Clinical trial NCT03643562
Conditions: Niemann-Pick Type C Disease
Keywords: Niemann-Pick NPC NPC Type 1 (NPC1)
Sponsor: Mandos LLC
Start date: 2018-06-18; Completion date: 2021-11-02
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was amended from expanded access to a clinical trial. Information will be collected about long-term safety and effectiveness of adrabetadex shots in the spine every 2 weeks.

Participants who were already taking adrabetadex will receive their stable dose. Participants who have not ever taken it will start by receiving 400 mg.

Participants will receive treatment every 2 weeks until their doctor finds it does not help them anymore, they withdraw, or the study is stopped for any reason. Participants will not receive additional study treatment after their participation in this protocol.

Detailed description:

Arms: arm 1: Participants will receive prescribed adrabetadex by intra-thecal (IT) injection every 2 weeks.
Interventions: intervention 1: Adrabetadex
Intervention descriptions: intervention 1: Administered via lumbar puncture (LP) and IT infusion

Protocol documents:
Prot_SAP_001.pdf: 
Page 1  
CONFIDENTIAL AND PROPRIETARY 
CLINICAL STUDY PROTOCOL 
Open-label Evaluation of Adrabetadex in Patients with Neurologic 
Manifestations of Niemann-Pick Type C Disease (NPC) 
Protocol Number: VTS-270-001 
Date of Original Protocol: 01 December 2017 
Date of Protocol Amendment 3: 23 June 2021 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company 
90 Washington Valley Road 
Bedminster, NJ 07921 
NTC #: NCT03643562


Protocol Amendment 3.0 
VTS-270-001 
Page 2  
CONFIDENTIAL AND PROPRIETARY 
PROTOCOL AMENDMENT 3 CHANGES 
SUMMARY OF CHANGES 
The objective of this amendment is reinforce the need for the investigator to assess whether 
subjects treated with intrathecal adrabetadex for Niemann-Pick type C1 disease (NPC1) are 
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 subjects 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 
for Amendment 3.0 is provided below.  
SUMMARY OF CHANGES FOR AMENDMENT 3.0 
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  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. 
 
This discussion with the subject 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 3.0 where the above 
changes may apply, either in whole or in part, are provided in the Study Synopsis, 
Duration of Patient Participation; Section 7.3, Benefit-Risk Assessment; Section 13, 
Evaluation by Visit; and Section 15.1, Early Discontinuation. 
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 3.0 
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CONFIDENTIAL AND PROPRIETARY 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ...........................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
1. 
SPONSOR SIGNATURE PAGE .................................................................................7 
2. 
INVESTIGATOR AGREEMENT ...............................................................................8 
3. 
LIST OF ABBREVIATIONS.......................................................................................9 
4. 
SYNOPSIS .................................................................................................................11 
5. 
INTRODUCTION ......................................................................................................15 
6. 
STUDY OBJECTIVES, ENDPOINTS AND OUTCOME MEASURES .................17 
7. 
TREATMENT AND ASSESSMENT PLAN ............................................................18 
7.1. 
Study Design ...............................................................................................................18 
7.2. 
Dose Adjustment ........................................................................................................18 
7.3 
Risk/Benefit Assessment ............................................................................................18 
8. 
CRITERIA FOR EVALUATION ..............................................................................20 
8.1. 
Primary Safety Evaluations ........................................................................................20 
8.2. 
Secondary Safety Evaluations ....................................................................................20 
9. 
PATIENT SELECTION .............................................................................................21 
9.1. 
Inclusion Criteria ........................................................................................................21 
9.2. 
Exclusion Criteria .......................................................................................................21 
10. 
CONCOMITANT MEDICATIONS ..........................................................................23 
11. 
TREATMENTS ..........................................................................................................24 
11.1. 
Method of Assigning Patients to Treatment Groups ..................................................24 
11.2. 
Blinding ......................................................................................................................24 
11.3. 
Test and Control Product ............................................................................................24 
11.3.1. 
Formulation of Test Product .......................................................................................24 
11.3.2. 
Packaging and Labeling ..............................................................................................24 
11.3.3. 
Supply of Investigational Drug at the Site ..................................................................24 
11.3.4. 
Dispensing ..................................................................................................................25 
11.3.5. 
Storage ........................................................................................................................25 
11.3.6. 
Investigational Drug Accountability ...........................................................................25 
11.4. 
Dosage/Dosing Regimen ............................................................................................25 


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CONFIDENTIAL AND PROPRIETARY 
11.5. 
Adrabetadex Administration by Lumbar Puncture .....................................................25 
11.6. 
Measures of Treatment Compliance ...........................................................................26 
12. 
STUDY PROCEDURES AND GUIDELINES..........................................................27 
12.1. 
General Assessments ..................................................................................................27 
12.1.1. 
Demographic Information ..........................................................................................27 
12.1.2. 
Medical History ..........................................................................................................27 
12.2. 
Safety Assessments .....................................................................................................27 
12.2.1. 
Prior and Concomitant Medications ...........................................................................27 
12.2.2. 
Adverse Events ...........................................................................................................27 
12.2.3. 
Vital Signs ..................................................................................................................28 
12.2.4. 
Physical Examination .................................................................................................28 
12.2.5. 
Neurological Examination ..........................................................................................28 
12.2.6. 
Audiologic Evaluation ................................................................................................28 
12.2.6.1. 
Audiologic Testing .....................................................................................................28 
12.2.7. 
Clinical Laboratory Measurements.............................................................................29 
12.2.7.1. 
Hematology .................................................................................................................29 
12.2.7.2. 
Blood Chemistry Profile .............................................................................................29 
12.2.7.3. 
Urinalysis ....................................................................................................................29 
12.2.7.4. 
Cerebrospinal Fluid for Routine Clinical Laboratory Tests .......................................29 
12.2.7.5. 
Pregnancy Test ............................................................................................................30 
12.2.8. 
Electrocardiogram .......................................................................................................30 
12.3. 
Efficacy and Quality of Life Assessments ..................................................................30 
13. 
EVALUATIONS BY VISIT ......................................................................................31 
14. 
ADVERSE EVENTS – DEFINITIONS AND REPORTING....................................32 
14.1. 
Definitions ..................................................................................................................32 
14.1.1. 
Adverse Event .............................................................................................................32 
14.1.2. 
Suspected Adverse Reaction .......................................................................................32 
14.1.3. 
Serious Adverse Event ................................................................................................32 
14.1.4. 
Unexpected Adverse Event/Unexpected Suspected Adverse Reaction ......................32 
14.1.5. 
Serious and Unexpected Suspected Adverse Reaction ...............................................33 
14.1.6. 
Adverse Event Severity ..............................................................................................33 
14.1.7. 
Adverse Event Relationship to Investigational Drug .................................................33 


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CONFIDENTIAL AND PROPRIETARY 
14.1.8. 
Adverse Events of Special Interest − Clinically Significant Hearing 
Impairment ..................................................................................................................34 
14.2. 
Reporting of Adverse Events and Pregnancies ...........................................................34 
14.2.1. 
Reporting Adverse Events ..........................................................................................34 
14.2.2. 
Reporting Serious Adverse Events .............................................................................35 
14.2.3. 
Reporting Pregnancy ..................................................................................................35 
15. 
DISCONTINUATION AND REPLACEMENT OF PATIENTS ..............................36 
15.1. 
Early Discontinuation .................................................................................................36 
15.2. 
Replacement of Patients .............................................................................................36 
16. 
PROTOCOL DEVIATIONS ......................................................................................37 
17. 
DATA MONITORING COMMITTEE ......................................................................38 
18. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................39 
19. 
DATA COLLECTION, RETENTION, AND MONITORING .................................40 
19.1. 
Data Collection Instruments .......................................................................................40 
19.2. 
Data Management Procedures ....................................................................................40 
19.3. 
Availability and Retention of Study Records .............................................................40 
19.4. 
Monitoring ..................................................................................................................40 
19.5. 
Patient Confidentiality ................................................................................................41 
20. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY 
CONSIDERATIONS ..................................................................................................42 
20.1. 
Protocol Amendments ................................................................................................42 
20.2. 
Institutional Review Boards .......................................................................................42 
20.3. 
Informed Consent Form ..............................................................................................43 
20.4. 
Publications .................................................................................................................43 
20.5. 
Clinician Responsibilities ...........................................................................................43 
21. 
REFERENCES ...........................................................................................................45 
22. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ........................................46 
 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
LIST OF TABLES 
Table 1: 
Adrabetadex Dose and Infusion Volume ....................................................................26 
Table 2: 
Adverse Event Severity Grading ................................................................................33 
Table 3: 
AE Relationship to Investigational Drug ....................................................................34 
Table 4: 
Schedule of Assessments and Procedures – Screening through Week 26 ..................46 
Table 5: 
Schedule of Assessments and Procedures – Week 28 and Thereafter, 
Including End of Study/Early Termination ................................................................49 
Table 6: 
Follow-up Visit ...........................................................................................................51 
 
 
 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
1. 
SPONSOR SIGNATURE PAGE 
My signature, in conjunction with the signature of the investigator, confirms the agreement of 
both parties that the clinical study will be conducted in accordance with the protocol and 
applicable laws and other regulations including, but not limited to, the International Council for 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the United States (US) Code 
of Federal Regulations (CFR) (where applicable), all applicable national and local regulations, 
protections for privacy, and generally accepted ethical principles for human research such as the 
Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care. 
 
Refer to the e-signature page 
 
 
Approved: 
 
Date: 
 
 
 
  
Mallinckrodt Pharmaceuticals 
 
 
 
 
 
 
 
 
 
 
 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
2. 
INVESTIGATOR AGREEMENT 
My signature confirms that I have read the VTS-270-001 clinical study protocol amendment and 
pledge that this study will be conducted in accordance with the protocol. In addition, by 
completing and signing the Statement of Investigator (FDA-Form 1572), I agree to abide, for the 
duration of this clinical trial, by all applicable laws and regulations including, but not limited to, 
the International Council for Harmonisation (ICH E6[R2)] Guideline for Good Clinical Practice 
(GCP), which has its ethical foundation in the Declaration of Helsinki, the US Code of Federal 
Regulations (CFR) (where appropriate), all applicable national and local regulations, protections 
for privacy, and provisions of my local Institutional Review Board. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care. 
 
 
Investigator’s Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
 
Investigator’s Name and Title (print) 
 
 
 
 


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CONFIDENTIAL AND PROPRIETARY 
3. 
LIST OF ABBREVIATIONS 
Abbreviations 
Description of Abbreviations 
ABR 
Auditory brainstem response 
ADL 
Activities of daily living 
AE 
Adverse event 
ALCOA 
Attributable, legible, contemporaneous, original, accurate 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CNS 
Central nervous system 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EQ-5D-3L 
EuroQol five-dimensional three-level version (health status instrument) 
EU 
European Union 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HP-β-CD 
2-hydroxypropyl-β-cyclodextrin 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug application 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
IRB 
Institutional Review Board 
IT 
Intrathecal(ly) 
LP 
Lumbar puncture 
NPC 
Niemann-Pick type C disease 
NPC1 
Niemann-Pick type C1 disease (also gene and phenotype in humans) 
NPC1 
Niemann-Pick type C1 cat phenotype 
Npc1 
Niemann-Pick type C1 mouse phenotype 
NPC-SS 
NPC Severity Scale 
PT 
Prothrombin time 
PTA 
Pure tone audiometry 
SAE 
Serious adverse event 
SUSAR 
Serious and unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
Vtesse 
Vtesse LLC, a Mallinckrodt Pharmaceuticals company 
 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
4. 
SYNOPSIS 
Title 
Open-label Evaluation of Adrabetadex in Patients with Neurologic Manifestations of 
Niemann-Pick Type C Disease (NPC) 
Sponsor 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company 
Number of 
Patients and Sites 
Approximately 60 subjects at 30 sites in the United States (US) 
Study Design 
No new subjects can be enrolled in the study effective 20 January 2021. 
This is a prospective, open-label study to evaluate the safety of adrabetadex in subjects with 
neurologic symptoms of Niemann-Pick type C disease (NPC). Eligible subjects will receive 
adrabetadex intrathecally (IT) via lumbar puncture (LP) every 2 weeks, and assessments of 
safety measures will be performed at prescribed intervals. Patients who had not previously 
been treated with adrabetadex will start at a dose of 400 mg, and subjects who had been 
previously receiving adrabetadex will receive their current stable dose of adrabetadex. 
Following a determination of a negative benefit/risk balance by the Sponsor, treatment will be 
allowed to continue up to 20 October 2021. Continuation of treatment is contingent upon re-
consent by the subject/legally acceptable representative as well as approval by the 
Institutional Review Board (IRB)/Ethics Committee (EC) and Food and Drug Administration 
(FDA). 
Dose  
Adjustment 
Effective as of the date of Amendment 2 (21 April 2021), subjects will remain at their current 
dose or their dose may be decreased for tolerability reasons. A subject’s dose may not be 
increased. 
Objectives 
Primary and secondary objectives and endpoints are presented in the table below. 
Primary Objectives 
Primary Endpoints 
To evaluate the longer-term safety and 
tolerability of adrabetadex administered IT 
via LP every 2 weeks 
Summary of TEAEs, SAEs, discontinuation 
due to TEAEs, and deaths 
Secondary Objectives 
Secondary Endpoints 
To summarize additional longer-term safety 
and tolerability of adrabetadex administered 
IT via LP every 2 weeks 
• 
Change in audiologic testing. 
• 
Laboratory changes from baseline 
(hematology, chemistry, coagulation, 
urinalysis.) 
• 
Vital sign measurements. 
• 
Physical and neurological examination. 
IT=intrathecal(ly); LP=lumbar puncture; SAE=serious adverse event; TEAE=treatment-
emergent adverse event 
 
Outcome 
Measures 
None. Efficacy assessments (NPC-severity scale [NPC-SS], Clinician Clinical Global 
Impression of Change [CGIC]) and self-reported outcomes (EuroQol five-dimensional three-
level version [EQ-5D-3L]) will not be collected or analyzed. 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
Patient Selection 
Criteria 
No new subjects can be enrolled in the study effective 20 January 2021. 
Inclusion Criteria 
To be included in the study, subjects must meet the following criteria: 
1. Male or female and at least 4 years of age at time of screening. 
2. Has a confirmed diagnosis of NPC and exhibits neurologic symptoms. 
3. Patient 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. Has the ability to undergo LP and IT drug administration. 
5. If taking miglustat (Zavesca®), must have been on a stable dose for the past 6 weeks 
and be willing to remain on a stable dose for the duration of participation in the 
study. Alternatively, subjects may elect to discontinue miglustat use and be eligible 
for entry into the study after undergoing a minimum 6-week washout period prior to 
study Day 1. 
6. If there is a history of seizures, the condition must be adequately controlled, ie, the 
pattern of seizure activity must be stable and the subject must be on a stable dose and 
regimen of antiepileptic medication during the 1 month prior to Screening, with no 
change in dose or regimen up to and including the day of the first dose of 
adrabetadex (Day 1). 
7. If not currently receiving adrabetadex, agrees to discontinue any other 
investigational treatments for at least 1 month prior to first dose of adrabetadex (Day 
1); subjects who are currently receiving intrathecal adrabetadex are eligible to 
participate.  
8. Sexually active females and males 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. 
9. Patient or parent/guardian must possess the ability, in the clinician’s opinion, to 
understand and comply with study requirements, including clinical outcome 
measurements and instructions, for the entire duration of the study. 
10. Caregiver, parent, guardian, or responsible adult must be able and willing to 
accompany the subject to study visits. 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Weighs less than 15 kg. 
2. Has uncontrolled psychosis. 
3. Has a history of hypersensitivity reactions to any product containing 2-
hydroxypropyl-β-cyclodextrin (HP-β-CD) or has a history of hypersensitivity 
reactions or allergy to anesthesia/sedation.  
4. Has received treatment with any other investigational product (other than 
adrabetadex) within 1 month prior to Day 1 of treatment. 
5. Is a female who is pregnant or nursing. 
6. Has a suspected infection of the central nervous system (CNS) or any systemic 
infection. 


Protocol Amendment 3.0 
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CONFIDENTIAL AND PROPRIETARY 
7. Has a spinal deformity that, in the opinion of the clinician, is likely to impact the 
ability to perform repeated LPs. 
8. In the opinion of the clinician, has a serious skin infection in the lumbar region 
within 2 months of entry into the study. 
9. Has neutropenia, defined as an absolute neutrophil count of less than 1.0 × 109/L. 
10. Has thrombocytopenia (platelet count less than 75 × 109/L). 
11. Has an activated partial thromboplastin time (aPTT) or prothrombin time (PT) 
prolonged by greater than 1.5 times the upper limit of normal (ULN) or a known 
history of a bleeding disorder. 
12. Has evidence of obstructive hydrocephalus or normal pressure hydrocephalus. 
13. Has recently used anticoagulants (in the 2 weeks prior to first dose of adrabetadex 
[Day 1]).  
14. In the opinion of the clinician, is unable to comply with the protocol or has a medical 
condition (eg, cardiovascular, respiratory, hematologic, neurologic, renal) that would 
potentially increase the risk of participation. 
Test and Control 
Product, Dose, 
and Route of 
Administration 
Adrabetadex will be provided in appropriately labeled vials, formulated as a 200 mg/mL 
injectable solution. A pharmacist/designee at each site will be responsible for dispensing or 
preparing the assigned dosage: 400 mg in 2 mL of solution, 600 mg in 3 mL of solution, or 
900 mg in 4.5 mL of solution. The total infusion volume should be 10 mL; to achieve a final 
total volume of 10 mL, 0.9% sterile sodium chloride for injection, USP should be added to 
the adrabetadex solution. Doses other than 400 mg, 600 mg or 900 mg will be prepared in the 
same manner. 
Adrabetadex administration via LP will be conducted every 2 weeks. Sedation or anesthesia 
may be used as indicated by the clinical condition of the subject. Sedation and anesthesia will 
follow institutional guidelines and procedures. Ultrasound or other imaging techniques may 
be used to guide IT administration of adrabetadex. 
Adrabetadex 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). Prior 
to the adrabetadex injection, a volume of cerebrospinal fluid approximately equal to the 
infusion volume (approximately 10 mL) will be removed.  
Patients will be required, if possible, to lie flat with feet elevated for 30 to 45 minutes 
following dosing. For the 3 days following each procedure, subjects should avoid acoustic 
overstimulation and minimize exposure to loud noises, eg, headphones for music or video 
games. 
Duration of 
Patient 
Participation 
Effective 20 January 2021, Mallinckrodt is recommending that treatment with adrabetadex be 
discontinued as soon as possible with appropriate clinician oversight. 
In recognition of the complexity of patient care, Mallinckrodt will make adrabetadex 
available for up to 9 months to allow time for the physician and subject/family to develop a 
transition plan. Continued treatment with adrabetadex is contingent upon a discussion 
between the treating physician and subject/family and re-consent. Likewise, continuation of 
treatment is also contingent upon approval by the respective IRB/Ethics Committee (EC) and 
health authority. 
After 21 June 2021 subjects may not continue to receive intrathecal 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 subjects treated with 


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CONFIDENTIAL AND PROPRIETARY 
adrabetadex and sham-treated subjects on any efficacy measures in this randomized, 
controlled trial. 
Primary Safety 
Evaluations 
• 
Summary of TEAEs, SAEs, discontinuation due to TEAEs, and deaths 
Secondary Safety 
Evaluations 
• 
Changes in audiologic testing 
• 
Laboratory changes from baseline (hematology, chemistry, coagulation, urinalysis) 
• 
Vital sign measurements 
• 
Physical and neurological examination. 
Statistics 
Data from the study will be summarized using descriptive statistics. No hypothesis testing 
will be conducted. 
Date 
23 June 2021 


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5. 
INTRODUCTION 
Niemann-Pick disease type C (NPC) is a lethal, neurodegenerative, autosomal recessive disease 
caused by a mutation in the NPC gene. Mutations result in defective NPC protein, which affects 
the intracellular trafficking of lipids and cholesterol. The defective NPC protein leads to a 
progressive accumulation of unesterified cholesterol and other lipids in the central nervous 
system (CNS) and certain visceral organs (Vanier 2010; Ory 2000). Niemann-Pick type C1 
(NPC1) disease has an estimated incidence of approximately 1 in 120,000 to 150,000 live births 
(Vanier 2003). The disease becomes apparent in patients at varying ages and with varying 
neurological manifestations; affected individuals typically exhibit ataxia, swallowing problems, 
and progressive impairment of motor and intellectual function in early childhood, and usually die 
in adolescence (Vanier 2010; Sévin 2007). 
Vtesse LLC, a Mallinckrodt Pharmaceuticals Company (hereafter referred to as Mallinckrodt), is 
developing adrabetadex (USAN for VTS-270), a specific and well-characterized mixture of 
2-hydroxypropyl-beta-cyclodextrin (HP-β-CD), a cyclic oligosaccharide, for the treatment of 
patients with NPC1. New treatments for NPC are urgently needed (Ottinger 2014). Currently 
there is no approved treatment for NPC1 in the United States (US). Miglustat (Zavesca®), 
approved in the European Union [EU] and used off label in the US, is a small iminosugar that 
partially inhibits glucosylceramide synthase and the synthesis of relevant glycosphingolipids. 
Miglustat use delays the onset of clinical signs in animal models of NPC1, but shows limited 
effect in humans (Patterson 2015; Patterson 2007; Lyseng-Williamson 2014; Pineda 2018). 
HP-β-CD has shown improvements in a mouse model of NPC1, and in a cat model of NPC1 
where it also showed the potential to preserve neurons and neurologic function, and impact 
cholesterol homeostasis, inflammation, and lifespan (Vite 2015; Ory 2017). Adrabetadex is 
believed to work in lysosomes (Rosenbaum 2010) by facilitating the release of abnormally 
accumulated cholesterol so that it can be metabolized normally (Liu 2012). 
Although there are case reports from a few expert treating physicians indicating a potential 
benefit of adrabetadex in NPC patients treated over a period of time, a comprehensive evaluation 
of all available clinical data shows no clear evidence of benefit of adrabetadex in the treatment of 
neurologic symptoms of NPC. In view of established risks of treatment with adrabetadex, 
Mallinckrodt concludes that the benefit/risk balance is negative. 
Effective 20 January 2021, Mallinckrodt is recommending that treatment with adrabetadex be 
discontinued as soon as possible with appropriate clinician oversight. 
In recognition of the complexity of patient care, Mallinckrodt will make adrabetadex available 
for up to 9 months to allow time for the physician and subject/family to develop a transition plan. 
Continued treatment with adrabetadex is contingent upon a discussion between the treating 
physician and subject/family and re-consent. Likewise, continuation of treatment is also 
contingent upon approval by the respective Institutional Review Board (IRB)/Ethics Committee 
(EC) and health authority. 
Hearing impairment has been associated with the use of adrabetadex in nonclinical and clinical 
studies. Disease progression in NPC1 (King 2014) is also associated with impacts on hearing. In 


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CONFIDENTIAL AND PROPRIETARY 
Study 13-CH-0001, mid- to high-frequency hearing impairment was documented in all 
14 participants (Ory 2017). The hearing impairment associated with adrabetadex is complex. The 
mechanism of hearing impairment associated with adrabetadex is not fully understood; however, 
based on nonclinical data and clinical experience, the dose and/or duration of dosing of 
adrabetadex may possibly be related to hearing changes. 
Information on nonclinical and clinical studies with adrabetadex can be found in the 
Investigator’s Brochure. 


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6. 
STUDY OBJECTIVES, ENDPOINTS AND OUTCOME 
MEASURES 
Primary and secondary objectives and endpoints are presented in the table below.  
Primary Objectives 
Primary Endpoints 
To evaluate the longer-term safety and 
tolerability of adrabetadex 
administered IT via LP every 2 weeks 
• 
Summary of TEAEs, SAEs, discontinuation due to 
TEAEs, and deaths. 
Secondary Objectives 
Secondary Endpoints 
To summarize longer-term additional 
safety and tolerability of adrabetadex 
administered IT via LP every 2 weeks 
• 
Changes in audiologic testing. 
• 
Laboratory changes from baseline (hematology, 
chemistry, coagulation, urinalysis). 
• 
Vital sign measurements. 
• 
Physical and neurological examination. 
IT=intrathecal(ly); LP=lumbar puncture; SAE=serious adverse event; TEAE=treatment-emergent adverse event 
 
 


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7. 
TREATMENT AND ASSESSMENT PLAN 
7.1. 
Study Design 
This is a prospective, open-label study to evaluate the longer-term safety of adrabetadex in 
subjects with neurological symptoms of NPC type C disease. The study is anticipated to enroll 
approximately 60 subjects from 30 sites in the US. Eligible subjects will receive adrabetadex 
intrathecally (IT) via lumbar puncture (LP) every 2 weeks, and assessments of safety measures 
will be performed at prescribed intervals. Patients who have not previously been treated with 
adrabetadex will start at a dose of 400 mg, and subjects who have been previously receiving 
adrabetadex will receive their current stable dose of adrabetadex. 
7.2. 
Dose Adjustment 
Patients who, in the opinion of the clinician, experience a drug-related adverse event (AE) after 
any IT treatment that is considered clinically relevant and impactful to the subject’s function may 
have their dose reduced back to the previously tolerated dose. The lowest dose is 400 mg; 
subjects unable to tolerate 400 mg will be discontinued from the study. 
The medical monitor can be consulted when there are questions regarding dose adjustment. 
7.3 
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, subjects 
typically develop progressive cerebellar dysfunction, hearing loss, and motor and cognitive 
deterioration with death typically occurring during adolescence. 
2-hydroxypropyl-β-cyclodextrin (HP-β-CD) administered IT into the cerebrospinal fluid (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 Investigational New Drug application [IND]). 
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 Study VTS301, a prospective, randomized, double-blind, 
sham-controlled trial of adrabetadex in subjects with neurologic manifestations of NPC1 shows 
no benefit of adrabetadex on the pre-specified co-primary endpoints, which were the sum of 4 
components of the Neimann Pick Type C Severity Scale (NPC-SS): ambulation, fine motor, 
cognition, and swallowing and the blinded Clinician-Global Impression of Change (CGIC).  A 
post-hoc analysis evaluating the effect of miglustat use showed that subjects receiving miglustat 
(with or without adrabetadex) showed evidence of disease stabilization but subjects receiving 


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adrabetadex without miglustat showed 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 
survival. It is important to note that this regimen is different from that employed in the National 
Institutes of Health 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 AEs or SAEs, is supported, only in 
those subjects (or legally authorized representative): 
• 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 subjects treated with 
adrabetadex and sham-treated subjects on any efficacy measures in this randomized, 
controlled trial. 


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8. 
CRITERIA FOR EVALUATION 
8.1. 
Primary Safety Evaluations 
• Adverse events. 
8.2. 
Secondary Safety Evaluations 
• Audiologic testing. 
• Clinical laboratory tests (hematology, chemistry, coagulation, and urinalysis). 
• Vital signs. 
• Physical and neurological examinations. 


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9. 
PATIENT SELECTION 
Effective 20 January 2021, no new subjects can be enrolled in the study. 
9.1. 
Inclusion Criteria 
To be included in the study, subjects must meet the following criteria: 
1. Male or female and at least 4 years of age at time of screening. 
2. Has a confirmed diagnosis of NPC and exhibits neurologic symptoms. 
3. Patient 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. Has the ability to undergo LP and IT drug administration. 
5. If taking miglustat (Zavesca®), must have been on a stable dose for the past 6 weeks and 
be willing to remain on a stable dose for the duration of participation in the study. 
Alternatively, subjects may elect to discontinue miglustat use and be eligible for entry 
into the study after undergoing a minimum 6-week washout period prior to study Day 1. 
6. If there is a history of seizures, the condition must be adequately controlled, ie, the 
pattern of seizure activity must be stable and the subject must be on a stable dose and 
regimen of antiepileptic medication during the 1 month prior to Screening, with no 
change in dose or regimen up to and including the day of the first dose of adrabetadex 
(Day 1). 
7. If not currently receiving adrabetadex, agrees to discontinue any other investigational 
treatments for at least 1 month prior to first dose of adrabetadex (Day 1); subjects who 
are currently receiving intrathecal adrabetadex are eligible to participate.  
8. Sexually active females and males 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. 
9. Patient or parent/guardian must possess the ability, in the clinician’s opinion, to 
understand and comply with study requirements, including clinical outcome 
measurements and instructions, for the entire duration of the study. 
10. Caregiver, parent, guardian, or responsible adult must be able and willing to accompany 
the subject to study visits. 
9.2. 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Weighs less than 15 kg. 
2. Has uncontrolled psychosis. 


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3. Has a history of hypersensitivity reactions to any product containing HP-β-CD or has a 
history of hypersensitivity reactions or allergy to anesthesia/sedation. 
4. Has received treatment with any investigational product (other than adrabetadex) within 
1 month prior to Day 1 of treatment. 
5. Is a female who is pregnant or nursing. 
6. Has suspected infection of the CNS or any systemic infection. 
7. Has a spinal deformity that, in the opinion of the clinician, could impact the ability to 
perform repeated LPs. 
8. In the opinion of the clinician, has a serious skin infection in the lumbar region within 
2 months of entry into the study. 
9. Has neutropenia, defined as an absolute neutrophil count of less than 1.0 × 109/L. 
10. Has thrombocytopenia (platelet count of less than 75 × 109/L). 
11. Has an activated partial thromboplastin time (aPTT) or prothrombin time (PT) prolonged 
by greater than 1.5 times the upper limit of normal (ULN) or a known history of a 
bleeding disorder. 
12. Has evidence of obstructive hydrocephalus or normal pressure hydrocephalus. 
13. Has recently used anticoagulants (in past 2 weeks prior to first dose of adrabetadex 
[Day 1]). 
14. In the opinion of the clinician, is unable to comply with the study or has a medical 
condition (eg, cardiovascular, respiratory, hematologic, neurologic, renal) that would 
potentially increase the risk of participation. 


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10. 
CONCOMITANT MEDICATIONS 
Any changes to medications should be noted in the subject’s medical record/source documents. 
Concomitant medications must be added to the appropriate case report form (CRF). 
Use of anticoagulants is prohibited during the study. The use of other investigational medications 
and treatments is also prohibited. (If a clinician has any questions about whether a medication is 
allowed or prohibited, he/she should contact the medical monitor). 


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11. 
TREATMENTS 
11.1. 
Method of Assigning Patients to Treatment Groups 
Effective 20 January 2021, no new subjects can be enrolled in the study. 
11.2. 
Blinding 
This is an open-label study. 
11.3. 
Test and Control Product 
Adrabetadex will be provided in appropriately labeled vials, formulated as a 200 mg/mL 
injectable solution. A pharmacist/designee at each study site will be responsible for dispensing or 
preparing the assigned dosage. The 400 mg dose will be administered in 2 mL of solution; a 
600 mg dose will be administered in 3 mL of solution, and a 900 mg dose will be administered in 
4.5 mL of solution. The total infusion volume should be 10 mL; to achieve a final total volume 
of 10 mL, 0.9% sterile sodium chloride for injection, USP should be added to the adrabetadex 
solution. Doses other than those provided in the examples above will be prepared in the same 
manner. 
No control product will be used in the study. 
11.3.1. 
Formulation of Test Product 
The formulation and filling of adrabetadex involves dissolving the Active Pharmaceutical 
Ingredient in water for injection, adding sodium chloride to 0.9% weight/volume (w/v) and 
adjusting the pH if necessary with sodium hydroxide or hydrochloric acid, and bringing to the 
final volume with water for injection. The product is then filled into vials (4.5 mL fill with 
sufficient overfill to allow product withdrawal) and autoclaved. The product is a clear, colorless 
solution that is free from visible foreign matter. 
11.3.2. 
Packaging and Labeling 
Preparation, packaging, and labeling of all study drugs will be in accordance with standard 
operating procedures, Good Manufacturing Practice (GMP) guidelines, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations. All investigational drug used in this study will be prepared, packaged, and 
labeled under the responsibility of the sponsor and its designees. Refer to the Pharmacy Manual 
for information on packaging and labeling. 
11.3.3. 
Supply of Investigational Drug at the Site 
The sponsor (or designee) will ship adrabetadex to the study sites. The initial adrabetadex 
shipment will occur after site activation (ie, all required regulatory documentation has been 
received by the sponsor or designee, and a contract has been executed). Subsequent adrabetadex 
shipments will be made after site request for resupply. Instructions for ordering, preparing, and 
handling study drug are provided in the Pharmacy Manual. 


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11.3.4. 
Dispensing 
A pharmacist/designee at each study site will be responsible for preparing the assigned dosage in 
a sterile environment (eg, under a laminar airflow hood or other clean room environment). 
Alternatively, the pharmacist/designee may dispense the assigned dosage for subsequent 
preparation by the IT administrator within the sterile field of the LP procedure room. 
11.3.5. 
Storage 
Investigational product should be stored between 15 and 25°C (59-77°F), inclusive. The 
pharmacy/designee is responsible for the secure and temperature-controlled storage of 
adrabetadex. This includes daily documentation of the storage and temperature conditions of 
adrabetadex as described in the Pharmacy Manual. 
11.3.6. 
Investigational Drug Accountability 
Drug supply will be managed by a designee at the site and the pharmacy/designee will maintain 
an accountability log for adrabetadex. The clinician is responsible for the accountability of the 
investigational product. This will include documentation of receipt, storage, and dispensing of 
adrabetadex. The clinician will return or destroy (per instruction of sponsor or designee) unused 
investigational drug at the conclusion of the study. 
11.4. 
Dosage/Dosing Regimen 
Adrabetadex will be provided in labeled 10 mL Type I glass vials, formulated as a 200 mg/mL 
injectable solution (4.5 mL fill with overfill). Examples of how the assigned dosage will be 
administered are provided in Table 1. 
The total infusion volume should be 10 mL; to achieve a final total volume of 10 mL, 0.9% 
sterile sodium chloride for injection, USP should be added to the adrabetadex solution (eg, add 
8 mL of 0.9% sodium chloride to 400 mg dose).  
Adrabetadex administration via LP will be conducted every 2 weeks. Sedation or anesthesia may 
be used as indicated by the clinical condition of the subject. Sedation and anesthesia will follow 
institutional guidelines and procedures. Ultrasound or other imaging techniques may be used to 
guide IT administration of adrabetadex.  
Treatment with adrabetadex will continue until the clinician considers adrabetadex to be no 
longer beneficial to the subject, the subject withdraws from the study, adrabetadex receives 
marketing authorization in the US, or the development program is discontinued. There are no 
adjustments of dosing regimen for weight or subject age. Patients participating in this study 
should not expect additional access to adrabetadex beyond this study. 
11.5. 
Adrabetadex Administration by Lumbar Puncture 
Adrabetadex 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 will be approximately 10 mL (Table 1). Prior to the adrabetadex injection, a volume 
of cerebrospinal fluid approximately equal to the infusion volume is to be removed. Anesthesia 
or sedation will be used for the IT dosing procedure, following institutional guidelines and 


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procedures. Patients will be required, if possible, to lie flat for 30 to 45 minutes following dosing 
with feet elevated. For the 3 days following each procedure, subjects should avoid acoustic 
overstimulation and minimize exposure to loud noises, eg, headphones for music or video games. 
Table 1: 
Adrabetadex Dose and Infusion Volume 
Dose Groupa 
Adrabetadex Volume 
Volume of 0.9% 
NaCL 
Total Infusion Volume 
400 mg 
2.0 mL 
8 mL 
10 mL 
600 mg 
3.0 mL 
7 mL 
10 mL 
900 mg 
4.5 mL 
5.5 mL 
10 mL 
a  Doses other than those provided in the examples above will be prepared in the same manner.  
NaCL = sodium chloride. 
11.6. 
Measures of Treatment Compliance 
Adrabetadex will be administered at the clinical site by a study clinician, and the amount of drug 
infused will be recorded in the dose preparation worksheet and maintained in the subject’s 
medical record/source documents. 


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12. 
STUDY PROCEDURES AND GUIDELINES 
A schedule of assessments and procedures by time point is presented in Section 22. 
Prior to conducting any protocol-related activities, written informed consent must be signed and 
dated by the subject or the subject’s legal representative. If appropriate, assent must also be 
obtained prior to conducting any protocol-related activities. 
Patients who have been screened, meet eligibility criteria, and have provided signed written 
informed consent will be enrolled. Baseline assessments will be completed at Screening, as 
described in Table 4. 
12.1. 
General Assessments 
12.1.1. 
Demographic Information 
Demographic information (eg, date of birth, gender, race, ethnicity) will be recorded at 
Screening. 
12.1.2. 
Medical History 
Relevant medical history, including history of NPC (eg, diagnosis date, prior treatments), other 
pertinent respiratory history, and information regarding underlying diseases, will be recorded at 
Screening. 
12.2. 
Safety Assessments 
12.2.1. 
Prior and Concomitant Medications 
Any medications used to treat NPC in the past (no time limit) and any other medications taken 
within 30 days of the Screening Visit will be collected at Screening. All concomitant medication 
and concurrent therapies will be documented at each study visit through Follow-up Visit 3. Dose, 
route, unit, frequency of administration, indication for administration, and dates of treatment will 
be captured using the appropriate CRF. 
12.2.2. 
Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study, beginning with 
the signing of informed consent and ending after procedures for Follow-up Visit 3. Information 
will be recorded on the appropriate CRFs. Definitions associated with AEs and the procedures 
for reporting them are presented in Section 14.1 and Section 14.2, respectively. 
Any time a subject has a reported AE of special interest, ie, AE related to hearing impairment 
(National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE] grade 3 
or higher), audiologic assessments need to be conducted. Audiologic assessments may also be 
conducted at the discretion of the investigator for hearing impairment AEs of 
CTCAE grade < 3(Section 12.2.6.1, Section 14.1.8).  


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12.2.3. 
Vital Signs 
Blood pressure, pulse rate, respirations, and body temperature will be measured after a 5-minute 
rest in a supine position. At all visits when adrabetadex is administered, vital signs will be 
measured at two different times: 1) prior to LP and 2) after recovery from LP (as defined by 
institutional practices). 
12.2.4. 
Physical Examination 
At Screening, a complete physical examination will be performed by either the clinician or a 
designee who is a physician. Qualified staff (physician, nurse practitioner, registered nurse, or 
physician assistant) may complete an abbreviated physical examination at all other visits (every 
6 months after first dose; first 6-month time point = Week 26). This abbreviated examination 
focuses on body systems with a change in health or new symptoms. New abnormal findings must 
be documented, captured as AEs, and followed by a physician or other qualified staff until the 
abnormality resolves or stabilizes, or until the subject discontinues from the study for reasons 
other than the AE. Weight will be collected at every visit. 
12.2.5. 
Neurological Examination 
A complete neurological examination will be performed by an experienced clinician at Screening 
and then every 12 months after first dose. An abbreviated neurological examination comprising 
assessments of eye movements, coordination, gait, and reflexes, will be conducted at every 
6 months in between. A complete neurological examination will be conducted at End of 
Study/Early Termination. Clinically significant changes in the neurological examination will be 
identified by the investigator, captured as AEs (if not related to medical history, underlying 
disease or to another existing AE), and followed by a physician or other qualified staff until the 
abnormality resolves or stabilizes, or until the subject discontinues from the study for reasons 
other than the AE.  
12.2.6. 
Audiologic Evaluation 
Acoustic reflexes, pure tone audiometry (PTA), and auditory brainstem responses (ABRs) have 
been used to date to evaluate abnormalities that have been previously reported in NPC subjects 
(King 2014). As of 20 January 2021, ABRs will not be collected, as the potential risks with the 
procedure outweigh the potential benefit of the data. 
12.2.6.1. Audiologic Testing 
Audiologic evaluations will be performed at the time points specified in Table 4. 
Audiologic assessments will include: 
• Evaluation of middle ear function (tympanometry). 
• Air conduction PTA. 
• Speech reception threshold. 


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• Bone conduction PTA (only at Screening and when a clinically significant change in 
hearing is observed in air conduction PTA). 
A clinically significant change is defined as: 
− ≥20 dB increase at any one test frequency relative to baseline measure. 
− ≥10 dB increase at any two adjacent test frequencies relative to baseline measure. 
− Loss of response at three consecutive test frequencies where responses were 
previously obtained (specifically the highest frequencies tested) on baseline 
measure. 
12.2.7. 
Clinical Laboratory Measurements 
All clinical laboratory samples obtained will be sent to central or local laboratories as specified 
in the Laboratory Manual.  
12.2.7.1. Hematology 
Blood will be obtained for a complete blood count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count, white blood cell differential, and platelet count), and coagulation 
studies (PT and aPTT) at Screening and every 6 months after first dose (first 6-month time point 
= Week 26). If platelet count is below 75 × 109/L, the platelet count should be repeated and the 
clinician will need to make a clinical determination whether the subject can be dosed or should 
be discontinued from the study. 
12.2.7.2. Blood Chemistry Profile 
Blood will be obtained for determination of serum sodium, potassium, chloride, bicarbonate, 
calcium, random glucose, blood urea nitrogen, creatinine, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin, albumin, 
and lactate dehydrogenase at Screening and every 6 months after first dose (first 6-month time 
point = Week 26). 
12.2.7.3. Urinalysis 
Urine will be obtained for determination of color, specific gravity, pH, protein, glucose, ketones, 
and blood. Urinalysis will be performed at Screening and every 6 months after first dose (first 
6-month time point = Week 26). 
12.2.7.4. Cerebrospinal Fluid for Routine Clinical Laboratory Tests 
At the time of first treatment with adrabetadex in the study, a sample of CSF will be collected 
from treatment-naïve subjects just prior to adrabetadex infusion to be used for routine CSF 
analysis (red blood cell count, white blood cell count, white blood cell differential, glucose, and 
protein). 


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12.2.7.5. Pregnancy Test 
For female subjects who are of childbearing potential, a serum pregnancy test will be obtained at 
Screening, and a urine pregnancy test will be obtained every 6 months after the first dose (first 
6-month time point = Week 26). 
12.2.8. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be obtained and interpreted locally (at the study sites) 
for baseline screening/safety monitoring at the Screening visit. 
12.3. 
Efficacy and Quality of Life Assessments 
Efficacy assessments (NPC severity scale [NPC-SS], Clinician Clinical Global Impression of 
Change [CGIC]) and self-reported outcomes (EuroQol five-dimensional three-level version [EQ-
5D-3L]) will not be collected. 


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13. 
EVALUATIONS BY VISIT 
See Table 4, Schedule of Assessments and Procedures. 
For subjects continuing in the study after 21 June 2021, the investigator must assess whether the 
subject is benefiting from treatment with intrathecal adrabetadex.  For those subjectss 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 subjectss treated with adrabetadex and sham-
treated subjectss 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. 
 


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14. 
ADVERSE EVENTS – DEFINITIONS AND REPORTING 
14.1. 
Definitions 
This section defines the different categories of AEs. The procedures for reporting AEs are 
described in Section 14.2. 
14.1.1. 
Adverse Event 
An AE 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] Title 21 
Part 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). 
14.1.2. 
Suspected Adverse Reaction 
A suspected adverse reaction is a subset of all AEs 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 (21 CFR 312.32). 
14.1.3. 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if, in the view of either the clinician 
or sponsor, it results in any of the following outcomes (21 CFR 312.32): 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization (hospitalizations 
for less than 24 hours with no admission are not considered “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 SAEs when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed. 
Procedures for reporting SAEs are described in Section 14.2. 
14.1.4. 
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 treatment plan (21 CFR 312.32). 
This also refers to AEs or suspected adverse reactions mentioned in the Investigator’s Brochure 


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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. 
14.1.5. 
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 (no labeling exists for 
adrabetadex since it has not been approved for marketing). 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. 
14.1.6. 
Adverse Event Severity 
The CTCAE, Version 4.03 should be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant. If the AE is not covered by the grading in the 
CTCAE, the general guidelines of the CTCAE grades should be applied (see Table 2) for grading 
the severity. 
Table 2: 
Adverse Event Severity Grading 
Severity (Toxicity Grade) 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrument ADL*. 
Grade 3 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
ADL = activities of daily living; AE=adverse event. 
14.1.7. 
Adverse Event Relationship to Investigational Drug 
The relationship of an AE to the investigational drug should be assessed using the following 
guidelines in Table 3. 


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Table 3: 
AE Relationship to Investigational Drug 
Relationship to 
Drug 
Comment 
Definite 
The AE follows a reasonable sequence from the time of study drug 
administration, follows a known response pattern of the study drug 
class, is confirmed by improvement on stopping the study drug, and/or 
the study drug definitely causes the event. 
Probable 
The AE follows a reasonable sequence from the time of study drug 
administration, follows a known response pattern of the study drug 
class, is confirmed by improvement on stopping the study drug, and/or 
is the most likely of all causes. 
Possible 
The AE follows a reasonable sequence from the time of study drug 
administration, but could also have been produced by the subject’s 
clinical state or by other drugs administered to the subject. 
Unrelated 
Concurrent illness, concurrent medication, or other known cause is 
clearly responsible for the AE. 
AE=adverse event. 
14.1.8. 
Adverse Events of Special Interest − Clinically Significant Hearing Impairment 
NPC and adrabetadex are both associated with hearing impairment. The severity and site of 
lesion of auditory damage may differ between adrabetadex- and NPC-induced hearing 
impairment; some lesion sites overlap, whereas some are more likely only in NPC. In addition, 
NPC hearing impairment progresses more slowly than drug-induced hearing impairment, which 
may occur abruptly within 24 hours of infusion at a given dose. 
Any time a subject has a reported clinical AE of special interest, ie, AE of hearing impairment 
(CTCAE grade 3 or higher) audiologic assessments need to be conducted. Audiologic 
assessments may also be conducted at the discretion of the investigator for hearing impairment 
AEs of CTCAE grade < 3. Hearing impairment AE evaluation is described in Section 12.2.6.1. 
14.2. 
Reporting of Adverse Events and Pregnancies 
14.2.1. 
Reporting Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study beginning with 
signing of the informed consent form (ICF) and ending with Follow-up Visit 3. A qualified 
clinician (eg, physician, physician assistant, nurse practitioner) will be specifically designated to 
assess and follow AEs for the subject being treated with adrabetadex. This clinician will probe, 
via discussion with the subject, for the occurrence of AEs during each subject visit and record 
the information in the subject’s medical record/source documents. Duration (start and stop dates 
and times), severity/grade (Section 14.1.6), outcome, treatment, relationship to investigational 


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drug (Section 14.1.7), and any corrective actions taken will be recorded on CRFs. Each AE 
should also be categorized as “serious” or “non-serious.” 
14.2.2. 
Reporting Serious Adverse Events 
Clinical sites will document all SAEs that occur (whether or not related to adrabetadex) in the 
subject’s medical record/source documents and on the appropriate CRFs. Information regarding 
occurrence of SAEs will be captured throughout the study beginning with signing of the ICF and 
ending with Follow-up Visit 3.  
All SAEs will be reviewed by the site clinician, and reported within 24 hours of the site learning 
of the event. Sites will report applicable SAE information to the sponsor or designee according to 
the instructions in the Operations Manual. 
The site will notify the sponsor or designee of additional information on the SAE, or follow-up 
information on the initial SAE report, as soon as relevant information is available. 
In accordance with the standard operating procedures and policies of the IRB, the site clinician 
will report SAEs to the IRB. 
14.2.3. 
Reporting Pregnancy 
The sponsor must be informed within 24 hours upon learning that a subject, or a male subject’s 
partner, has become pregnant any time after the first dose of adrabetadex until 60 days after the 
last dose of adrabetadex. The pregnancy form should be used to report the pregnancy to the 
sponsor or designee. The pregnant subject should be discontinued from the study per the 
exclusion criteria (Section 9.2). Pregnancy is not generally considered an AE; however, subject 
pregnancies (or pregnancy of a male subject’s partner) must be followed until termination of 
pregnancy or the birth of the child. The pregnancy outcome form should be used to report 
information regarding the status of the infant and mother. 
Patients who become pregnant will be discontinued from treatment. 


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15. 
DISCONTINUATION AND REPLACEMENT OF PATIENTS 
15.1. 
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. 
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 
to start alternative treatment unless there are additional time restrictions mandated by an IRB/EC 
or health authority. 
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 subjects treated with adrabetadex and sham-
treated subjects 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. 
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 visit and the safety follow-up visit are 
noted in Table 5. 
If a subject is withdrawn from treatment due to an AE, the subject will be followed and treated 
by the clinician until the abnormal parameter or symptom has resolved or stabilized. 
Reasonable attempts will be made by the clinician 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. 
15.2. 
Replacement of Patients 
Patients who discontinue from the study will not be replaced. 


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16. 
PROTOCOL DEVIATIONS 
A protocol deviation occurs when the subject or clinician fails to adhere to study requirements. 
Major protocol deviations are those that involve: 
1. Deviations from the required consent procedure. 
2. Failure to meet inclusion or exclusion criteria. 
3. Wrong treatment or incorrect dose. 
4. Failure to follow any other protocol-specified procedure that, in the opinion of the 
clinician, sponsor, or sponsor representative, impacts the integrity of the study or puts the 
study subjects at increased risk. 
All major protocol deviations will be reported to the IRB as the IRB regulations dictate. 


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17. 
DATA MONITORING COMMITTEE 
No data monitoring committee will be used in this study. 


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18. 
STATISTICAL METHODS AND CONSIDERATIONS 
Study data will be summarized using descriptive statistics. No hypothesis testing will be 
conducted. Descriptive statistics (N, mean, median, standard deviation) will be provided for 
continuous variables and counts and proportions (N, %) will be provided for categorical 
variables. All analyses will be based on available data. Missing data will not be imputed. 
Data generated in this study may be pooled with others in the adrabetadex clinical program or 
from historical cohort for comparison. Details of any pooled analysis will be prospectively 
documented in a separate statistical analysis plan. 
Summary of Safety Endpoints 
Treatment-emergent AEs (TEAEs) are defined as those AEs that are not present at Day 1 of 
study or represent the exacerbation of a pre-existing condition during the treatment period. 
All AEs reported in this study will be coded using version 23.1 of the Medical Dictionary for 
Regulatory Activities (MedDRA®). Coding will be to lowest level terms. The verbatim text, the 
preferred term, and the primary system organ class will be listed. 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of subjects with at least 1 TEAE by system organ 
class and preferred term. 
• TEAEs by severity, presented by system organ class and preferred term. 
• TEAEs by relationship to treatment (related, not related), presented by system organ 
class and preferred term.  
Deaths and other SAEs will be listed and summarized. TEAEs leading to permanent treatment 
discontinuation will be listed and summarized. 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. Shift tables based on baseline 
normal/abnormal and other tabular and graphical methods may be used to present the results for 
laboratory tests of interest. Listings will be provided with flags indicating the out of laboratory 
range values. 
Vital signs (body temperature, pulse rate, blood pressure, and respiration rate) will be 
summarized by baseline and change from baseline to each scheduled assessment time with 
descriptive statistics. 
Changes in audiologic testing will be summarized by visit based on accumulated data at the time 
of analysis. 


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19. 
DATA COLLECTION, RETENTION, AND MONITORING 
19.1. 
Data Collection Instruments 
The clinician will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the investigational 
drug. Case report forms will be used to collect study data. 
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the CRF when the information corresponding to that visit is available. Patients 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 and subject identification number. 
If a correction is required in the CRF, it should be made by a using a single line to strike out any 
text. The staff member making the correction should initial and date the correction. All 
corrections in study-related documents must follow ALCOA (ie, attributable, legible, 
contemporaneous, original, accurate) data integrity principals. 
The clinician 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 clinician. 
19.2. 
Data Management Procedures 
The data will be entered into the subject’s medical records/source documents and CRFs. The 
sponsor or designee will be responsible for data processing, in accordance with procedural 
documentation. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting ICH and EU guidelines for the handling and analysis of data for clinical trials. 
19.3. 
Availability and Retention of Study Records 
The clinician must make study data accessible to the monitor, other authorized representatives of 
the sponsor (or designee), IRB, and regulatory agency inspectors upon request. A file for each 
subject must be maintained that includes the signed ICF, confidentiality commitments, assent 
form, and copies of all source documentation related to that subject. The clinician must ensure 
the reliability and availability of source documents from which the information in the CRF was 
derived. 
All study documents (subject files, signed ICFs, copies of CRFs, etc.) must be kept secured for a 
period of 2 years following marketing of the investigational product or for 2 years after sites 
have been notified that the Investigational New Drug application 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. 
19.4. 
Monitoring 
Monitoring of data will be conducted by the sponsor or designee according to ICH Guidelines 
for GCP (E6). By signing this protocol, the clinician grants permission to the sponsor (or 


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designee) and appropriate regulatory authorities to conduct on-site monitoring and/or auditing of 
all appropriate study documentation. 
19.5. 
Patient Confidentiality 
In order to maintain subject confidentiality, only a site number and subject identification number 
will identify all study subjects on documentation submitted to the sponsor. Additional subject 
confidentiality issues (if applicable) are covered in the Study Agreement. 


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20. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY 
CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, IRB requirements, and 
local regulations. 
To maintain confidentiality, all laboratory specimens, CRFs, reports, and other records will be 
identified by a coded number. 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 
clinician must also comply with all applicable privacy regulations (eg, Health Insurance 
Portability and Accountability Act of 1996, European Union Data Protection Directive 
95/46/EC). 
20.1. 
Protocol Amendments 
Any amendment to the study protocol will be written by the sponsor. Protocol amendments 
cannot be implemented without prior written IRB approval except as necessary to eliminate 
immediate safety hazards to subjects. A study amendment intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, provided the IRBs are notified 
as soon as possible. 
20.2. 
Institutional Review Boards 
The protocol and consent form will be reviewed and approved by the IRB of each participating 
site prior to study initiation. Serious adverse events regardless of causality will be reported to the 
IRB in accordance with the standard operating procedures and policies of the IRB, and the 
clinician will keep the IRB informed as to the progress of the study. The clinician will obtain 
assurance of IRB compliance with regulations. 
Any documents that the IRB 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. The IRB’s written unconditional approval of the study and the ICF will be 
in the possession of the clinician before the study is initiated. The IRB’s unconditional approval 
statement will be transmitted by the clinician to the sponsor 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. 
Study and/or informed consent modifications or changes may not be initiated without prior 
written IRB 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 and written verification that the modification was 
submitted and subsequently approved should be obtained. 
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse events occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 


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adversely the safety of the subjects or the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
20.3. 
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, and 
local regulations. 
The informed consent document will contain the elements required by the ICH and will also 
comply with 21 CFR Part 50. The clinician will send an IRB-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 IRB, assent from the subject will also be obtained. If a subject is 
unable to sign the ICF and privacy authorization (if applicable), 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. 
Separate consent (on the same ICF) will be obtained from subjects providing blood samples to 
use for research on plasma bile acid biomarkers. 
20.4. 
Publications 
The sponsor’s decision to publish or otherwise publicly communicate the results of this study 
will be made in accordance with all applicable laws, regulations, and sponsor policies regarding 
publication and communication of clinical study results. 
Terms and provisions of the investigator’s publication rights are governed by the Publication 
Section in the Clinical Trial Agreement. 
20.5. 
Clinician Responsibilities 
By signing the Agreement of Clinician form, the clinician agrees to: 
1. Conduct the study in accordance with the protocol and make changes only after notifying 
the sponsor (or designee), except when to protect the safety, rights, or welfare of subjects. 
2. Personally conduct or supervise the study. 
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 make 
those records available for inspection with the sponsor (or designee). 


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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 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 required safety reports). 
9. Seek IRB approval before any changes are made in the 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. 
 


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21. 
REFERENCES 
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. 
Liu B. Therapeutic potential of cyclodextrins in the treatment of Niemann-Pick type C disease. 
Clin Lipidol. 2012 Jun;7(3):289-301. 
Lyseng-Williamson KA. Miglustat: A review of its use in Niemann-Pick disease type C. Drugs. 
2014:74:61-74. 
Ory DS. Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys 
Acta. 2000 Dec 15;1529(1-3):331-9. 
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).  
Ottinger EA, Kao ML, Carrillo-Carrasco N, Yanjanin N, Shankar RK, Janssen M, et al. 
Collaborative development of 2-hydroxypropyl-β-cyclodextrin for the treatment of Niemann-
Pick type C1 disease. Curr Top Med Chem. 2014;14(3):330–9. 
Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick 
C disease: A randomized controlled study. Lancet Neurol. 2007;6(9):765-72. 
Patterson MC, Mengel E, Vanier MT, et al. Stable or improved neurological manifestations 
during miglustat therapy in patients from the international disease registry for Niemann-Pick 
disease type C: An observational cohort study. Orphanet J Rare Dis. 2015;10:65.   
Pineda M, Waterbur M, Patterson MC. Miglustat in Niemann-Pick disease type C patients: A 
review. Orphanet J Rare Dis. 2018. 13:140. 
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 Mar 23;107(12):5477-82. 
Sévin M, Lesca G, Baumann N, et al. The adult form of Niemann-Pick disease type C. Brain. 
2007 Jan;130(Pt 1):120-33. 
Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5(16):1-18. 
Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81. 
Vite CH, Bagel JH, Swain GP, Prociuk M, Sikora TU, Stein VM, 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. 


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22. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 4: 
Schedule of Assessments and Procedures – Screening through Week 26 
Visit Number 
 
1 
2 – 13 
14 
Day 
–45 through –1 
1 
15 – 169 
183 
Window (weeks) 
 
 
(± 1) 
(± 1) 
Time Point or Frequency 
Screening 
1st Dosea 
Every 2 weeks  
(Weeks 2 – 24) 
Week 26 
Procedure 
 
 
 
 
Informed consent 
X 
 
 
 
Confirm patient eligibility 
X 
X 
 
 
Demographics 
X 
 
 
 
Medical history b 
X 
 
 
 
Clinician-CGIC assessment c 
X 
 
 
X 
NPC-SS Intake c 
X 
 
 
X 
EQ-5D-3L assessment c 
X 
 
 
X 
Height 
X 
 
 
 
Weight 
X 
X 
X 
X 
Vital signs d,e 
X 
X
f 
X
f 
X
f 
Physical examination g 
X 
 
 
X 
Urinalysis 
X 
 
 
X 
Serum pregnancy test 
X 
 
 
 
Urine pregnancy test 
 
 
 
X 
12-lead ECG 
X 
 
 
 
Neurological examination h 
X 
 
 
X 
Audiologic testing i 
X 
 
 
X 
Diagnostic threshold auditory 
brainstem response j 
X 
 
 
 


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Visit Number 
 
1 
2 – 13 
14 
Day 
–45 through –1 
1 
15 – 169 
183 
Window (weeks) 
 
 
(± 1) 
(± 1) 
Time Point or Frequency 
Screening 
1st Dosea 
Every 2 weeks  
(Weeks 2 – 24) 
Week 26 
Procedure 
 
 
 
 
Blood for clinical laboratory 
tests k 
X 
 
 
X 
Blood for plasma bile acids l 
X 
 
 
X 
LP and adrabetadex 
administrationm 
 
X 
X 
X 
CSF for routine CSF analysis n 
 
X 
 
 
Adverse events e 
X 
X 
X 
X 
Prior and concomitant 
medications/therapies e 
X o 
X 
X 
X 
a Patients who are already receiving adrabetadex may be screened and enrolled (receive first dose) on the same 
day. 
b Medical history includes history of NPC, diagnosis date, and prior NPC treatments. 
c The efficacy assessments (Clinician-CGIC, NPC-SS, and EQ-5D-3L) should be performed prior to other 
assessments and procedures. In addition, the Clinician-CGIC should be conducted prior to other efficacy 
assessments. 
d Vital signs (blood pressure, pulse rate, respirations, and body temperature) will be recorded following a 
5-minute rest in supine position. 
e The collection period of adverse events, and concomitant medications will begin after informed consent is 
obtained and end at Follow-up Visit 3; the collection of vital signs will begin after informed consent is obtained 
and end at Follow-up Visit 1 (see Table 6). 
f A second set of vital signs will be recorded following recovery from LP. 
g Complete physical examination at Screening; abbreviated physical examination at all other visits. 
h Complete neurological examination at Screening; abbreviated neurological examination at Week 26. A 
complete neurological examination will be conducted at End of Study/ Early Termination. 
i Audiologic evaluations will also be performed prior to each dose escalation (within72 hours prior with results 
available at the study visit), within 72 hours prior to the subsequent visit following a dose escalation (with results 
available at the study visit) per Section 7.2, at 1-month intervals following a change in hearing until stable 
hearing is confirmed; and when indicated by a subjective hearing impairment AE of CTCAE grade 3 or higher, or 
at the discretion of the investigator for subjective hearing impairment AE of CTCAE grade < 3 (Section 14.1.8) 
Hearing impairment AE evaluation will be performed as described in Section 12.2.6.1. 
j Only collected for subjects unable to provide reliable behavioral PTA results. For these subjects, Diagnostic 
ABR will be collected at Screening, within 72 hours prior to dose escalation and within 72 hours prior to the visit 
subsequent to dose escalation, once every 2 months after a clinically significant change in hearing is observed 
until hearing is reported to be stable, and once per year when hearing is otherwise thought to be stable. For 
subjects who are unable to provide reliable behavioral PTA results at the 6-month interval, this evaluation will 
not be performed.  


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Visit Number 
 
1 
2 – 13 
14 
Day 
–45 through –1 
1 
15 – 169 
183 
Window (weeks) 
 
 
(± 1) 
(± 1) 
Time Point or Frequency 
Screening 
1st Dosea 
Every 2 weeks  
(Weeks 2 – 24) 
Week 26 
Procedure 
 
 
 
 
k Clinical laboratory blood tests include chemistry, hematology, and coagulation. 
l Only for subjects who provide separate consent for this assessment. 
m Prior to each dose escalation, an audiology examination should be performed (within 72 hours) to assess for 
hearing impairment. If hearing impairment is observed, dose escalation should not proceed. An audiology 
examination should also be performed within 72 hours prior to the subsequent visit following a dose escalation 
(with results available at the study visit) to see if the subject can continue at the same dose.  
n Collected from treatment-naïve subjects only. Red blood cell count, white blood cell count, white blood cell 
differential, glucose, and protein. 
o Any medications used to treat NPC in the past (no time limit) and any other medications taken within 30 days of 
the Screening Visit will be recorded at the Screening Visit. 
CGIC = Clinical Global Impression of Change; CSF = cerebrospinal fluid; ECG = electrocardiogram; 
LP = lumbar puncture; NPC = Niemann-Pick type C disease; NPC-SS = Niemann-Pick Type C Disease Severity 
Scale 
 
 
 
 
 


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Table 5: 
Schedule of Assessments and Procedures – Week 28 and Thereafter, 
Including End of Study/Early Termination 
Window (weeks) 
(± 1) 
(± 1) 
(± 1) 
(+ 1) 
Frequency (starting at Week 28) or 
Time Point 
Every 2 Weeks 
After 1st Dose 
(Weeks 28, 30, 
32, etc.) 
Every 6 Months 
After 1st Dose  
(Weeks 52, 78, 
104, 130, 156, 
182, etc.) 
Additional 
Assessment 
Every 12 Months 
After 1st Dose  
(Weeks 52, 104, 
156, 208, etc.) 
End of Study/ 
Early 
Termination 
Procedure 
 
 
 
 
Clinician-CGIC assessment a 
 
–b 
 
 
NPC-SS Intake a 
 
–b 
 
 
EQ-5D-3L assessment a 
 
–b 
 
 
Weight 
X 
X 
 
X 
Vital signs c,b,d 
X e 
X e 
 
 
Abbreviated physical examination 
 
X 
 
X 
Urinalysis 
 
X 
 
X 
Urine pregnancy test 
 
X 
 
X 
Neurological examination f 
 
X 
 
X 
Audiologic testing
 g 
 
X 
 
X 
Diagnostic threshold auditory 
brainstem response
 h 
 
–h 
-h 
-h 
Blood for clinical laboratory testsj,i 
 
X 
 
X 
Blood for plasma bile acids k,j 
 
–b 
 
 
LP and adrabetadex administrationk 
X 
X 
 
 
Adverse events d 
X 
X 
 
X 
 
 


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Window (weeks) 
(± 1) 
(± 1) 
(± 1) 
(+ 1) 
Frequency (starting at Week 28) or 
Time Point 
Every 2 Weeks 
After 1st Dose 
(Weeks 28, 30, 
32, etc.) 
Every 6 Months 
After 1st Dose  
(Weeks 52, 78, 
104, 130, 156, 
182, etc.) 
Additional 
Assessment 
Every 12 Months 
After 1st Dose  
(Weeks 52, 104, 
156, 208, etc.) 
End of Study/ 
Early 
Termination 
Procedure 
 
 
 
 
Concomitant medications/therapies d 
X 
X 
 
X 
All subjects who discontinue protocol treatment will be requested to return to the clinic to complete an Early 
Termination Visit. 
Note: Any assessment done every 6 months is, by definition, done every 12 months. 
a The efficacy assessments (Clinician-CGIC, NPC-SS, and EQ-5D-3L) should be performed prior to other 
assessments and procedures. In addition, the Clinician-CGIC should be conducted prior to other efficacy 
assessments. 
b Procedure(s) should not be performed starting when the protocol amendment is approved by the respective 
IRB/Ethics Committee. 
c Vital signs (blood pressure, pulse rate, respirations, and body temperature) will be recorded following a 5-minute 
rest in supine position. 
d The collection period of adverse events, and concomitant medications will begin after informed consent is 
obtained (see Table 4) and end at Follow-up Visit 3; the collection of vital signs will begin after informed consent is 
obtained and end at Follow-up Visit 1 (see Table 6). 
e A second set of vital signs will be recorded following recovery from LP. 
f Complete neurological examination every 12 months after first dose (starting at Week 52 in this table) and 
abbreviated neurological examination every 6 months in between. A complete neurological examination will be 
conducted at End of Study/Early Termination. 
g Audiologic evaluations will also be performed prior to each dose escalation (within 72 hours prior with results 
available at the study visit), within 72 hours prior to the subsequent visit following a dose escalation (with results 
available at the study visit) per Section 7.2, at 1-month intervals following a change in hearing until stable hearing is 
confirmed; and when indicated by a subjective hearing impairment AE of CTCAE grade 3 or higher, or at the 
discretion of the investigator for subjective hearing impairment AE of CTCAE grade < 3 (Section 14.1.8). Hearing 
impairment AE evaluation will be performed as described in Section 12.2.6.1. 
h Do not perform starting 20 January 2021 (implemented in advance of amendment 2 as there is a direct impact to 
subject safety). 
i  Clinical laboratory blood tests include chemistry, hematology, and coagulation. 
j Only for subjects who provide separate consent for this assessment. 
k Before each dose escalation, an audiology examination should be performed (within 72 hours) to assess for 
hearing impairment. If hearing impairment is observed, dose escalation should not proceed. An audiology 
examination should also be performed within 72 hours prior to the subsequent visit following a dose escalation (with 
results available at the study visit) to see if the subject can continue at the same dose.  
CGIC = Clinical Global Impression of Change; ECG = electrocardiogram; LP = lumbar puncture; 
NPC-SS = Niemann-Pick Type C Disease Severity Scale 
 


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Table 6: 
Follow-up Visit 
Window (weeks) 
(± 1) 
Procedure 
Follow-up Visita 
(2 weeks after 
EOS/ET visit) 
Complete physical 
examination 
X 
Vital signsb 
X 
Urine pregnancy test 
X 
Audiologic testingc 
X 
Adverse events 
X 
Concomitant 
medications/therapies 
X 
a Follow-up visits not required for subjects who transition to another sponsor study. 
b Vital signs (blood pressure, pulse rate, respirations, and body temperature) will be recorded following a 5-minute 
rest in supine position. 
c Diagnostic ABR testing will not be performed after 20 January 2021.  
EOS = End of Study; ET = Early Termination 
 


Signature Page for VV-CLIN-028280 v1.0
Signature Page for VV-CLIN-028280 v1.0
Approval
24-Jun-2021 23:00:48 GMT+0000