjects who take the rescue option will be considered dropouts and will need to 
have their missing Week 52 assessment imputed.    To protect against the potential bias that 
may occur if outcomes for the completers are different from those for the non‐completers (i.e., 
missing not at random; MNAR), the approach taken will be to impute all missing observations 
from either treatment arm as if they came from the sham group.    That is, the average change 
from baseline for the sham group will be added to the baseline observation of each subject 
with a missing assessment at Week 52.    The missing value imputation will occur at the 
individual domain level.    An ANCOVA, with treatment group, study part, and baseline 
NPC‐SS composite score included in the model, will be performed to test for differences in the 
change from baseline to Week 52 between VTS‐270 and sham groups in the co‐primary 
efficacy outcome measure.    Considering the small sample size, this ANCOVA will be 
performed using a nonparametric approach such that the outcome data will be ranked.   
Average ranks will be assigned in case of ties.    The null hypothesis will be H0 : ∆d ‐ ∆s = 0 , and 
the alternative hypothesis will be H1 : ∆d ‐ ∆s ≠ 0, where ∆d is the mean rank of the change from 
baseline for the drug VTS‐270 group and ∆s is the mean rank of the change from baseline for 
the sham group.    The null hypothesis will be tested with both means adjusted for study part 
in which the subject was randomized to (A or B) and baseline NPC‐SS composite score.    This 
test will be performed at α=0.05 level (two‐sided) of significance. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 32 
CONFIDENTIAL 
The analysis of the blinded Clinician CGIC at Week 52 will be conducted using the 
nonparametric Van Elteren method to test for the treatment effect using study part as a 
blocking variable.    Average ranks will be assigned when there are ties within a block.   
Missing Week 52 assessments will be imputed.    To protect against the potential bias that may 
occur if outcomes for the completers are different from those for the non‐completers (i.e., 
MNAR), the approach taken will be to impute all missing observations from either treatment 
arm as if they came from the sham group.    That is, the average blinded Clinician‐CGIC at 
Week 52 for the sham group will be imputed for each subject with a missing assessment at 
Week 52.    Because the average value of the sham group used for imputation may not be an 
integer, but needs to be in order to fit the ordinal categories of the blinded Clinician‐CGIC, the 
ceiling (worst case) will be applied to the average value before imputation.       
Sensitivity analyses for the co‐primary endpoints 
In order to determine if the conclusions from the co‐primary efficacy analyses are robust, 
several sensitivity analyses will be conducted.   
First, the ANCOVA of the NPC‐SS composite score co‐primary endpoint will be repeated 
using the raw, unranked change from baseline to Week 52 data.    Missing data will be 
imputed as described above.    The Shapiro‐Wilk test for normality will be performed to test 
the normality assumption.     
Second, the co‐primary efficacy analyses will be repeated using the PP population, assuming 
there are differences between the mITT and PP populations.    Missing values in the PP 
population will be imputed in the same way as described above for the co‐primary efficacy 
analyses. 
Third, the co‐primary efficacy analyses will be repeated excluding the 6 subjects randomized 
to the 1200 mg and 1800 mg dose levels in Part A.   
Fourth, the co‐primary efficacy analyses will be repeated excluding the 3 subjects from site 
 because subjects from this site had extremely poor adherence to the protocol. 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 33 
CONFIDENTIAL 
Fifth, the proportion of Clinician CGIC responders (defined as a score of no change, minimally 
improved, moderately improved, or markedly improved) at Week 52 will be analyzed using 
the Cochran‐Mantel‐Haenszel (CMH) test, stratified by the following stratification groups: 
 
Subjects randomized in Part A 
 
Subjects randomized in Part B, miglustat use +, NPC‐SS total score ≥ 20 
 
Subjects randomized in Part B, miglustat use ‐, NPC‐SS total score ≥ 20 
 
Subjects randomized in Part B, miglustat use +, NPC‐SS total score < 20 
 
Subjects randomized in Part B, miglustat use ‐, NPC‐SS total score < 20 
Key secondary endpoints and analyses 
The following key secondary endpoints comparing VTS‐270 treated subjects with the sham 
controls will be analyzed using a hierarchical testing, serial gatekeeping strategy based on the 
mITT population. 
 
Proportion of Clinician CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 
 
Change from baseline to Week 52 in the NPC‐SS total score with the hearing domain 
and ABR modifiers removed 
 
Proportion of responders (defined as no change or improvement) on NPC‐SS total score 
with the hearing domain and ABR modifiers removed, at Week 52   
A serial gatekeeper testing strategy will be used to protect the overall type I error rate of 0.05 
(two‐sided). These key secondary efficacy endpoints will be tested only if both co‐primary 
efficacy null hypotheses described in Section 11.1 have been rejected, thus maintaining the 
overall significance level at 5% (two‐sided).    Each family will be tested at α=0.05 level (two‐
sided) provided all analyses in the preceding families were significant (Figure 1). 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 34 
CONFIDENTIAL 
Figure 1. Serial Gatekeeper Strategy 
 
The analysis of the proportion of Clinician CGIC responders (defined as a score of no change, 
minimally improved, moderately improved, or markedly improved) at Week 52 will be 
conducted using the CMH test, stratified by study part.    Missing Week 52 assessments will be 
imputed using similar methods to the co‐primary efficacy analysis methods prior to 
determining responder status.    The analysis and resulting p‐value will be considered 
exploratory if either of the co‐primary efficacy endpoints is not statistically significant at 
α=0.05 level (two‐sided). 
The NPC‐SS total score, excluding the hearing domain and ABR modifier results, will be 
analyzed in the same way as the co‐primary efficacy endpoint using ranked data.    Missing 
data at Week 52 and dropouts will be handled using the same methods as for the co‐primary 
efficacy endpoint.    The analysis and resulting p‐value will be considered exploratory if the 
Family 1
F1: (Both co‐primary efficacy endpoints): Change 
from baseline in NPC‐SS composite score at Week 
52 AND Blinded Clinician CGIC at Week 52
Family 2
F2: Proportion of Clinician CGIC responders 
(defined as a score of no change, minimally 
improved, moderately improverd, or 
markedly improved) at Week 52
Family 3
F3: Change from baseline to Week 52 in the 
NPC‐SS total score with the hearing domain 
and ABR modifiers removed 
Family 4
F4: Proportion of responders (defined as no 
change or improvement) on NPC‐SS total 
score, with hearing domain and ABR modifiers 
removed, at Week 52


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 35 
CONFIDENTIAL 
key secondary efficacy endpoint analysis of proportion of Clinician CGIC responders is not 
statistically significant at α=0.05 level (two‐sided). 
The NPC‐SS total score, excluding the hearing domain and ABR modifier results, will be 
evaluated by a responder analysis to assess whether the VTS‐270 group had a greater average 
response compared to the sham group.    Missing Week 52 values will be imputed in the same 
way as described above prior to determining responder status.    The responder analysis will 
consist of a tabulation of the number and percent of subjects falling into the predefined 
categories, and a CMH test, stratified by study part, will be performed to examine any 
difference between the treatment groups.    The analysis and resulting p‐value will be 
considered exploratory if the secondary efficacy endpoint analysis of change from baseline to 
Week 52 in total NPC‐SS, excluding the hearing domain and ABR modifier, is not statistically 
significant at α=0.05 level (two‐sided). 
For sensitivity analyses, the above key secondary endpoint analyses will be repeated using the 
PP population, assuming there are differences between the mITT and PP populations.   
Missing values in the PP population will be imputed in the same way as described above for 
the key secondary efficacy endpoint analyses. 
Other secondary endpoints and analyses 
The following other (non‐key) secondary endpoints will be performed to assess the treatment 
effect using the mITT population.    The tests will be non‐hierarchical and type I error will not 
be adjusted for multiple testing.     
 
Proportion of Caregiver CGIC responders (defined as a score of no change, minimally 
improved, moderately improved or markedly improved) at Week 52 will be analyzed 
using a CMH test, stratified by study part, to assess for any differences in the group 
treated with VTS‐270 vs. the sham control group. 
 
Responses to the EQ‐5D‐3L proxy questionnaire following 52 weeks of treatment for VTS‐
270 treated subjects compared to sham controls will also be summarized by study part 
and treatment group using appropriate descriptive statistics. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 36 
CONFIDENTIAL 
 
Percentage of subjects who qualified for the rescue option in the VTS‐270 group 
compared to sham‐treated subjects, following a minimum of 26 weeks of treatment, will 
be analyzed using the CMH test, stratified by study part. 
 
Change from baseline to Week 52 in each of the 9 clinical domains of the NPC‐SS in the 
group treated with VTS‐270 vs. the sham control group will be analyzed using 
nonparametric methods similar to the co‐primary endpoint analysis.     
 
Change from baseline to Week 52 in the total NPC‐SS, with hearing domain and ABR 
modifier included, in the group treated with VTS‐270 vs. the sham control group will be 
analyzed using nonparametric methods similar to the co‐primary endpoint analysis. 
 
Time to event analyses – time to increase in NPC‐SS composite of 1 or more (worsening). 
The product‐limit survival analysis method will be used to estimate the time to event of 
interest and Cox’s proportional hazards model will be used to assess the treatment effect 
on hazard ratios (HRs) adjusted for study part. 
 
The composite NPC‐SS mean annualized rate of change (slope) from baseline to Week 52 
will be analyzed using nonparametric methods similar to the co‐primary efficacy 
endpoint analysis.    In this case, the rank of the slope [365.25 * ((measurement at post‐
baseline visit – measurement at baseline)/(date of post‐baseline visit – date of baseline 
visit + 1))], rather than the change from baseline at Week 52 in the composite NPC‐SS 
score, will be the dependent variable in the model.     
 
TUG test results following 52 weeks of treatment compared to baseline for VTS‐270 
treated subjects compared to sham controls will be analyzed using methods similar to the 
co‐primary endpoint analysis.    Where several assessments are made at the same visit, the 
average of the test results will be used for analysis. 
 
9‐hole peg test results following 52 weeks of treatment compared to baseline for VTS‐270 
treated subjects compared to sham controls will be analyzed using methods similar to the 
co‐primary endpoint analysis.    Where several assessments are made at the same visit, 
the average of the test results will be used for analysis. 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 37 
CONFIDENTIAL 
Multiplicity 
A hierarchical, serial gatekeeper testing strategy will be used to protect the overall type I error 
rate of α=0.05 (two‐sided) when testing the co‐primary endpoints together with the key 
secondary endpoints (as described in section 11.3).    No adjustment for multiplicity will be 
performed for testing the other (non‐key) secondary endpoints. 
Exploratory endpoints and analyses 
The following analyses will be performed for exploratory purposes: 
 
The co‐primary efficacy NPC‐SS composite analysis will be repeated based on a 
completers analysis where subjects missing week 52 assessments will remain missing.     
 
The co‐primary efficacy NPC‐SS composite endpoint analysis will be performed 
assuming data missing at random (MAR).    A standard multiple imputation will be 
implemented using separate imputation models for the VTS‐270 and sham groups.   
Only the baseline and week 52 assessments will be included in the analysis. 
 
The co‐primary efficacy NPC‐SS composite endpoint analysis will be performed using a 
pattern mixture model.    Only the baseline and week 52 assessments will be included in 
the analysis. 
 
Individual level outcomes applied to each of the NPC‐SS composite domains following 
52 weeks of treatment for VTS‐270 treated subjects compared to sham controls.    Each 
individual level outcome will be assigned the value of +1 if the change from baseline is 
negative (i.e., the subject improves over time), 0 if the change from baseline is 0, and ‐1 
if the change from baseline is positive (i.e., the subject declines over time).    The 
analysis of the individual‐level outcome will be based on the exact likelihood ratio test 
to test the null hypothesis that the values are the same across the two groups.    The 
analysis will be applied to each of four composite domains of the NPC‐SS scores 
separately. 
 
The proportion of subjects that are responders (defined as a score of 0 or +1) on each 
domain (ambulation, cognition, fine motor, swallowing) of the NPC‐SS composite will 
be analyzed using the CMH test, stratified by study part. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 38 
CONFIDENTIAL 
 
Cross‐tabulation analysis of Clinician CGIC responders (defined as a score of no 
change, minimally improved, moderately improved, or markedly improved) and 
individual NPC‐SS composite domain responders (defined as no change or 
improvement) at Week 52. 
Subgroup analyses 
Subgroup analyses will be performed on the following efficacy endpoints: 
 
Change from baseline in NPC‐SS composite score at Week 52 
 
Blinded Clinician CGIC at Week 52 
 
Change from baseline in NPC‐SS total score at Week 52 
 
Change from baseline in NPC‐SS total score minus hearing and ABR at Week 52 
 
Change from baseline in individual scores for the 9 domains of the NPC‐SS score at 
Week 52 
 
Composite NPC‐SS mean annualized rate of change (slope) from baseline at Week 52 
The endpoints above will be summarized by treatment group for the subgroups defined on the 
basis of the categorized variables listed below: 
Grouping variable
Subgroups 
Baseline Miglustat use 
Yes, 
No 
Baseline NPC severity 
<20, 
>20 
Duration of neurological 
symptoms at baseline (years) 
<4, 
4‐8, 
>8 
Post‐baseline Miglustat use 
Yes, 
No 
Clinician‐CGIC severity 
Minimally worse,   
Moderately worse,   


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 39 
CONFIDENTIAL 
Markedly worse 
12. 
Safety summaries 
All of the assessments in the sections below will be performed both for Part B using the Safety 
population and Part C using the Part C Open‐Label population.     
Adverse events 
Adverse events will be coded using the most current version of MedDRA and summarized by 
SOC, PT, and worst National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE version 4.03) grade per subject.   
Investigators will assess the relationship of each adverse event to study drug. The relationship 
of each adverse event to study drug will be categorized as not related, unlikely related, 
possibly related, probably related, and definitely related.   
12.1.1.Hearing AEs of special interest 
There are two types of possible hearing impairment AEs – subjective and objective 
AEs.     Subjective events will be reported to the AE assessor during their interaction with the 
subject/family (i.e. hearing impairment associated with spoken language, tinnitus, turning up 
the TV, functional concerns, etc.).   Objective events will be identified by the Audiologist 
during the audiologic evaluation.    Objective hearing impairment AEs are identified by 
assigning a CTCAE or ABR Adverse Event grade at every Audiologic evaluation after 
screening/baseline.   A modified CTCAE scale is used to grade audiologic evaluations obtained 
through behavioral audiometry.    An ABR Adverse Event Scale is used when behavioral 
audiometry is not obtainable, and an Auditory Brainstem Response test is used to determine 
hearing thresholds. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 40 
CONFIDENTIAL 
The following is a modified grading system, derived from the CTCAE (v4.03) scale that will be 
used to determine the AE grade for hearing impairment when hearing thresholds are obtained 
via pure tone audiometry: 
 
Grade 1: (on a 1, 2, 3, 4, 6 and 8 kHz audiogram): Threshold shift >20 dB at 8 kHz in at 
least one ear. 
 
Grade 2: (on a 1, 2, 3, 4, 6 and 8 kHz audiogram): Threshold shift >20 dB at 4 kHz and 
above in at least one ear. 
 
Grade 3: (on a 1, 2, 3, 4, 6 and 8 kHz audiogram): hearing impairment sufficient to 
indicate therapeutic intervention, including hearing aids; threshold shift >20 dB at 3 kHz 
and above in at least one ear; additional speech‐ language related services indicated. 
 
Grade 4: Decrease in hearing to profound bilateral impairment (absolute threshold >80 
dBHL at 2 kHz and above); non‐serviceable hearing 
The following is the “ABR Adverse Event Scale” (developed specifically for use in VTS301) 
that will be used to determine the AE grade for hearing impairment when hearing thresholds 
are obtained via diagnostic ABR not using pure tone thresholds:     
 
Grade 1: Threshold shift >10 < 20 dB at 4 kHz in at least one ear 
 
Grade 2: Threshold shift >20 dB at 4 kHz in at least one ear 
 
Grade 3: Threshold shift >20 dB at 2 kHz in at least one ear 
 
Grade 4: Absolute thresholds >80 dBeHL from 1‐4 kHz (not previously present at 
baseline) bilaterally 
12.1.2.AE summaries 
All AE presentations will summarize treatment emergent adverse events (TEAEs) defined as 
adverse events with onset on or after randomization or onset prior to randomization but with 
worsened severity post‐randomization.    In case of partially missing AE start and stop dates, 
the dates will be imputed by comparing to first dose date of study medication so that the 
corresponding AEs will be made treatment‐emergent whenever possible, unless the available 
partial date information clearly indicates that the event happened outside of the treatment 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 41 
CONFIDENTIAL 
period.    In general, a conservative strategy will be followed with respect to the assignment of 
AEs with partial start dates.     
Presentations for Part A/B will include all adverse events with an onset date through the first 
Part C dose date ‐ 1.    Presentations for Part C will include all adverse events with an onset 
date on or after the first VTS‐270 dose date.    The incidence of TEAEs will be shown in terms 
of the total number of subjects and not in terms of the total number of events. 
The following presentations of treatment‐emergent adverse events will be summarized by 
study part and treatment group: 
 
Serious adverse events 
 
All adverse events 
 
Adverse events by greatest toxicity grade (greatest severity will be used where toxicity 
grade is missing) 
 
Adverse events ≥ Grade 3 toxicity (severity will be used where toxicity grade is missing) 
 
Adverse events related to study drug (i.e., AEs classified as possibly, probably, and 
definitely related) 
 
Adverse events related to LP procedure (Adverse events were categorized as ‘related to 
LP procedure’ if the event was marked as related to intrathecal procedure or other 
protocol required procedures.)   
 
Adverse events of special interest: Related to or resulting in hearing impairment, and 
seizures, other agitation, aphasia, dystonia and other neurologic AE’s. 
 
Adverse events leading to study discontinuation. 
All of the above summaries, other than the AEs related to study drug summary, will be 
repeated based on related AEs.    All AEs will be listed with MedDRA coding, onset and 
resolution dates, seriousness, severity, relationship, actions, and outcome. 
In addition, the adverse events for subjects who took study medication from batch 
 
will be summarized to evaluate any impact of the decrease in pH over time. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 42 
CONFIDENTIAL 
The following subgroup analyses will also be performed. 
 
Treatment emergent adverse events by SOC, PT, and post‐baseline Miglustat use (yes, 
no) 
 
Treatment related treatment emergent adverse events by SOC, PT, and post‐baseline 
Miglustat use (yes, no) 
 
Treatment emergent serious adverse events by SOC, PT, and post‐baseline Miglustat 
use (yes, no) 
Deaths 
The number of subjects who died will be summarized by treatment regimen. A by‐subject 
listing of deaths will include death date, cause of death, and relationship to study treatment. 
Vital signs 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) are collected at 
screening, baseline, and every two weeks thereafter according to the schedule in Exhibit 2 – 
Exhibit 7.    Weight is collected at screening and week 52 and will be included in the vital signs 
summary.    Vital sign values and changes from baseline will be summarized by study part, 
treatment group and time point.    Figures may be used if appropriate. 
Physical examination 
Physical examinations are planned at screening. The number and percentage of subjects with 
an abnormal result for the latest pre‐randomization examination will be summarized by study 
part and treatment group for each body system examined. During the study, the number and 
percentage of subjects with an abnormal result for each body system (change or no change 
from the last examination) will be summarized by study part, treatment group and visit. If 
more than one physical examination is performed for a subject at the same visit, the latest 
examination will be used. Early withdrawal examinations will be assigned to the closest visit 
at which an examination was scheduled to occur. The denominators will only include subjects 
with a study visit being summarized.   


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 43 
CONFIDENTIAL 
All physical examination abnormal results will be listed. 
 Laboratory data 
Exhibit 2 – Exhibit 7 displays the timing of laboratory tests.    Clinical laboratory values and 
changes from baseline will be summarized by study part, treatment group and time point. 
Laboratory data will be summarized by presenting shift tables from baseline to each post‐
baseline time point.    Figures may be used if appropriate.   
Audiologic evaluation 
Audiologic evaluations were used as exploratory clinical endpoints as well as additional safety 
measurements assessing ototoxicity. The audiologic evaluations performed over the course of 
the study included: behavioral assessment of pure tones and speech measures (threshold and 
word discrimination), tympanometry, otoacoustic emissions, and ABR. Pure tone assessment 
(Air Conduction and Bone Conduction) will be summarized as it best captures possible 
ototoxicity.   
Air conduction (AC) was tested at the following frequencies: 250 Hz, 500 Hz, 1000 Hz, 
2000 Hz, 3000 Hz, 4000 Hz, 6000 Hz, and 8000 Hz.    Bone conduction (BC) was tested at the 
following frequencies: 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz.    Descriptive statistics 
of hearing thresholds in decibels will be presented by study part, treatment group, conduction 
type, visit, frequency and ear. 
Pure tone averaging was done for both AC and BC across low frequencies of 500 Hz, 1000 Hz, 
and 2000 Hz.    Pure tone averaging will also be done for AC at high frequencies of 4000 Hz, 
6000 Hz, and 8000 Hz. If at least two non‐missing thresholds are obtained per conduction type 
and ear, the pure tone average (PTA) for AC and the bone conduction average (BCA) for BC 
will be calculated by adding up the threshold levels in decibels (dB), and then dividing the 
sum by the number of thresholds obtained.    PTA and BCA will be summarized by study part, 
treatment group, visit and ear.   


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 44 
CONFIDENTIAL 
A diagnostic ABR was tested at the following frequencies: 500 Hz, 1000 Hz, 2000 Hz, and 
4000 Hz.    Descriptive statistics of hearing thresholds in decibels will be presented by study 
part, treatment group, visit, frequency and ear.   
When conducting the PTA and ABR, the sites recorded the type of hearing impairment and 
hearing impairment severity.    Hearing impairment severity was categorized as follows (more 
than one could apply to a subject at each assessment).     
 
Normal hearing (‐10 to 15 dB) 
 
Slight hearing impairment (16 to 25 dB) 
 
Mild hearing impairment (26 to 40 dB) 
 
Moderate hearing impairment (41 to 55 dB) 
 
Moderate‐severe hearing impairment (56 to 70dB) 
 
Severe hearing impairment (71 to 90 dB) 
 
Profound hearing impairment (91 + dB) 
 
High Frequency Hearing Impairment (defined as an impairment at 4k and above) 
Hearing impairment severity will be summarized for both PTA and ABR by study part, 
treatment group and visit. 
All audiometry assessments will be listed by subject. 
A sensitivity analysis will be performed to address the impact that the known risk of 
ototoxicity from study drug may have on the adequacy of blinding.    The concern comes if the 
site staff performing the NPC‐SS assessment notices over the course of the study that the 
subject experiences clinical hearing impairment.    Will the knowledge of hearing impairment 
cause the NPC‐SS assessment to be knowingly or unknowingly biased?    Because the 
audiologic evaluation results are kept blinded from the site staff performing the NPC‐SS 
assessment, we will instead use the reporting of hearing impairment as an adverse event (by 
the blinded AE rater) due to clinical manifestation as a marker of hearing impairment in this 
analysis.    A standard MedDRA query for hearing impairment will be used to identify these 
terms.    The recommendation for hearing aides to a subject will also be included in this 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 45 
CONFIDENTIAL 
analysis.    The site staff member performing the NPC‐SS assessment also is blinded to the AEs 
that are recorded for the subject.     
In order to assess whether there was an impact due to unblinding, the co‐primary efficacy 
NPC‐SS composite endpoint analysis will be repeated (a nonparametric ANCOVA, with 
treatment group, study part, and baseline included in the model), but will also include a 
variable indicating the recording of hearing impairment (AE or recommendation for hearing 
aid) and a hearing impairment by treatment group interaction variable in the model.    A 
significant hearing impairment by treatment group interaction variable (two‐sided α=0.05 level 
of significance) will provide evidence that an unblinding bias has occurred.   
 Auditory brainstem response 
Auditory Brainstem Response, conducted at screening and Week 52 or early termination, will 
be summarized by study part and treatment group. 
Neurological evaluation 
Neurological evaluations will be summarized at baseline and at subsequent follow‐up weeks 
by study part and treatment group. 
12‐lead ECG 
Summaries will present the results of 12‐lead ECG testing. 
Serum pregnancy   
Serum pregnancy test results will be listed.   
Device safety and tolerability substudy   
The following safety evaluations will be listed and/or summarized for the B. Braun Celsite 
Spinal Access Port utilized to administer VTS‐270 in the device safety and tolerability 
substudy of subjects in Part C.    Descriptive statistics used will be appropriate to the type of 
measurement (continuous or discrete).     
 
Wound check, examination of port site and catheter track at access port infusion visits 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 46 
CONFIDENTIAL 
 
Intracranial pressure (ICP) via LP 
Device implant procedure data will be listed.     
 


VTS301: STATISTICAL ANALYSIS PLAN 
   August 27, 2018 
Page 47 
CONFIDENTIAL 
13. 
Appendices 
NPC Clinical Severity Scale   
 
Table A1. NPC Clinical Severity Scale 
Ambulation 
Score
Eye Movement
Score
Normal 
0 
Normal eye movement 
0 
Clumsy 
1 
Mild vertical supranuclear gaze 
palsy (VSGP), detected by physician only 
1 
Ataxic unassisted gait or not walking by 
18 months 
2 
Functional VSGP, noted by family or 
compensation with head movements 
2 
Assisted ambulation or not walking by 
24 months 
4 
Total VSGP, abnormal horizontal saccades 
may be present 
3 
Wheelchair dependent 
5 
Total ophthalmoplegia (vertical and 
horizontal saccades absent) 
5 
Speech 
Score
Swallow
Score
Normal speech 
0 
Normal, no Dysphagia 
0 
Mild dysarthria (easily understood) 
1 
Cough while eating* 
 
 
 
 
Intermittent Dysphagia w/liquids 
+1 
 
 
 
Intermittent Dysphagia w/solids 
+1 
Severe dysarthria (difficult to understand) 
2 
 
Dysphagia w/liquids 
+2 
 
 
 
Dysphagia w/solids 
+2 
Non‐verbal/functional communication 
skills for needs 
3 
Nasogastric tube or gastric tube for 
supplemental feeding 
4 
Minimal communication 
5 
Nasogastric tube or gastric tube feeding 
only 
5 
Fine Motor Skills 
Score
Cognition
Score
Normal 
0 
Normal 
0 
Slight dysmetria/dystonia (independent 
manipulation) 
1 
Mild learning delay, grade appropriate for 
age 
1 
Mild dysmetria/dystonia (requires little to 
no assistance, able to feed self without 
difficulty) 
2 
Moderate learning delay, individualized 
curriculum or modified work setting 
3 
Moderate dysmetria/dystonia (limited fine 
motor skills, difficulty feeding self) 
4 
Severe delay/plateau, no longer in school or 
no longer able to work, some loss of 
cognitive function 
4 
Severe dysmetria/dystonia (gross motor 
limitation, requires assistance for self‐care 
activities) 
5 
Minimal cognitive function 
5 
 
 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 48 
CONFIDENTIAL 
 
Table A1. NPC Clinical Severity Scale, continued 
Hearing (sensorineural) 
Score
Memory
Score
Normal hearing (all tones ≤ 15 dB HL) 
0 
Normal 
0 
High frequency hearing loss (PTA** ≤ 15 dB HL, 
>15 dB HL in high frequencies) 
1 
Mild short‐term or long‐term memory loss 
1 
Slight‐mild hearing loss (PTA 16‐44 dB HL) 
2 
Moderate short‐term or long‐term memory 
loss (gets lost) 
2 
Moderate hearing loss (PTA 45‐70 dB HL) 
3 
Difficulty following commands 
3 
Severe hearing loss (PTA 71‐90 dB HL) 
4 
Unable to follow commands or short‐ and 
long‐term memory loss 
4 
Profound hearing loss (PTA > 90 dB HL) 
5 
Minimal memory 
5 
Seizures 
Score
No history of seizures 
0 
 
 
Hx of single seizure 
1 
 
 
Rare seizures 
2 
 
 
Seizures, well controlled with meds 
3 
 
 
Seizures, difficult to control with meds 
5 
 
 
Modifiers 
Gelastic Cataplexy 
Score
Hyperreflexia
Score
No history 
0 
None 
0 
Definitive history 
+1 
Mild (3+) 
+1 
Frequent (every month) 
+2 
Severe (+ clonus) 
+2 
Narcolepsy 
Score
Incontinence
Score
No history 
0 
No problems 
0 
Definitive history 
+1 
Occasional 
+1 
Frequent (every month) 
+2 
Frequent 
+2 
Behavior 
Score
ABR
Score
No problems 
0 
Normal 
0 
Hx of ADHD, aggressive 
+1 
Abnormal 
+1 
Harmful to self/others 
+2 
Absent 
+2 
Psychiatric 
Score
Respiratory
Score
No problems 
0 
No problems 
0 
Hx of mild depression 
+1 
Hx pneumonia 
+1 
Hx of major depression, hallucinations, or 
psychotic episodes 
+2 
Pneumonia ≥ 2x/year or active therapeutic 
intervention 
+2 
*Score is additive within these two subsections 
**Pure tone average reported on the audiogram
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 49 
CONFIDENTIAL 
 
Schedule of Assessments 
Exhibit 2. Study Parts A and B schedule of assessments (Screening through Week 26) 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Day 
Day -45
to Day -1
0 
14 
28 
42 
56 
70 
84 
98 
112
126
140
154
168
182
Window (days) 
 
 
(±3)
(±3)
(±3)
(±3)
(±3) (±7) (±7)
(±7)
(±7)
(±7)
(±7)
(±7)
(±7)
 
Time Point (Week) 
 
Screening
1st 
Study 
Dose 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
Study Procedure 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical hxa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect urineb 
X 
 
 
 
 
X# 
 
X 
 
 
 
 
 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
Xd 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Xd,e 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological examinationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory testingg 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Audiologic testing 
X 
X 
X# 
X# 
X# 
X 
 
 
 
X 
 
 
 
X 
 
Auditory brainstem response 
X 
 
 
 
 
X# 
 
 
 
 
 
 
 
 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 50 
CONFIDENTIAL 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Day 
Day -45
to Day -1
0 
14 
28 
42 
56 
70 
84 
98 
112
126
140
154
168
182
Window (days) 
 
 
(±3)
(±3)
(±3)
(±3)
(±3) (±7) (±7)
(±7)
(±7)
(±7)
(±7)
(±7)
(±7)
 
Time Point (Week) 
 
Screening
1st 
Study 
Dose 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
NPC Clinical Severity Intake 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Clinician-CGICh and 
Caregiver-CGIC 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
TUG Test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
9-Hole Peg Test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
EQ-5D-3L QoL 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Confirm subject eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect plasma biomarker 
samplesj 
 
X 
 
 
 
X# 
 
X 
 
 
 
 
 
X 
 
Sham or lumbar puncture and 
study drug administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect CSF samples 
(study drug subjects only) 
 
X 
 
 
 
X# 
 
X 
 
 
 
 
 
X 
 
Collect whole blood for 
genetic testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC = Clinical Global Impression of Change; CSF=cerebrospinal fluid; ECG = electrocardiogram; hx=history; NPC = Niemann‐Pick disease, type C; NPC1=Niemann‐Pick disease, type C1; QoL=quality 
of life; TUG=timed up and go 
a Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
b Urine will be obtained for urinalysis and biomarker testing   


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 51 
CONFIDENTIAL 
c Full physical exam at Screening; abbreviated physical exam at all other visits. 
d Vital signs, including blood pressure, will be recorded following a 5‐minute rest in supine position. 
e A second set of vital signs will be recorded following recovery of sedation from lumbar puncture or sham procedure. 
f Full, videotaped neurological exam at Screening and Week 52; brief, videotaped neurological exam at Week 24. 
g Clinical laboratory tests include chemistry, hematology, and coagulation. 
h Blinded Clinician to meet with subject and assess overall status and functionality that will form baseline for future Clinician‐CGIC assessments. 
i Randomization may occur on or before Study Visit 1, Day 0, after receipt of NPC Clinical Severity Score from central rater to confirm eligibility. 
j Plasma samples for biomarkers should be obtained prior to intrathecal or sham treatment. 
k The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
# Part A participants ONLY     
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 52 
CONFIDENTIAL 
Exhibit 3. Study Parts A and B schedule of assessments (Week 28 through Week 54) 
Visit Number 
15 
16 
17
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Follow-upn 
ET 
Study Day 
196 
210 
224 238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
378 
441      
 
Window (days) 
(±7) 
(±7) 
(±7) (±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) (±7) 
(±7) 
(±7) 
(±7) 
(±7)
(±7)         
Time Point (Week) 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
63     
Study Procedure 
 
 
 
 
Informed consent 
 
 
 
Xm 
Demographics, medical historya  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect urineb 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Xc 
 
 
 
Pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xc 
 
 
X 
Physical examd 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Vital signs e,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
 
 
X 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Neurological examinationh 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory testingi 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Xj 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Audiologic testing 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Auditory brainstem response 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
NPC Clinical Severity Intake 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Clinician-CGICk and Caregiver-
CGIC 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
TUG Test 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
9-Hole Peg Test 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
EQ-5D-3L QoL 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Confirm subject eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 53 
CONFIDENTIAL 
Visit Number 
15 
16 
17
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Follow-upn 
ET 
Study Day 
196 
210 
224 238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
378 
441      
 
Window (days) 
(±7) 
(±7) 
(±7) (±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) (±7) 
(±7) 
(±7) 
(±7) 
(±7)
(±7)         
Time Point (Week) 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
63     
Collect plasma biomarker 
samplesl 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Sham or lumbar puncture and 
study drug administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
 
 
 
 
Collect CSF samples (study 
drug subjects only) 
 
 
 
 
 
 
X 
 
 
 
 
 
Xm 
 
 
 
 
Adverse eventsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
CGIC = Clinical Global Impression of Change; CSF=cerebrospinal fluid; ECG = electrocardiogram; ET=early termination; NPC = Niemann‐Pick disease, type C; NPC1=Niemann‐Pick disease, type C1; 
QoL=quality of life; TUG=timed up and go 
a Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
b Urine will be obtained for urinalysis and biomarker testing   
c Urine will be collected at Follow‐up Visit 1 (Week 54) for pregnancy test. No other tests will be performed with urine. 
d Full physical exam at Screening; abbreviated physical exam at all other visits.   
e Vital signs, including blood pressure, will be recorded following a 5‐minute rest in supine position.   
f A second set of vital signs will be recorded following recovery of sedation from lumbar puncture or sham procedure. 
g The second set of vital signs will only be recorded for subjects proceeding to Part C following recovery of sedation from lumbar puncture or sham procedure. 
h Full, videotaped neurological exam at Screening, Week 52 and Early Termination; brief, videotaped neurological exam at Week 24. 
i Clinical laboratory tests include chemistry, hematology, and coagulation. 
j Clinical laboratory tests include chemistry, hematology, coagulation, urinalysis, and pregnancy. 
k Blinded Clinician to meet with subject and assess overall status and functionality that will form baseline for future Clinician‐CGIC Score assessments. 
l Plasma samples for biomarkers should be obtained prior to intrathecal or sham treatment. 
m To be performed only for subjects proceeding to Part C. 
n Only subjects who will NOT be continuing into Part C, the open‐label extension, will complete the Follow‐up visits. 
o All subjects who discontinue study treatment will be requested to return to the clinic to complete an Early Termination (ET) visit. 
p The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
# Part A participants ONLY 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 54 
CONFIDENTIAL 
Exhibit 4. Study Part C schedule of assessments (Screening through Week 28) 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Study Day 
Day -45 
to Day -1
0 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
196 
Window (days) 
 
 
(±3)
(±3)
(±3)
(±3)
(±3)
(±7) (±7)
(±7)
(±7)
(±7)
(±7)
(±7) 
(±7)
(±7)
Time Point (Week) 
Screen
a 1st Study 
Dose
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
Study Procedure 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect urinec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
Xe 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological examinationg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Wound check/port site exam for IT 
access port subjectsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
(X) 
Clinical laboratory testingi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Audiologic testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Auditory brainstem response 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician-CGIC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 55 
CONFIDENTIAL 
Exhibit 5. Study Part C schedule of assessments (Screening through Week 28), continued 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Study Day 
Day -45 
to Day -1
0 
14 
28
42
56
70
84 
98
112
126
140
154
168 
182
196
Window (days) 
 
 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
 
Time Point (Week) 
Screen
a 1st Study 
Dose 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
NPC-SS Intake 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
EQ-5D-3L 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lumbar puncture and study drug 
administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IT access port study drug 
administration for IT access port 
subjects h 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
(X) 
CSF lab tests and trough  
HP--CD for IT access device 
subjects h 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
(X) 
Adverse events j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; IT = intrathecal; NPC = Niemann‐Pick disease, Type C; NPC‐SS = NPC Severity Scale 
a Screening visit is only for subjects newly enrolled at Part C; for subjects continuing from Part B, the Week 52 visit functions as the Screening visit for Part C. 
b Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
c Urine will be obtained for urinalysis only. 
d Full physical exam at Screening; abbreviated physical exam at all other visits. 
e Vital signs, including blood pressure, will be recorded following a 5‐minute rest in supine position. 
f A second set of vital signs will be recorded following recovery of sedation from lumbar puncture procedure. 
g Full neurological exam at Screening and Week 52; abbreviated neurological exam at Week 26. 
h Subjects participating in the European site‐specific IT access port safety and tolerability assessment will remain in their Part C schedules and will add additional port‐specific assessments as detailed     
      in the device‐specific schedule of events for the first nine port infusions (Protocol Table 14). Where there is duplication of assessments with Part C, only 1 assessment will be conducted.    CSF samples for 
subjects on 900 mg VTS‐270 may also be used for trough HP‐‐CD measurements. 
i Clinical laboratory tests include chemistry, hematology, and coagulation. 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 56 
CONFIDENTIAL 
j The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 57 
CONFIDENTIAL 
Exhibit 6. Study Part C schedule of assessments (Week 30 through Week 52) 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Study Day 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
Window (days) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52
j 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consenta 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical historyb 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
 
 
 
 
 
 
 
 
 
 
 
 
Collect urinec 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 
Pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
Xj,l 
Physical examd 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 
Vital signs 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f 
Xe,f,j 
Weight 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological examination 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 
Wound check/port site exam for IT access 
port subjects g 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Clinical laboratory testingh 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Audiologic testing 
 
 
 
 
 
 
 
 
 
 
 
Xi,l 
Auditory brainstem response 
 
 
 
 
 
 
 
 
 
 
 
Xi,l 
Clinican-CGIC assessment 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 
NPC-SS Intake 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 58 
CONFIDENTIAL 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Study Day 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
Window (days) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
Time Point (Week) 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52
j 
EQ-5D-3L assessment 
 
 
 
 
 
 
 
 
 
 
 
Xj,k 
Lumbar puncture and study drug 
administration i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IT access port study drug administration for 
IT access port subjects g 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
CSF lab tests and trough HP--CD for device
subjects g 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Adverse events m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; IT = intrathecal; NIH = National Institutes of Health NPC1 = Niemann‐Pick disease, type 1; NPC‐SS = NPC 
Severity Scale 
a Study Visit 1 Only 
b Medical history includes history of NPC1 disease, diagnosis date, and prior treatments. 
c Urine will be obtained for urinalysis only. 
d Full physical exam at Screening; abbreviated physical exam at all other visits. 
e Vital signs, including blood pressure, will be recorded following a 5‐minute rest in supine position. 
f A second set of vital signs will be recorded following recovery of sedation from LP procedure.   
g Subjects participating in the European site‐specific IT access port safety and tolerability assessment will remain in their Part C schedules and will add additional port‐specific assessments as detailed in the 
device‐specific schedule of events for the first nine port infusions (Protocol Table 14). Where, there is duplication of assessments with Part C, only 1 assessment will be conducted. 
h Clinical laboratory tests include chemistry, hematology, and coagulation. 
i Subjects who have transitioned from the NIH phase 1 study will continue to receive IT administration of VTS‐270 every 2 weeks (or as per authorized amended dosing regimen). 
j All subjects who discontinue study treatment will be requested to return to the clinic to complete an Early Termination (ET) visit comprising these evaluations. 
kAfter Study Visit 27, record every 6 months thereafter. 
l After Study Visit 27, record annually thereafter. 
m The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 59 
CONFIDENTIAL 
Exhibit 6. Study Part C schedule of assessments (Week 54 through Week 182) 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 60 
CONFIDENTIAL 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 61 
CONFIDENTIAL 
Exhibit 7. Part C European Site-specific Device Safety and Tolerability Substudy Schedule of Assessments 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 62 
CONFIDENTIAL 
 
 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 63 
CONFIDENTIAL 
 


VTS301: STATISTICAL ANALYSIS PLAN 
August 27, 2018 
Page 64 
CONFIDENTIAL 
14. 
References 
1. Millat, G.; Marçais, C.; Rafi, M.A.; Yamamoto, T.; Morris, J.A.; Pentchev, P.G.; et al. 
Niemann‐Pick C1 Disease: the I1061T Substitution is a Frequent Mutant Allele in Patients 
of Western European Descent and Correlates with a Classic Juvenile Phenotype. Am J 
Hum Genet. 1999, 65(5), 1321‐9. 
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). International 
Conference on Harmonization; 1998. 
3. SAS, Version 9.1, Cary NC: SAS Institute; 2002. 
4. Meinert, C. Clinical Trials: Design, Conduct, and Analysis. New York: Oxford University 
Press, 1986.