Conditions: Niemann-Pick Disease, Type C1
Keywords: 2-Hydroxypropyl-B-Cyclodextrin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
Background:

For people who have Niemann-Pick disease, type C1 (NPC1), cholesterol and other fats have trouble moving out of liver and other tissue cells. This makes the cells sick. Researchers want to find out if a drug called VTS-270 can help.

Objective:

To test if VTS-270 is safe and effective in treating chronic liver disease associated with NPC1.

Eligibility:

People ages 3-60 with NPC1

Design:

Participants may be screened by phone or under another protocol.

Participants will have visits once a month for 12 months. If they have intrathecal injections, the study may last 15 months or more. The first visit will last about 5 days. Others will last 2-3 days.

Participants will get VTS-270 injected into a vein at each visit. They can also choose to have intrathecal injections. These are like spinal taps.

Some visits will also include:

Physical exam

Urine tests

Blood tests. A small tube or needle will be inserted into the participants vein to collect blood. The small tube will also be used to give the VTS-270.

Hearing tests: For one test, participants will have electrodes taped to their head. These will record brain waves.

Breathing tests

Ultrasound of abdomen: Sounds waves will take pictures of the participant s body.

Chest x-ray: This is a picture of the lungs.

Detailed description:
Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. NPC results from mutation of either the NPC1 (approximately 95% of cases) or NPC2 genes. Biochemically, NPC is characterized by the endolysosomal storage of unesterified cholesterol and lipids in both the central nervous system and peripheral tissues such as the liver. Individuals with NPC demonstrate progressive cerebellar ataxia and dementia. Acute cholestatic liver disease is frequently observed in the neonatal/infantile period but subsequently resolves. However, chronic, sub-clinical liver disease persists. Intrathecal 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD, VTS-270) has proven effective in reducing signs and prolonging life in NPC1 animal models, and Phase 1/2a data support efficacy in NPC1 patients. Parenteral administration of VTS-270 has also been shown to be effective in treating liver disease in the NPC1 cat.

In this Phase 1/2a, open-label, randomized, parallel dose, single-center study, we will examine whether VTS-270 can be used to treat chronic subacute liver disease in NPC1 patients. Our primary objective is to determine the safety and tolerability of intravenous VTS-270 in NPC1 disease. Secondary objectives will be to evaluate the efficacy of VTS-270 to reduce plasma cholestane-3beta,5alpha,6beta-triol, an NPC1-specific pharmacodynamic biomarker, and to normalize the degree of liver injury. Exploratory testing will include lipid and protein biomarkers. This study will evaluate three dose levels (500, 1000 and 1500 mg/kg) administered monthly for twelve months. Safety will be assessed by adverse event recording, clinical laboratory testing and physical examination. Clinical efficacy will be evaluated by assessment of liver chemistries, determination of liver size; and liver STIFFNESS. Biochemical efficacy will be assessed by measurement of plasma cholestane-3beta,5alpha,6beta-triol and other biomarkers.

Arms:
arm 1: Participant received dose of 500 mg/kg of intravenous VTS-270 administered over 2 hours monthly for 12 months. Participant also received 900 mg intrathecal VTS-270 therapy monthly for 18 months. arm 2: Participant received 1000 mg/kg of intravenous VTS-270 over 4 hours monthly for 12 months. Participant also received 900 mg intrathecal VTS-270 therapy monthly for 18 months.

Interventions: intervention 1: VTS-270
Intervention descriptions: intervention 1: Intravenous VTS-270 was administered on a monthly dosing schedule for 12 months. Each participant received one of two doses (500 or 1000mg/kg). Participants also received monthly 900 mg intrathecal VTS-270 therapy.

Protocol document:
Prot_SAP_000.pdf: 
1
 
Protocol Title:
Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological 
Disease Associated with Niemann-Pick Disease, type C1
Abbreviated Title:  IV VTS-270 therapy for NPC1 
Protocol Number: 19-CH-0028
Date of This Submission/Version: July 2nd, 2021/Version 6
Principal Investigator:  
Forbes D. Porter, MD, PhD
DTM/NICHD
10CRC/5-2571
301-435-4432
fdporter@mail.nih.gov
Human Research Protections Program Investigator and Staff Training:
Training of individuals working on this protocol will.
Total requested accrual  
    
 18 Patients      
   0 Healthy Volunteers 
 
Project Uses Ionizing Radiation: 
 No 
X Yes 
Medically-indicated only
Research-related only 
X Both
IND/IDE
 No 
X Yes 
Drug/Device/#  
IND 142671
Sponsor: _______ NICHD___________________
Durable Power of Attorney 
 No 
X Yes 
Multi-institutional Project
X No 
 Yes
Institution#1_____N/A____________    FWA #_________ 
Date of IRB approval ______________ 
Institution#2______N/A___________    FWA #_________ 
Date of IRB approval ______________ 


2
Data and Safety Monitoring Board 
X No 
 Yes 
Technology Transfer Agreement 
 No 
X Yes 
Agreement type and number   CRADA  03272_______
Samples are being stored 
 No  
X Yes 
Flesch-Kincaid reading level:  Consent – 10.4; Assent – 6.4 ____________ 


3
Table of Contents 
Précis:..................................................................................................................................4
List of Abbreviations .........................................................................................................5
1. Introduction and Background......................................................................................7
2. Study Objectives ..........................................................................................................14
3. Subjects.........................................................................................................................15
4. Study Design and Methods .........................................................................................19
5. Management of Data and Samples.............................................................................30
6. Additional Considerations ..........................................................................................33
7. Risks and Discomforts.................................................................................................33
8. Subject Safety Monitoring ..........................................................................................38
9. Outcome Measures ......................................................................................................42
10. Statistical Analysis.....................................................................................................43
11. Human Subjects Protection ......................................................................................44
12. Anticipated Benefit ....................................................................................................48
13. Classification of Risk  (for the study as a whole) ....................................................49
14. Consent Documents and Process..............................................................................49
15. Data and Safety Monitoring .....................................................................................51
16. Quality Assurance......................................................................................................51
17. Reporting of Unanticipated Problems, Adverse Events and Protocol Deviations
...........................................................................................................................................52
18. Alternatives to Participation.....................................................................................55
19. Privacy ........................................................................................................................55
20. Confidentiality............................................................................................................57
21. Conflict of Interest.....................................................................................................57
22. Technology Transfer .................................................................................................58
23. Research and Travel Compensation ........................................................................58
24. References...................................................................................................................59
25. Attachments/ Appendices..........................................................................................61
26. Consent Forms ...........................................................................................................61


4
Précis:
Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal 
storage disorder characterized by neurodegeneration in early childhood and 
death in adolescence. NPC results from mutation of either the NPC1 (~95% of 
cases) or NPC2 genes.  Biochemically, NPC is characterized by the 
endolysosomal storage of unesterified cholesterol and lipids in both the central 
nervous system and peripheral tissues such as the liver.  Individuals with NPC 
demonstrate progressive cerebellar ataxia and dementia. Acute cholestatic liver 
disease is frequently observed in the neonatal/infantile period but subsequently 
resolves.  However, chronic, sub-clinical liver disease persists. Intrathecal 2-
hydroxypropyl-β-cyclodextrin (HPβCD, VTS-270) has proven effective in reducing 
signs and prolonging life in NPC1 animal models, and Phase 1/2a data support 
efficacy in NPC1 patients.  Parenteral administration of VTS-270 has also been 
shown to be effective in treating liver disease in the NPC1 cat.
In this Phase 1/2a, open-label, randomized, parallel dose, single-center study, 
we will examine whether VTS-270 can be used to treat chronic subacute liver 
disease in NPC1 patients. Our primary objective is to determine the safety and 
tolerability of intravenous VTS-270 in NPC1 disease. Secondary objectives will 
be to evaluate the efficacy of VTS-270 to reduce plasma cholestane-3β,5α,6β-
triol, an NPC1-specific pharmacodynamic biomarker, and to normalize the 
degree of liver injury. Exploratory testing will include lipid and protein biomarkers. 
This study will evaluate three dose levels (500, 1000 and 1500 mg/kg) 
administered monthly for twelve months. Safety will be assessed by adverse 
event recording, clinical laboratory testing and physical examination. Clinical 
efficacy will be evaluated by assessment of liver chemistries, determination of 
liver size and liver stiffness. Biochemical efficacy will be assessed by 
measurement of plasma cholestane-3β,5α,6β-triol and other biomarkers. 


5
List of Abbreviations 
Abbreviations
Description of Abbreviations
24(S)-HC
24-(S) hydroxycholesterol
ABR
Auditory brainstem response
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
activated Partial Thromboplastin Time
AST
Aspartate aminotransferase
AUA
American Urological Association
AUC
Area under the curve
AUC0-t
Area under the plasma or CSF concentration-time curve from zero (0) 
hours to time (t)
BAER
Brain stem auditory evoked response
Caregiver-CGIC
Caregiver-Clinical Global Impression of Change
CFR
Code of Federal Regulations
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration equation 
Clinician-CGIC
Clinician-Clinical Global Impression of Change
Cmax
Maximum plasma concentration
CNS
Central nervous system
CSF
Cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DPOAE
Distortion Product Otoacoustic Emission(s)
DSC
Dose Selection Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate


6
Abbreviations
Description of Abbreviations
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GRAS
Generally regarded as safe
HPβCD
2-hydroxypropyl-β-cyclodextrin
IC
Intracisternal
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICV
Intracerebroventricularly
IEC
Independent Ethics Committee
iIND
Investigator Sponsored Investigational New Drug Application
IND
Investigational New Drug Application
IRB
Institutional Review Board
IT
Intrathecal
IUD
Intrauterine device
IV
Intravenous
LE/LY
Late endosomal/lysosomal
LP
Lumbar puncture
LSOs
Lysosomal storage organelles
mITT
Modified intent-to-treat
NCI
National Cancer Institute
NICHD
National Institute of Child Health and Human Development
NIH
National Institutes of Health
NOAEL
No observable adverse effect level
NPC
Niemann-Pick disease, type C
NPC/Npc1 and 
NPC2
Genes that, when mutated, cause NPC phenotypes
NPC1
Niemann-Pick disease, type C1 
PT
Prothrombin time
PTA
Pure Tone Audiometry


7
Abbreviations
Description of Abbreviations
QoL
Quality of life
SAE
Serious adverse event
SC
Subcutaneous
SCr
Serum creatinine
SD
Standard deviation
SE
Standard error
SOP
Standard operating procedure
SPL
Sound pressure level
SUSAR
Serious and unexpected suspected adverse reaction
TUG
Timed up and go
ULN
Upper Limit of Normal
US
United States
Vd,ss
Volume of distribution at steady-state
VSNGP
Vertical supranuclear gaze palsy
1. Introduction and Background
1.1 Niemann-Pick disease, type C1 
Niemann-Pick disease, type C (NPC) is a recessive lysosomal storage disorder 
characterized by impaired intracellular trafficking and subsequent endolysosomal 
accumulation of unesterified cholesterol and other lipids in the central nervous 
system and visceral organs [2].  NPC results from mutation of either the NPC1 or 
NPC2 genes, with the vast majority (~95%) of cases due to impaired NPC1 
function. Incidence of classical NPC has been estimated to be on the order of 
1/89,000-104,000 with potential of a late-onset variant of NPC1 with incidence on 
the order of 1/36,000 [2, 3].  The NPC1 phenotype is heterogeneous with respect 
to both age of onset and symptom complex. Visceral disease including 
hepatosplenomegaly and cholestatic jaundice of variable severity can be present 
in early childhood and is followed by progressive neurological disability [4, 5].  
Common neurological signs and symptoms include vertical supranuclear gaze 
palsy, cerebellar ataxia, gelastic cataplexy, seizures and cognitive impairment. 
An adult-onset variant with prominent psychiatric symptoms has recently been 
characterized [6].  Diagnosis of NPC1 is frequently delayed, but the recent 


8
development of a serum-based diagnostic test will facilitate earlier diagnosis [7-
9]. There are no FDA approved therapies for NPC1, although miglustat 
(Zavesca®) has been approved for use in the European Union and multiple other 
countries [10-13] based on a controlled trial and long-term extension studies.   
1.2 Liver Disease in Nieman-Pick disease, type C1
In infantile and juvenile forms of the disease, patients frequently present with 
cholestasis or hepatosplenomegaly.  NPC has been reported to be the second 
most common genetic metabolic disorder in neonatal liver disease [14], and was 
diagnosed in up to 8% of neonates presenting with intrahepatic cholestasis in 
one case series [15]. In the majority of cases the liver disease becomes 
subacute, although in other cases the liver disease can progress to liver failure. 
In the majority of cases, liver inflammation and dysfunction persist, as evidenced 
by chronic elevations in serum transaminases and abnormal prothrombin (PT) 
and partial thromboplastin (PTT) times.   Approximately two-thirds of NPC1 
subjects enrolled in the NIH Natural History study (06-CH-0186) have had 
elevated serum transaminases.  Liver disease in NPC can result in a lethal 
degree of hepatic fibrosis and the chronic disease predisposes to hepatocellular 
carcinoma [16-19].  Although Phase 1/2a trial data indicates that IT therapy has 
an impact in slowing neurological disease progression [1], direct CNS delivery 
appears unlikely to have an effect on peripheral disease, based on liver 
chemistries.  In the NPC1 cat model subcutaneous administration of 2-
hydroxypropyl-β-cyclodextrin (HPβCD) 1000 mg/kg biweekly (11 treatments over 
21 weeks) reduced serum ALT from ~6-fold elevated to 2-fold elevated [20].  This 
was accompanied by correction of the severe vacuolization of hepatocyte and 
Kupffer cell cytoplasm observed in untreated cats. In human NPC1 patients 
dosed under an individual IND, IV administration of HPβCD (2500 mg/kg 
biweekly) reduced by 2-fold plasma cholestane-3β,5α,6β-triol [21], an NPC 
disease-specific biomarker that monitors oxidizable free cholesterol in liver tissue 
[8].  Taken together, the preclinical and human data suggest that IV HPβCD may 
be effective in reducing liver inflammation and injury and may prevent the long-
term sequelae, such as cirrhosis and risk of hepatocellular carcinoma.
1.3 Investigational Product Description
HPβCD, a generally regarded as safe (GRAS) 
substance, is a membrane-impermeant cyclic 
oligosaccharide with a distinctive truncated cone 
configuration 
containing 
7 
cyclo-α-(1,4)-
anhydroglucose units with hydroxypropyl groups 
randomly substituted onto the C2, C3 and C5 
positions of the substituent glucoses (Fig. 1). All 
HPβCDs are amorphous mixtures of different 
isomers, characterized by the degree of substitution, which represents the 
average of substitution of the hydroxyl with propyl groups per HPβCD molecule. 
Figure 1. VTS-270, HP-β-CD


9
The active drug substance in VTS-270 is KLEPTOSE® HPB parenteral grade, 
which has an average degree of substitution of 4.34 or on a molar basis of 0.63 ± 
0.01. 
Cyclodextrins, as well as HPβCDs in 
general, are used extensively to solubilize 
pharmaceuticals 
and 
various 
regulatory 
authorities 
have 
approved 
them 
as 
excipients. 
 
HPβCD 
is 
a 
cyclic 
polysaccharide that can be used to solubilize 
hydrophobic 
compounds 
such 
as 
cholesterol. 
The 
potential 
therapeutic 
efficacy of HP-β-CD was first investigated by 
Camargo et al [22] utilizing a NPC1 mouse 
model [23, 24], but only slight neurological 
efficacy was observed. Subsequent studies 
by Liu et al [25, 26] and Davidson et al [27] 
demonstrated 
delayed 
progression 
of 
neurological signs and death in Npc1 mutant 
mice.  Therapeutic efficacy has also been 
demonstrated in the feline NPC1 model [20].
HPβCD enters cells by the endocytic pathway and is delivered to the 
endolysosomal storage organelles where unesterified cholesterol accumulates in 
NPC deficiency. HPβCD replaces the function of NPC1 protein and promotes 
transport of the accumulated unesterified cholesterol to the endoplasmic 
reticulum for esterification by acetyl CoA cholesterol:acyl transferase, and 
subsequent efflux [28, 29]. While the precise mechanism of HPβCD action to 
bypass or replace NPC1 function is not yet defined, HPβCD normalizes 
intracellular cholesterol trafficking by binding the hydrophobic moieties of 
cholesterol and other lipids.
HPβCD does not efficiently cross the blood-brain-barrier [30], thus necessitating 
the use of extremely high peripheral doses or direct intrathecal infusion to reach 
the CNS.  A Phase 1/2a trial of intrathecal VTS-270 has been conducted at the 
NIH Clinical Center, and the 18-month data demonstrates a significant 
stabilization of neurological disease progression ([1]; Figure 2). Based on these 
data, a multicenter, multinational Phase 2b/3 trial of intrathecal VTS-270 was 
initiated in the fall of 2015.  With the development of a potentially effective 
therapy for the neurological aspects of NPC1, consideration needs to be given to 
the treatment of visceral issues.   
1.3.1 Non-clinical Toxicology Studies  
The pharmacological properties of HPβCD have been extensively studied in 
Npc1-/- mice and NPC1 cats. The pharmacokinetic properties have been studied 
Figure 
2. 
NPC1 
neurological 
disease 
progression is significantly decreased in 14 
NPC1 subjects treated with intrathecal VTS-
270 (black) compared to an age similar 
cohort of 21 Natural History participants 
(
) [1]


10
in rats, dogs, and the Npc1-/- mice and NPC1 cats. The safety of HPβCD was 
evaluated in a comprehensive toxicology program conducted by Janssen 
Research Foundation (Janssen) to support its use as a pharmaceutical excipient. 
Preclinical toxicology studies included single and repeat-dose toxicity studies, in 
vitro and in vivo genotoxicity assays, carcinogenicity studies, reproductive and 
developmental toxicity (Segment I, II and III) studies and special toxicity (local 
tolerance and mechanistic toxicity) studies. HPβCD has been approved for use 
as an excipient in oral and intravenous (IV) pharmaceuticals for over a decade. 
Mallinckrodt, the supplier of the drug, has obtained the rights to reference the 
Roquette Freres Type IV Drug Master File No. 9420 for HPβCD, the drug 
substance. Mallinckrodt will provide a letter of reference to the VTS-270 IND to 
support this investigator sponsored trial.   
1.3.2 Acute Toxicity Studies
After a single IV dose of HPβCD, mortality occurred in mice at a dose ≥ 10,000 
mg/kg body weight. The most common clinical abnormality at all dose levels 
(5,000-20,000 mg/kg body weight) in mice was viscous urine. At lethal doses, 
typical signs of toxicity included soft feces, sedation, piloerection, clonic 
convulsions, dyspnea, hypothermia, loss of righting reflex, palpebral ptosis, and 
tremors. IV doses of 2,000 and 4,000 mg/kg body weight were not lethal in rats 
but did result in hyperemia. Rats in the 4,000 mg/kg body weight group also were 
observed with viscous urine, hypotonia, ataxia, and swelling of the ears, nose, 
and paws. Dogs survived single IV doses of 5,000 mg/kg body weight HPβCD. 
No clinical abnormalities were noted in the females, but coughing, diarrhea/soft 
feces, and emesis were observed in the males. 
1.3.3 Repeat Dose Toxicity Studies
Repeat dose studies utilizing IV administration were performed in rats and dogs. 
Urinary tract changes were present after IV administration and included swollen 
and granular tubular cells in the kidney, swollen epithelial cells in the urinary 
bladder and renal pelvis, and vacuolated cortical tubules in the kidney. The no-
observed-adverse-effect-levels (NOAELs) in the 3-month IV studies were 50 
mg/kg body weight in the rat and 100 mg/kg body weight in the dog. In rats, 
higher doses (100 and 400 mg/kg body weight) led to reduced body weight gain. 
Hematological changes and altered serum chemistry were seen at the highest 
dose (400 mg/kg body weight). Urinary parameters were slightly modified and 
included increases in white blood cells, cylindrical epithelial cells, occult blood, 
and granular casts and decreases in specific gravity and creatinine associated 
with larger urine volume. Adrenal gland, spleen, and kidney weights were 
increased. Kidneys were pale at necropsy. Histological changes in the liver and 
lung included increased presence of Kupffer cells in the liver and foamy cells and 
white stipples in the lung. Following the 1, 2, or 3 months of recovery, most of 
these changes reverted to normal. After 3 months of recovery, the only remaining 
abnormalities were slightly elevated liver transaminases (400 mg/kg body 


11
weight), pale kidney (100 and 400 mg/kg body weight), swollen epithelial cells in 
the urinary bladder and pelvic epithelium (all doses levels). The corticotubular 
changes resolved completely (25 mg/kg body weight), almost completely (50 
mg/kg body weight) or were partially reversible (100 and 400 mg/kg body 
weight). In dogs, IV administration of 400 mg/kg body weight, HPβCD led to 
transient soft feces and slightly elevated alanine aminotransferase (ALT) and 
bilirubin or haptoglobin. Macroscopic and microscopic (foamy cells) lung changes 
were seen as well. All of these changes resolved after 1 month of recovery. At 
the end of the 3-month recovery, swollen epithelial cells were seen in the urinary 
bladder and renal pelvis but vacuolated cortical tubules (with swollen lysosomes) 
were not found any longer. Repeat-dose studies extracted from the literature also 
support these findings [31].
1.3.4 Reproductive and Developmental Toxicity Studies
Reproductive function (fertility) was not adversely affected by IV administration of 
HPβCD in rats. Maternal and paternal toxicity was limited to a slight reduction in 
body weight. No primary embryotoxicity was noted following IV administration in 
rats or rabbits. Associated with maternal toxicity, decreased survival and reduced 
birth weight and body weight evolution of the rat pups were noted at 400 mg/kg 
body weight. In a 2nd un-dosed generation, all variables were normal. No 
developmental toxicity was noted in any study. 
1.3.5 Genotoxicity
The genotoxic potential of HPβCD was investigated in Ames tests (S. 
typhimurium and E. coli), a mammalian cell assay, chromosome aberration test, 
micronucleus tests, and deoxyribonucleic acid (DNA) repair tests. No mutagenic 
potential was evident in any of these studies.
1.4 Previous and Ongoing Human Experience with Intravenous HPβCD
The investigators are aware of eight NPC1 patients in the US being dosed with 
IV HPβCD supplied by Johnson & Johnson/Janssen with the intent to treat CNS 
disease under expanded use INDs. Doses up to 2500 mg/kg were infused over 
eight hours (312.5 mg/kg/hr) twice per week. Matsuao et al [32] reported on two 
NPC1 subjects who were given up to 2000 or 2500 mg/kg two or three times per 
week. Transient diffuse pulmonary cloudiness and fever were reported, perhaps 
due to an infusion reaction, in one subject dosed with 2500 mg/kg. Decreased 
liver size and AST level were observed in this same subject after 3-4 months of 
therapy.  The FDA has approved at least three emergency INDs for IV VTS-270 
treatment of neonatal liver disease in NPC1. As part of our effort to evaluate the 
role of IV HPβCD in the treatment of NPC1 liver disease, a complementary study 
involving infants is being conducted at St. Louis Children’s Hospital. This study 
(NCT03471143) has been approved by the Washington University IRB and is 
conducted under IND#136489.  


12
The investigators are aware of two other unaffiliated studies (NCT02912793, 
NCT02939547) which are evaluating a different preparation of IV HPβCD. 
1.4 Study Rationale
As described earlier (section 1.2), chronic, 
subacute liver inflammation persists beyond 
the infantile period.  Approximately two-thirds 
of NPC1 participants enrolled in the NIH 
Natural History study have had elevated serum 
transaminases (Fig. 3A, B).  Although bilirubin 
and albumin levels are typically normal, 
prothrombin (PT) and partial thromboplastin 
(PTT) times are frequently mildly elevated (Fig. 
4). FibroScans, which measure liver tissue 
stiffness, can be abnormal in adult NPC1 
subjects (Fig. 5). In addition, development of 
hepatocellular carcinoma has been reported in 
NPC1 patients [16-19] and developed in one 
subject followed at the NIH (Fig. 3C). We 
hypothesize 
that 
reduction 
of 
hepatic 
cholesterol storage through parenteral delivery 
of VTS-270 will be effective in reducing liver 
inflammation and restore normal hepatic 
function in NPC1 patients. The ultimate goal of 
this therapy is to prevent liver fibrosis and 
lower the risk of hepatocellular carcinoma.  
1.5 Route of Administration and Dose 
Selection Rationale        
A Phase 1/2a trial of intrathecal VTS-270 has 
been completed (13-CH-0001; NCT01747135) 
and a multinational Phase 2b/3 trial (16-CH-
0016; NCT02534844) evaluating the safety 
and efficacy of intrathecal VTS-270 for the treatment of the neurodegenerative 
aspects of NPC1 disease is in progress. In these trials, VTS-270 is being 
administered by lumbar intrathecal (IT) infusions since the drug is largely 
excluded from crossing the blood-brain barrier. Analysis of the 18-month Phase 
1/2a trial data indicates that intrathecal therapy slows neurological disease 
progression (Fig. 1) [1]. However, direct CNS delivery, probably due to relatively 
low systemic exposure, appears unlikely to have an effect on peripheral disease. 
Figure 3. Serum transaminase (A,B) 
levels in NPC1 subjects from the NIH 
Natural History cohort. Dashed line 
indicates upper limit of normal. C) Serial 
α-fetoprotein levels in an NPC1 subject 
who 
developed 
hepatocellular 
i


13
In the NPC1 cat model, subcutaneous 
administration of HPβCD 1000 mg/kg 
biweekly (11 treatments over 21 weeks) 
reduced serum ALT from approximately 6-
fold elevated to 2-fold elevated [20]. This 
was accompanied by correction of the 
severe vacuolization of hepatocyte and 
Kupffer 
cell 
cytoplasm 
observed 
in 
untreated cats. In human NPC1 patients 
dosed under an individual IND, intravenous 
(IV) administration of HPβCD (2500 mg/kg 
biweekly) 
reduced 
by 
2-fold 
plasma 
cholestane-3β,5α,6β-triol [21], an NPC1 
disease-specific biomarker that monitors 
oxidizable free cholesterol in liver tissue [4]. 
Liver volume and AST were reduced in one 
of two subjects treated with 2500 mg/kg 
[32].  Toxicity appears to be limited, though 
at 
least 
one 
subject 
demonstrated 
pulmonary infiltrates at 2500 mg/kg [32].  IV 
HPβCD 
has 
been 
used 
under 
an 
emergency IND for acute liver failure in an 
NPC1 neonate.  IV administration of a 
single dose of 1000 mg/kg HPβCD reduced 
the level of both cholestane-3β,5α,6β-triol 
and 7-ketocholesterol (another oxysterol 
elevated 
in 
NPC1 
patients) 
by 
approximately 40 and 60%, respectively, 
within two days (personal communication, 
Dr. Gabrielle C. Geddes).   
Taken together, the preclinical and human data suggest that VTS-270 
administered by the IV route may be effective in reducing liver inflammation and 
injury and may mitigate severe long-term sequelae, such as cirrhosis and risk of 
hepatocellular carcinoma. For the proposed trial, IV doses of 500, 1000 and 1500 
mg/kg are being planned, which are expected to be efficacious, while minimizing 
potential toxicity.   
Outside of the neonatal period, neurological disease is the primary clinical 
problem in NPC1, thus as part of this 
protocol we may offer subjects the option 
of receiving intrathecal VTS-270 at a 
dose of 900 mg per month at the NIH 
Clinical Center. Monthly dosing of 900 
mg is consistent with our Phase 1/2A 
study which studied doses between 50 
Figure 4.  Assessment of liver synthetic function in 
NPC1 subjects for the NIH Natural History cohort.  
A) 
Partial 
thromboplastin 
time 
(PTT), 
B) 
Prothrombin time (PT) and C) International 
Normalized Ratio (INR) values in NPC1 subjects.  
Dashed lines denote upper limit of the normal range.  
Figure 5.  Liver FibroScans from NPC1 patients in 
the NIH Natural History cohort.  Elasticity of liver 
tissue versus age is shown in NPC1 subjects from 
the NIH Natural History cohort.  Normal is <7 kPa 
and >10 kPa is an indication to biopsy.


14
and 1200 mg [1].  The current Phase 2B/3 study is evaluating 900 mg 
administered every two weeks.  Subjects in whom we initiate intrathecal VTS-270 
therapy may be evaluated for exploratory outcome measures related to 
neurological disease.  
2. Study Objectives 
The primary objective of this study is to assess the safety and tolerability of 
intravenous VTS-270 in subjects with Niemann-Pick Disease, type C1.
The secondary objective of this study is to assess the potential efficacy of IV 
VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, 
type C1 as measured by reduction in plasma cholestane-3β,5α,6β-triol, an 
NPC1-specific pharmacodynamic biomarker. 
Exploratory objectives will include liver enzyme levels, biomarkers, and 
assessment of liver size and stiffness. 
An additional exploratory objective will be to obtain additional information related 
to potential neurological efficacy of intrathecal (IT) VTS-270.  VTS-270 does not 
efficiently cross the blood-brain-barrier, thus the intravenous experimental 
therapy will not address the neurological aspects of NPC1. Based on the positive 
clinical results of our phase 1/2 data [1], we believe that offering IT therapy will 
be indicated in most cases; however, this will be optional. For participants 
electing to receive concurrent intrathecal VTS-270 therapy, neurological efficacy 
data obtained during their course of treatment will be of value.  Therefore, we will 
collect data related to neurological progression under our Natural History protocol 
(06-CH-0186).  Participation in these assessments is optional.           
Specific Aims
Aim 1. To conduct a Phase 1/2a, open-label, parallel dose, randomized, single-
center study to establish safety and tolerability of intravenous VTS-270 in treating 
liver disease associated with NPC1  
Aim 2. To evaluate the potential clinical efficacy of intravenous VTS-270 in 
treating liver disease associated with NPC1 by measuring reduction in plasma 
cholestane-3β,5α,6β-triol levels


15
Aim 3. To evaluate the relationship between clinical response, as measured by 
serum transaminases, imaging biomarkers and exploratory research outcome 
measures
3. Subjects
3.1 Description of study population
Patients will be diagnosed as having NPC1 based on criteria specified in Section 
3.4. Subjects will be recruited from ongoing NIH protocols and patient support 
organizations. For potential subjects for whom a definitive diagnosis is not 
available, the investigators may assist the primary care physician in making a 
diagnosis. Alternatively, clinical testing (such as mutation analysis) can be 
performed using the NICHD protocol for evaluation of patients with genetic 
disorders (PI: Perreault, 16-CH-0103).  Potential subjects referred for the study 
may be screened by phone to make a preliminary determination of eligibility. 
After signing a screening consent, we may obtain standard liver chemistries to 
help determine chronicity of the liver disease prior to admission to the NIH 
Clinical Center. Due to the nature of this disease, this study will enroll minors and 
adults with variable degrees of cognitive impairment; in these cases, parents, 
guardians or legally authorized representatives will provide informed consent for 
participation in the study. No exclusions will be made based upon gender, race or 
ethnicity.
3.2 Accrual Ceiling and target number of evaluated subjects
Our goal is to have 15 subjects complete this study. The study will enroll into the 
treatment phase up to a maximum of 18 patients to account for potential subject 
withdrawal or discontinuation.  The study may screen up to 30 individuals.  
3.3 Subject replacement
Any usable data from withdrawn patients will be included in safety and efficacy 
evaluations. Patient withdrawn from the IV aspect of this protocol may be 
replaced.  
3.4 Inclusion Criteria 
1.  Age ≥ 3 and ≤ 60 years old at time of enrollment 
2.  Diagnosis of NPC1 based upon one of the following:


16
A.  Two NPC1 mutations* 
B.  Biochemical Positive for NPC (oxysterol/bile acid** and 
sphingomyelinase levels consistent with a diagnosis of NPC)  and one 
NPC1 mutation*
*NPC1 mutations will be interpreted using standards established for the 
interpretation of sequence variants [33].    
** Oxysterol/Bile Acid testing refers to cholestane-3β,5α,6β-triol [7, 8] or 
3β,5α,6β-trihydroxycholanic acid and its glycine conjugate [34].
3. Evidence of chronic NPC1-related liver disease defined as one of the following 
(A, B or C):  
A.  Abnormal liver chemistries as defined by one of the following:
i.  Plasma aspartate aminotransferase (AST) ≥ 1.5-times age-
appropriate upper limit of normal
ii.  Plasma aspartate aminotransferase (AST) ≥ 1.25-times age-
appropriate upper limit of normal and plasma alanine aminotransferase 
(ALT) > 1.25-times age-appropriate upper limit of normal
iii. Plasma aspartate aminotransferase (AST) ≥ 1.25-times age-
appropriate upper limit of normal and AST/ALT ratio ≥ 2.0
AND
    Abnormal liver chemistries as defined above at least 8 weeks apart. 
B.  Abnormal Liver Ultrasound* defined as one of the following:
1.  Intraparenchymal echogenic bands consistent with fibrosis
2.  Abnormal liver echogenicity with AST or ALT above the upper 
limit of normal (applicable ranges referenced in previous inclusion 
criteria 3A).
3.  Hepatomegaly with AST or ALT above the upper limit of normal 
(applicable ranges referenced in previous inclusion criteria 3A)..
To define hepatomegaly, we will use the suggested limit of 
normal of the longitudinal dimension of the right lobe of the 


17
liver as published by Konus et al. [35]. These values are 
approximately 2 standard deviations above the mean. 
Please see table 1 for specific age dependent values.
C.  Abnormal liver stiffness (FibroScan**) for age. 
To define Liver Stiffness Measurement we will use the normal age 
dependent ranges published by Tokuhara et al. [36].  Values above the 
95th centile will be considered abnormal.  Age dependent abnormal 
values are provided in Table 2.
5.  Ability to travel to the NIH Clinical Center repeatedly for evaluation and follow-
up.
6. Willingness to discontinue all non-prescription supplements, except for an age 
appropriate multivitamin/mineral supplement.
7.  Stable miglustat dose for 3 months prior to entry into the IV portion of the trial.
8. Women of reproductive age must be willing to use an effective method of 
contraception for the duration of the trial if sexually active.
9. Willingness to participate in all aspects of the IV trial 
Table 1.  Definition of hepatomegaly (adapted from [35])
Age Range
(years)
Longitudinal Dimension of the Right 
Lobe (mm)
≥ 3 to < 5
115
≥ 5 to < 7
125
≥ 7 to < 9
130
≥ 9 to <11
135
≥ 11 to < 15
140
≥ 15
145
Table 2.  Definition of increased Liver Stiffness Measurement 
Age Range (years)
LSM (kPa)
≥ 3 to < 6 
≥ 4.6


18
  ≥ 6 to < 12
≥ 6.1
≥ 12 
≥ 7.9
*Ultrasound will be performed as a clinical scan without modification.  
**Fibroscan will be performed as a clinical scan without modification.  
Inclusion criteria testing may be obtained using our NPC1 natural history
protocol or as part of this protocol prior to administration of drug. To establish 
chronicity, AST and ALT testing may be performed by an outside clinical 
laboratory prior to enrollment in this protocol.  
3.5 Exclusion Criteria 
1.  Age <3 or > 60 years of age at time of enrollment in the trial.  
2. Subjects who have received any form of parenteral cyclodextrin, an HDAC 
inhibitor, or an experimental therapy for NPC in the prior six months.  Prior 
Intrathecal VTS-270 treatment is allowed per section 4.5.6.
 
3. History of hypersensitivity reactions to cyclodextrin or components of the 
formulation.
4. Pregnancy or breastfeeding. Females of childbearing potential unwilling to 
utilize a highly effective form of contraception (i.e., barrier method with 
spermicide, intrauterine device, steroidal contraceptive in conjunction with a 
barrier method, or abstinence if it is the patient’s baseline preference) for the 
duration of the study and for 30 days after participation.
5. Any systemic infection at the time of enrollment.
6. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 
    per microliter.  Subjects with benign cyclic/ethnic neutropenia may be enrolled 
    if not clinically symptomatic. 
7. Thrombocytopenia defined as a platelet count less than 75,000 per microliter. 
8. Established history of a chronic clotting or bleeding disorder.
9. Use of anticoagulants within 3 months of enrollment
10.  Severe or acute liver disease as defined by one of the following:
A.   AST or ALT greater than 10-times age-appropriate upper limit of 
normal


19
B.  Jaundice or right upper quadrant pain
C.  INR >1.8 
11.  Individuals with AST and ALT greater than 4-times the age-appropriate 
upper limit of normal will be excluded if they have a positive NIH Clinical Center 
Viral Markers Hepatitis Screen (HBsAG, anti-HCV and Anti-HAV IgM).  This 
screening test will not be obtained unless AST and ALT are elevated. An 
equivalent panel from another laboratory may be used if this elevation is noted 
on screening.  Individuals excluded under this criterion may be rescreened after 
the acute pathology resolves (e.g. Hepatitis A infection).   
12. Presence of anemia defined as two standard deviations below normal for age
and gender.
13. Serum creatinine level greater than 1.5 times the age-appropriate upper limit 
of normal or for individuals ≥ 6 years of age an eGRF < 60 mL/min/1.73 m2.
14. Hematuria on a single urinalysis, as defined by the American Urological 
Association (AUA) as five or more red blood cells per high-power field on 
microscopic evaluation of urinary sediment from a properly collected 
urinalysis specimen. The patient will not be excluded if two subsequent urine 
specimens are negative for hematuria as defined by the AUA.
15. Proteinuria (1+ protein on repeat urinalysis) unless evaluated and classified 
as benign.
16. Active pulmonary disease, oxygen requirement or clinically significant history 
of decreased blood oxygen saturation (SaO2 <95% on room air), pulmonary 
therapy, daily use of a cough assist device or pulmonary vest, requiring active 
suction, or with a tracheostomy.   
17. Patients with uncontrolled seizures per either of the criteria below. 
 
a.  Unstable frequency, type or duration of seizures. Quantified by a seizure
          log over one month prior to enrollment.
b.  Subject requiring antiepileptic medication changes (other than dose 
          adjustments for weight) in the month prior to enrollment. 
18.  Individuals receiving parenteral nutrition will be excluded.
19. Patients, who in the opinion of the investigators, are unable to comply with 
the protocol or have specific health concerns that would potentially increase 
the risk of participation.


20
Exclusion criteria testing may be obtained using our NPC1 natural history
protocol or as part of this protocol prior to administration of drug.
3.5.1 Additional exclusion criteria for intrathecal VTS-270
1.  Neurologically asymptomatic.  Determination made by the investigators based 
on history, neurological exam and consultant input.   
2.  Suspected infection of the central nervous system
3.  Spinal deformity that would impact the ability to perform a lumbar puncture
4.  Skin infection in the lumbar region
5.  Prior use of anticoagulants or a bleeding disorder with increased risk of 
clinical bleeding.
6.  Patients unable to complete a behavioral audiological evaluation including 
pure-tone threshold assessment (500 Hz to 8000 Hz).  In consultation with 
the medical monitor and audiologists, a sedated ABR may be utilized to 
monitor ototoxicity if the participant is being sedated to receive IT VTS-270.
7.  Patients, who in the opinion of the investigators, are unable to comply with the 
protocol or have specific health concerns that would potentially increase the 
risk of participation.
3.5.2 Justification for exclusion of pregnant and lactating women
This protocol is a phase 1/2a study of an investigational drug.  The potential 
risks of this drug to a fetus or exposure to a nursing infant are not known.  
4. Study Design and Methods
4.1 Study Overview
The proposed trial will be a Phase 1/2a, open-label, randomized, parallel dose, 
single-center study of VTS-270 in subjects with NPC1 dosed monthly with IV 
VTS-270 for 12 administrations. The study will evaluate the feasibility, safety, 
tolerability, pharmacodynamic and disease-modifying activity of IV VTS-270 on 
visceral disease manifestations.  Information obtained from this trial will be 
valuable in designing a future controlled trial to establish efficacy.  


21
The primary outcome measure to monitor potential drug efficacy will be reduction 
in plasma cholestane-3β,5α,6β-triol, a cholesterol oxidation product that serves 
as a pharmacodynamic (PD) marker of the effect of the drug to reduce the 
oxidizable cholesterol pool in liver tissue.
This study will also evaluate the effect of intravenous VTS-270 on a series of 
disease-associated biomarkers, plasma liver enzyme levels (AST and ALT), liver 
size and liver stiffness. 
Patients who have been screened for eligibility will be admitted to the NIH 
Clinical Center qualification assessments after written informed consent has 
been obtained. Patient screening may include obtaining serum liver tests 
including AST and ALT if this data is not available from our Natural History study 
(06-CH-0186).  A telephone screening consent will be used.  Only one 
parent/guardian signature will be required for the screening consent if the 
participant is not able to consent themselves.  Telephone consent for this 
screening may be obtained by any investigator on this protocol.      
To address neurological aspects of this disorder, this trial will include the option 
of monthly intrathecal VTS-270 administration.  Individuals receiving intrathecal 
VTS-270 will be enrolled in our Natural History/Observational protocol (06-CH-
0186) to monitor neurological aspects of the disease.  Optional IT dosing will be 
discussed below (Section 4.5.6).  If intrathecal VTS-270 therapy is initiated, IV 
dosing will be delayed until after at least three doses of IT VTS-270. 
The first admission for IV VTS-270 administration will last approximately five 
days.
Baseline studies including liver/spleen ultrasound and liver FibroScan will be 
obtained. These baseline studies can occur to 35 days prior to the first IV 
administration.  Subsequently the subject will be admitted on a monthly (4 ± 1 
week) basis for IV drug administration.
A total of 12 IV doses will be given. The first IV dosing admission will be as an 
inpatient to facilitate post-dose monitoring.  Subsequent admissions for drug 
infusion will typically use the 1NW day hospital.  Follow-up liver/spleen 
ultrasound, liver FibroScan, and audiological evaluations will be obtained on the 
admission following the 6th dose. One month (4 ± 1 weeks) after the twelfth drug 
administration the subject will be admitted to the NIH CC for liver/spleen 
ultrasound, liver Fibroscan and audiological evaluation. Clinical and research 
laboratory and research testing will be performed at each admission.
4.1.1 Outline of protocol admissions and testing: Intravenous VTS-270 


22
We plan to study 15 participants.  To account for potential subject withdrawal or 
discontinuation, up to a maximum of 18 participants may be enrolled. Up to 30 
individuals may be screened for this protocol. It is anticipated that this study will 
take three years to complete including a 2-year enrollment period and 12 months 
of IV dosing for each patient.      
    
Study-related assessments will be conducted at the NIH Clinical Center and will 
include study admissions. The intravenous VTS-270 study will involve up to 
fourteen admissions during the one year of each subject’s participation.  Three 
additional admissions will occur if IT VTS-270 is provided.  Admissions will be a 
combination of inpatient and day hospital.  
The protocol includes “at home” interval safety testing involving phlebotomy and 
interval phone safety interviews.
IV VTS-270 administration timeline
Time
  
Major Events
Admission Type*
Length** 
Screening/
Enrollment and intravenous consent,
Inpatient/Day Hospital   4-5 days
Baseline
Imaging evaluation
1st dose
 
1-2 weeks
Safety labs
At home
-
1 month
2nd dose
Day Hospital
2
2
3rd dose
Day Hospital
2
3
4th dose
Day Hospital
2
4
5th dose
Day Hospital
2
5
6th dose
Day Hospital
2
6
Imaging evaluation 
Day Hospital
2-3
7th dose
7
8th dose
Day Hospital
2
8
9th dose
Day Hospital
2
9
          10th dose
Day Hospital
2
10
          11th dose
Day Hospital
2
11
          12th dose
Day Hospital
2
12
          Imaging evaluation
Day Hospital
2-3
*May adjust as needed
**Approximate.  
4.1.2 Outline of protocol admissions and testing: Intrathecal VTS-270
Given our data supporting the potential efficacy of intrathecal VTS-270 [1], 
participants will have the option of receiving monthly doses of IT VTS-270 
concurrent with this protocol.  To avoid confounding interpretation of adverse 
events due to either intrathecal or intravenous, intrathecal administration will be 
initiated at least three months prior to initiation of intravenous therapy.    


23
Time
Major Events
Admission Type*
Length**
Screening/
Intrathecal Consent
Inpatient
3-4 days 
Baseline
Neurocognitive, gait and 
audiological testing 
Administration of first IT dose (IT1)
1
Second IT dose (IT2)
Outpatient
1-2
2
Third IT dose (IT3)
Outpatient
1-2
*May adjust as needed
**Approximate
IV admistration may be started 2 days after the third IT administration if 
participant is on a stable dose.   
If for some reason a participant, in the opinion of the investigators, can no longer 
be safely started or continued on IV VTS-270 after intitiation of the IT therapy, 
Investigators will work to transfer the participant to an outside provider under an 
expanded access IND after an additional four IT doses. However, we can not 
assure participants that an outside provider can be identified.     
If after starting IT VTS-270 the participant/guardians elect not to participate in or 
electively withdraw from the IV VTS-270 trial, IT VTS-270 administration under 
this protocol will be discontinued at that time. Investigators will work to transfer 
the participant to an outside provider that can provide IT VTS-270 under an 
expanded access IND.  However, we can not assure participants that an outside 
provider can be identified.     
For participants who complete the IV VTS-270 trial, IT therapy may be provided 
under this protocol up to IT18.  Investigators will work to transfer the participant 
to an outside provider who will provide VTS-270 under an expanded access IND.  
However, we can not assure participants that an outside provider can be 
identified.     
IT VTS-270 dosing will be as described in section 4.5.4.  If a stable IT dose can 
not be established by IT6, participants will have the option of continuing with the 
IV VTS-270 only.        
4.2 Recruitment and accrual
4.2.1 Recruitment Strategy
Participants will be recruited using several approaches.  NPC1 patients currently 
or previously enrolled in one of our protocols may be contacted.  We may also 
discuss this protocol with families that contact us.  Information about this protocol 
will be distributed to the NPC patient community via patient support groups and 
posting on ClinicalTrials.gov.  Due to our longstanding relationship with the NPC 
community, investigators associated with this protocol are frequently asked to 
provide research updates to the NPC1 community by family support groups. The 
family support organizations frequently suggest that parents contact us for 


24
information about studies. In our experience guardian to guardian communication 
via social media frequently leads to self-referral.  We also have families referred 
to us by physicians familiar with our prior work.      
4.3.2 Anticipated accrual rate
We anticipate enrolling at least 5 subjects per year.   
4.4 Subject Screening
Review of eligibility may be performed through chart review, written query or via 
telephone. Medical records may be requested.  A screening log will be 
maintained indicating status.
Investigators may facilitate obtaining studies required for determining eligibility 
(e.g. NPC1 genotyping), obtain these studies under 06-CH-0186 if the potential 
participant is enrolled in that study or utilize the NICHD genetics evaluation 
protocol (16-CH-0016).  
If not already available, serum liver tests may be obtained to establish chronicity 
of the liver disease 8 weeks or more prior to enrollment in this trial.  A screening 
consent may be used in this case.  This consent may be obtained by any 
member of the research team and may be done by telephone.  Only one 
parent/guardian signature will be required on the screening consent.    
   
No study procedures will be conducted under this protocol until after consent is 
obtained.  
4.5 Study Procedures
4.5.1 Study Drug
Mallinckrodt, Inc. will provide the study drug. Parenteral and intrathecal VTS-270 
will not be provided under this protocol after completion of this study. The study 
team may work with participants/guardians to facilitate a transition to an 
expanded access IND for intrathecal VTS-270 after completion of this study.   
4.5.2 Prior and Concomitant Medications
Participants will be allowed to continue an age-appropriate multivitamin/mineral 
supplement, and other required medications as prescribed by their physicians.  
Miglustat dose will be held constant starting 3 months prior to entry into the IV 
portion of the trial and during the trial. All concomitant medications will be 


25
recorded in the appropriate case report form (CRF). The use of other 
nonprescription supplements will be discontinued at least one month prior to 
enrollment in this trial. Prescription medications will be maintained at a constant 
dose level/regimen throughout the duration of the study, unless dose adjustment 
is clinically necessary, or the dose needs to be adjusted for weight. Such 
adjustments will be recorded in the patient’s CRF.  
 
Participants will be given the option of receiving intrathecal VTS-270 at a dose of 
900 mg per month if previously receiving this or a higher dose.  For naïve 
participants we will initiate dosing at 600 mg with escalation to 900 mg if the 600 
mg dose is tolerated.  Individuals already receiving VTS-270 at a dose lower than 
900 mg may be dose escalated to 900 mg or stay at their prior dose level.  IT 
dosing in this trial will be monthly in all cases.   
This group of patients will undergo exploratory evaluations related to neurological 
aspects of NPC1 using protocol 06-CH-0186.  
4.5.3 Randomization
Dose will be either 500, 1000 or 1500 mg/kg. Subjects will be randomized in 
blocks of three to one of these three doses.  The randomization table will be 
produced prior to the start of the trial.  Assignment to the treatment group will not 
be blinded.  
4.5.4 Intravenous Dosing 
VTS-270 will be administered intravenously to specifically target liver disease. 
Study subjects will be randomized in to one of 3 dosing regiments: 500, 1000, or 
1500 mg/kg of intravenous VTS-270.  Maximal dose will be 35, 70 or 105 gm, 
respectively, for the three dosing levels.    
Dose levels and maximum dose for each cohort are:
    Dose            
  Maximum dose
Cohort 1
5 subjects
  500 mg/kg
   35 g administered over 2 hours
Cohort 2   
5 subjects  
1000 mg/kg
   70 g administered over 4 hours
Cohort 3   
5 subjects
1500 mg/kg      105 g administered over 6 hours
IV VTS-270 will be administered via peripheral IV at a rate of 250 mg/kg/hr.  
For the initial administration of the drug the subject will remain in the clinical 
center for at least 24 hours.  Vital signs (temperature, heart rate, respiratory rate, 
blood pressure and SaO2) and standard neurological checks will be conducted 
every 30 ± 10 minutes during and then for the first two hours after drug 


26
administration, at 4 and 6 hours post infusion, and then at least every 6 hours 
until 24 hours post infusion. Standard code cart with medications to address 
infusion reactions is available on the unit.   
For subsequent doses, vital signs (temperature, heart rate, respiratory rate, blood 
pressure and SaO2) and standard neurological checks will be conducted at least 
every 30 ± 10 minutes during the first two hours and then every 2 hours until 
complete.  Standard code cart with medications to address infusion reactions is 
available on the unit.
The infusion site will be monitored for signs of inflammation/irritation.   
4.5.5 Intravenous Dose and Rate Adjustments
Subjects who do not tolerate (Section 7.9) the 500 mg/kg dose will be withdrawn 
from the study.
Subjects who do not tolerate the 1000 mg/kg dose may have the dose decreased 
to 500 mg/kg. 
Subjects who do not tolerate the 1500 mg/kg dose may have the dose decreased 
to 1000 or 500 mg/kg.   
Subjects may be withdrawn for any Grade 3 AE (per NCI’s CTCAE version 5.0) 
possibly or definitely related to study drug.  
Subjects will be withdrawn for any Grade 4 toxicity, Grade 3 pulmonary 
complications or evidence of Grade 3 renal injury.
Subjects will be withdrawn if it is determined by the investigators in consultation 
with the IRB that the limit of safety or tolerability has been reached.
Rate may be decreased in 25 mg/kg/hr increments to 175 mg/kg/hr if required. 
The rate and reason for reduction will be recorded.  Subject will be withdrawn if 
the 175 mg/kg rate is not tolerated.  
4.5.6  Interim analysis of Intravenous Dose
An interim analysis will be performed after obtaining 4-month cholestane-
3β,5α,6β-triol and safety data on six trial participants.  These data will be used to 
propose rational changes in the dosing regimen if a lower dose levels appears to 
be ineffective or a higher level is less tolerated than an apparent effective lower 
dose.   


27
4.5.7 Intrathecal VTS-270 Dosing and Dose Adjustments
1. Participants may elect to receive intrathecal VTS-270 in conjunction 
with this protocol.  Intrathecal VTS-270 is not a requirement of 
participation in this study.  If elected, IT VTS-270 must be started prior 
to receiving IV VTS-270.
2.  For participants ≥ 4 years old, the IT VTS-270 dose will be initiated at 
600 mg and then dose escalated, if tolerated, to 900 mg every 4 weeks 
± 1 week.  Individuals already receiving IT VTS-270 at a dose ≥ 900 
mg may be started at 900 mg.  Individuals already receiving an IT 
VTS-270 dose < 900 mg may be dose escalated to 900 mg or 
maintained on either 400 or 600 mg for the duration of the trial.
For participants ≥ 3 and < 4 years old, the IT VTS-270 dose will be 
initiated at 200 mg and then dose escalated, if tolerated, to 400 mg 
every 4 weeks ± 1 week.   Individuals already receiving a stable and 
tolerated dose of VTS-270 may be maintained at that dose up to a 
maximum of 900 mg.  
3. Subjects (≥ 4 years old) who do not tolerate the 900 mg dose may have 
the dose decreased to 600 mg.  Subjects who do not tolerate the 600 
mg dose may have the dose decreased to 400 mg.  Intrathecal VTS-
270 will be discontinued in subjects who do not tolerate 400 mg. They 
may continue, if tolerated, to receive IV VTS-270.  The reason for the 
dose reduction will be recorded.  Once reduced, doses will not be 
increased for the duration of the study.
Subjects (≥ 3 and < 4 years old) who do not tolerate the 400 mg dose 
may have the dose decreased to 200 mg.  Intrathecal VTS-270 will be 
discontinued in subjects who do not tolerate the 200 mg dose.   The 
reason for the dose reduction will be recorded.  Once reduced, doses 
will 
not be increased for the duration of the study.
4. The intrathecal dose must be stable for two doses prior to initiation of 
the IV study.  For VTS-270 naïve participants, the IV study may be 
initiated 2 days after the second stable IT dose.  
5. If the first IV drug administration is performed on the same visit as the 
third IT administration, then it may be administered 2 days after the IT 


28
administration. If the first IV drug administration is performed on 
another visit, the first intrathecal dose will not be administered until ≥ 
18 hours post IV infusion.
  
6. IT administration can be performed concurrently with IV administration 
after the first IV administration if the IV dose has not been changed.   If 
a participant is receiving a new IV dose, the intrathecal dose will not be 
administered until ≥ 18 hours post IV infusion.
7. Subjects already receiving IT VTS-270 under another mechanism may 
enroll in this trial.  Dose and interval will be 900 mg monthly.   If the 
subject is already on a dose lower than 900 mg due to documented 
intolerance, then they may be enrolled into this study at a dose of 
either 600 or 400 mg.  Dosing interval will be monthly irrespective of 
the prior dosing interval.  If the dose is not escalated, the dose may be 
considered stable based upon review of the patients history.     
4.6 Assessments, Procedures and Testing  
 
Baseline and timing in this section is relative to the initiation of peripheral VTS-
270 therapy.
For 6 and 12-month assessment 6 ± 1 and 12 ± 1.5 months is acceptable.
 
For testing performed monthly, ± 1 week is acceptable.
4.6.1 Medical History and Physical/Neurological Examinations
A medical history will be obtained, and a physical exam will be conducted after 
admission to the NIH Clinical Center and enrollment into the study. This will 
ensure that the patient’s medical health is adequate to participate in this study. 
An interval history and a physical exam will be obtained on all subsequent 
admissions. 
Anthropomorphic measures including weight and height will be obtained with 
each admission.  Head circumference will be obtained on the initial visit.   
Physical and neurological examinations will be obtained. Medical evaluations 
may include videotaping of neurological assessments. Recordings may be sent 
to other physicians in an effort to develop rating systems. Although the patients’ 


29
names will not be provided, the video recording may include the face or other 
identifiable features. 
4.6.2 NPC1 Neurological Severity Score
The NPC1 Neurological Severity Scale [4] consists of clinical signs and 
symptoms in nine major domains (scored 0 to 5: ambulation, cognition, eye 
movement, fine motor, hearing, memory, seizures, speech, and swallowing) and 
eight minor domains (scored 0 to 2: auditory brainstem response, behavior, 
gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, and 
respiratory problems). Subjects will be evaluated using this scale at baseline, 6 
and 12 months.   
4.6.3 Pulmonary Function Assessment
A baseline CXR will be obtained prior to the first administration of the study drug.  
Pulmonary function testing will be obtained at baseline and 12 months. CXR will 
only be repeated if clinically indicated.   Assessment will consist of PFT (≥ 5 yo) 
or impulse oscillometer (< 5 yo) and 6-minute walk test.  Pulmonary functional 
assessment may be performed at anytime during the study if clinically indicated.  
4.6.4 Liver Enzyme Assessment
Plasma AST and ALT will be obtained each visit.  Total and direct bilirubin, 
gamma glutamyl transferase (GGT) and alkaline phosphatase will be measured.   
4.6.5 Abdominal Ultrasound  
An abdominal ultrasound exam will be conducted at baseline, 6 and 12 months to 
determine liver and spleen volume.  
4.6.6 Liver FibroScan
A liver FibroScan will be obtained at baseline, 6 and 12 months.  
4.6.7 Audiological Evaluation. 
A behavioral audiological evaluation will be obtained at baseline, 6 and 12 
months relative to IT VTS-270.  Additional audiological evaluations may be 
obtained if clinically indicated.  
4.6.8 Clinical Laboratory Tests
Clinical laboratory testing will be conducted by the NIH Department of Laboratory 
Medicine.                                              


30
4.6.8.1 Hematology/Chemistry
Fasting blood samples for the clinical laboratory tests will be collected by a 
qualified person using either indwelling catheter or by venipuncture. 
Testing will include the following:
Hematology:  complete blood count (CBC) with differential and platelet count
Coagulation:  prothrombin time (PT) and partial thromboplastin time (PTT)
Clinical chemistry:  electrolytes, fasting glucose, blood urea nitrogen (BUN), 
creatinine, AST, ALT, GGT, alkaline phosphatase, bilirubin (direct and total), 
albumin, calcium, magnesium, phosphorus, and CK.
eGFR will be determined using the Schwarz method to monitor renal function. 
This testing will occur on each admission.
In addition to the above, serum antiepileptic drug levels and other clinically 
indicated laboratory testing will be obtained as necessary in applicable subjects.
4.6.8.2 Urinalysis
Urinalysis will include assessment of protein, blood, leukocytes, glucose, 
ketones, bilirubin, urobilinogen, pH, and specific gravity and microscopic 
analysis. This testing will occur on each admission.
4.6.8.3 Pregnancy Testing
All female subjects ≥10 years old or menstruating will have either a serum or 
urine pregnancy test performed prior to drug administration or study related 
procedures for all admissions.  Guardians will be informed of a positive test. 
Investigators will assist if needed in identifying appropriate primary care and 
pregnancy outcome will be ascertained.   
4.6.10 Research Laboratory Testing
4.6.10.1 Plasma and Serum
Plasma and serum will be collected under standardized conditions for biomarker 
analysis.  Testing may be performed in clinical or research laboratories.  
Research testing may be prioritized if there is an issue of blood limits.  Research 
testing may include, but is not limited to the following:


31
Markers of cholesterol homeostasis (Baseline, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 
12 months)
1.  Plasma lipid panel (Cholesterol, Triglycerides, HDL cholesterol and 
LDL cholesterol)  
2.  Plasma lathosterol
3.  Cholestane-3β,5α,6β-triol
4.  Plasma oxysterol profile (4β-HC, 7-KC, 24-HC, 27-HC)
5.  Lipoprotein analysis (NMR)
Plasma lipidomics  (Baseline, 6, 12 months)
1. Sphingolipids: sphingoid bases, ceramides, glucosylceramides, 
lactosylceramides, gangliosides
2. Lysosphingolipids: lyso-sphingomyelin, and lyso-SM 509
Biomarkers of inflammation  (Baseline, 2, 4, 6, 8, 10 and 12 months)
Such as LGAL3, cathepsin D, lysozyme, cytokines
Plasma bile acids  (Baseline, 6, 12 months)
Alpha-fetoprotein (Baseline, 6, 12 months)
Markers of liver pathology (Baseline, 2, 4, 6, 8, 10 and 12 months)  
Such as Hyaluronic Acid, TIMP1 and P3NP
4.6.10.2 Peripheral Mononuclear Cells
Blood may be collected for isolation of peripheral mononuclear cells (Baseline, 6, 
12 months). Cells may be used to characterize expression of genes associated 
with cholesterol homeostasis or for lipidomics.   
4.6.11 Assessments related to intrathecal VTS-270 administration
These assessments are optional and are components of our Natural History 
protocol (06-CH-0186). These evaluations include:
1.  Motor function and gait analysis (every 6 ± 1 months)
a.  Gait analysis
b.  Balance testing
c.  Motion analysis of Finger-nose-finger test
2.  Occupational therapy assessment (every 3 ± 1 months)
a.  Dynometer Grip Strength Assessment
b.  9-hole Peg Test
c.  Jebsen-Taylor Hand Function Test
3.  Timed Up and Go  (every 3 ± 1 months)
4.  Neurocognitive evaluation  (every 6 ± 1 month)


32
4.  Speech and swallow evaluation (every 6 ± 1 month) 
4.7 End of participation
Parenteral and intrathecal VTS-270 will not be provided under this protocol after 
completion of this study. The study team may work with participants/guardians to 
facilitate a transition to an expanded access IND for intrathecal VTS-270 after 
completion of this study.  Participants may continue to be seen by our research 
team at the NIH Clinical Center if enrolled in our Natural History study (06-CH-
0186).
See section 8.4 with respect to patient withdrawal.
Participants will have access to all clinical tests and evaluations via the patient 
portal or copies of the medical record.  
Research results will be shared in aggregate with the NPC1 patient and research 
community at conferences and ultimately via publication.   
5. Management of Data and Samples
5.1   Biomaterial Storage and Use
Blood (serum and plasma) and urine will be collected as part of this protocol.  
CSF may be collected in subjects that are receiving IT VTS-270. Samples will be 
maintained under standard conditions in the NICHD biorepository. Coded 
samples may be sent to collaborators at either the NIH or other institutes.  
Material transfer agreements will be obtained when applicable per NIH policy. 
Biomaterial and data collected as part of this study may be used for future 
research related to Niemann-Pick disease. Coded or anonymized biomaterial 
and data collected as part of this study may be used for other projects specifically 
approved by an Institutional Review Board.  Priority will go to studies related to 
Niemann-Pick disease.   
Loss or destruction of specimens will be reported to the IRB.
At the conclusion of this study, biospecimens will be transferred to our ongoing 
Natural History protocol (06-CH-0186).
5.2.  Genomic Data Sharing:  Not Applicable
5.3 Data sharing


33
Data and samples may be shared with collaborating laboratories at NIH or 
outside of NIH or submitted to NIH-designated repositories and databases.  
Repositories receiving data or samples from this protocol may be open-access or 
restricted access.
Samples and data will be stripped of identifiers and may be coded (“de-
identified”) or unlinked from an identifying code (“anonymized”). When coded 
data is shared, the key to the code will not be provided to collaborators but will 
remain at NIH.    Submissions to NIH-sponsored or supported databases and 
repositories will be reported at the time of Continuing Review.  Submission to 
non-NIH sponsored or supported databases and repositories will be submitted for 
prospective IRB approval.
Required approvals from the collaborating institution will be obtained and 
materials will be shipped in accordance with NIH and federal regulations.   
Our research data sharing policy for clinical studies is attached.   
Deidentified data may be provided to Mallinckrodt to support development or 
regulatory approval of this drug.   Deidentified data may be provided to another 
entity under a CRADA if Mallinckrodt elects to not pursue regulatory approval of 
VTS-270 per the provisions of the existing CRADA.   
5.4 Data Handling and Record Keeping
5.4.1 Electronic Data
The protocol and associated data will be stored in the NICHD Clinical Trials 
Database (CTDB). The CTDB is a 21 CFR Part 11 compliant web-based 
application that supports flexible data capture, and reporting.  
 
5.4.2 Case Report Form Completion
CRFs will be completed for each study patient. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the patient’s CRF. Source documentation supporting the 
CRF data should indicate the patient’s participation in the study and should 
document the dates and details of study procedures, AEs, and patient status.
The Investigator will maintain copies of the CRFs at the study site. For patients 
who discontinue or terminate from the study, the CRFs will be completed as 
much as possible, and the reason for the discontinuance or termination clearly 
and concisely specified on the appropriate CRF.


34
In addition, electronic data capture will be used for the study. History, physical 
examination, clinical chemistry laboratory values, and procedure records will be 
documented in clinical research information system (CRIS) by the medical care 
team. Completed electronic CRFs are to be signed off by the Investigator or 
his/her designee
5.4.3 Retention of Study Records
The Investigator will maintain all study records according to ICH/GCP guidelines 
and applicable regulatory requirements. Records will be retained for at least two 
years after the last marketing application approval and until there are no pending 
or contemplated marketing applications or two years after formal discontinuation 
of the clinical development of the investigational product or according to 
applicable regulatory requirements. If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to an 
appropriate person willing to accept the responsibility. If a custodial change 
occurs, it must be documented.
5.4.4 Direct access to source data 
The Investigators will permit trial-related monitoring, audits, IRB review, and 
regulatory inspections as requested by FDA, the Sponsor, or the Sponsor 
designee, including direct access to source data/documents (i.e., original medical 
records, laboratory reports, hospital documents, progress reports, signed 
informed consent forms, etc.), in addition to CRFs.
5.4.5 Publication Policy
All information concerning use of VTS-270 in the context of this trial is considered 
confidential and shall remain the property of the NIH. In accordance with NIH 
policy, data will be shared outside of the consortium group principally through 
publications and presentations at scientific conferences. Publications reporting 
the results of this trial will be submitted in a timely way.  Data will be made 
available to Mallinckrodt under a Cooperative Research Agreement or similar 
mechanism. There are no anticipated delays or impediments to free publication 
of these results regardless of the outcome.  
5.4.6  Return of results and community engagement 
Participants will have access to all clinical testing/evaluations through the NIH 
Clinical Center Portal.   Protocol status is reviewed with participating families.   
Research results will be presented to the NPC1 disease community via 
presentations or updates to the family support groups. Copies of  publications 
related to this research will also be made available to the family support groups.  


35
The trial will be registered on ClinicalTrials.gov and results will be posted per 
FDAAA requirements.      
Information about this trial will be provided to families participating in our NPC1 
Natural History Protocol, distributed to family support groups and provided to 
medical providers or diagnostic laboratories that see NPC1 patients.
6. Additional Considerations
6.1 Research with investigational drugs or devices
VTS-270 is an investigational drug.  This study requires an IND.  VTS-270 will be 
provided by Mallinckrodt to develop VTS-270 for the treatment of NPC and will 
be stored in the NIH pharmacy.  
6.2 Gene therapy
Not applicable.
6.3 FDA Consideration
Subjects currently enrolled under current IND 142671, currently receiving 
intrathecal adrabetadex appear to be benefiting from adrabetadex. Guardians of 
enrolled subjects perceive benefit of the drug that outweighs the risks, and they 
previously elected to continue the optional intrathecal administration through the 
end of this study when Mallinckrodt initially made the decision to discontinue their 
development program based on Phase 2/3 trials results. In enrolled participants, 
assessment of disease progression using the NPC Neurological Severity Scale 
and clinical assessment by individuals experienced with NPC are consistent with 
less than expected neurological disease progression.
Both participants and their legally authorized representatives have been informed 
and re-consented with the information received from Mallinckrodt. They also 
understand the risks associated with adrabetadex, including hearing loss, and 
understand that Mallinckrodt has reported no significant difference between 
patients treated with adrabetadex and sham-treated patients on any efficacy 
measures in their randomized, controlled trial. Families of the two participants are 
making arrangements to continue in the Rush University Expanded Access 
Program due to this perceived benefit. 
At this time, both patients have already completed the phase of the study in 
which they would have experienced the hearing loss side effects of the study 
drug that were identified by Mallinckrodt as contributing to the negative risk-
benefit ratio. Once both patients complete the optional IT portion of this study, we 
will be closing this study. 


36
7. Risks and Discomforts
Efforts will be made to reduce physical and psychological stress by carefully 
explaining the study’s procedures to the individual patients. Except when the 
patients are sedated by anesthesiology, guardians can elect to be present. 
Individual procedures and associated personal risks are briefly described below.
7.1 Medical Evaluations
There are no significant risks associated with the physical, neurological, and 
neuropsychiatric examinations. Multiple independent evaluations may be 
stressful to a child or an impaired patient. Clinical photographs or video may be 
obtained, and these could potentially be embarrassing to some patients.
7.2. Risk of Intravenous VTS-270
The risks of intravenous VTS-270 are not known. Animal studies and human 
experience with HPβCD and VTS-270 to date suggest that this can be done 
relatively safely; however, a major purpose of this study is to determine safety 
and tolerability of intravenous VTS-270 in NPC1 patients. 
IV administration of an experimental drug could have untoward consequences 
including permanent disability or death. 
Known toxic effects from the cat disease model include acute respiratory distress 
and death, and apparent irreversible deafness: 

Cats receiving 8,000 mg/kg HP-β-CD by subcutaneous injection 
developed acute respiratory distress and died due to this complication. 

Cats receiving multiple subcutaneous doses of 4,000 mg/kg or a single 
subcutaneous dose of 8,000 mg/kg HP-β-CD developed apparent 
irreversible deafness [37]. 

A majority of mice receiving a single 8000 mg/kg subcutaneous dose of 
HP-β-CD had hearing loss due to loss of outer hair cells [38].  However, 
chronic dosing at 4000 mg/kg showed an initial hearing loss that 
subsequently recovered suggesting that homeostatic mechanisms could 
adjust to the lower dosing.   

Pulmonary toxicity has been reported in young pigs receiving IV HP-β-CD 
infusions [39].  Infusion of 1 g/kg of 40% HP-β-CD in normal saline over 40 
minutes resulted in cardiovascular instability.  Five infusions over two 
weeks of 0.25-0.5 g/kg over 40 minutes resulted in inflammatory 
pulmonary changes.   
No adverse events related to pulmonary function have been reported for the 
children receiving IV or IT HPβCD under individual use INDs cited in the initial 
IND (IND 113273). The investigators are not aware of any pulmonary adverse 
events being reported in the eight other individuals receiving IV HPβCD under 


37
expanded access INDs in the United States. Those individuals are typically 
receiving 2500 mg/kg HPβCD every week. Individuals in the US are receiving 
Kleptose HPB, from which VTS-270 is derived.  Matasuo et al [32] reported 
transient diffuse pulmonary infiltrates and fever following infusions of IV HPβCD 
after 23 months of therapy. These resolved with prednisolone and antihistamine 
pretreatment and interpreted by the authors as an infusion related immunological 
reaction. The adverse pulmonary events appear to be related to high peripheral 
dosing. The HPβCD used by Matasuo et al is not the same preparation as VTS-
270.   
While an allergic or anaphylactic reaction to VTS-270 is unlikely, the first drug 
administration at each dose level will take place in a NIH Clinical Research 
Center inpatient unit; in order to closely monitor the patient for acute adverse 
effects including anaphylactic response to VTS-270. Nursing and medical staff 
are trained in Code Blue procedures as well as Advanced Life Support, and 
many staff members are trained in Pediatric Advanced Life Support. Emergency 
resuscitation carts (Code Carts) are in place on every Patient Care Unit.
Exact doses for emergency resuscitation drugs for pediatric patients (defined as 
less than 18 years of age) who weigh less than 50 kg are calculated immediately 
upon each admission and recorded on the Pediatric Emergency Drug Sheet 
(PEDS). These include medications necessary for managing anaphylactic 
reactions (epinephrine, diphenhydramine and hydrocortisone). A copy of this 
document is kept on the patient’s medical record as well as on the Code Cart on 
the Patient Care Unit for the duration of the admission. The Clinical Center Code 
Team includes a pediatric physician.
IV VTS-270 will be administered by peripheral IV.  It is possible that this will 
result in irritation, inflammation or pain at the site of administration.  We will 
monitor the infusion site for infustion related problems.   
7.3 Urine Collection and Pregnancy Testing
There are no to minimal risks involved with a urine pregnancy test. A blood-
based pregnancy test may be substituted.  The patient will not be eligible to 
participate in the study if she is pregnant. A urine cup, toilet hat, or a urine bag to 
collect urine will be used. Patients will not be catheterized for this study. This 
collection may be inconvenient and there may be mild discomfort associated with 
bagging.  For cognitively impaired adults, guardians will be informed of a positive 
test. A serum pregnancy test may be conducted in lieu of a urine pregnancy test. 
The consent document will inform sexually active subjects that they should 
practice effective birth control during the duration of this study.


38
7.4 Phlebotomy
Phlebotomy is a risk/discomfort of this study. An anesthetic cream such as EMLA 
is an option. Infection and bruising are possible at the site of the blood draw. The 
amount of blood to be drawn will not exceed the NIH CC guidelines of for 
children or adults of 5 or 10.5 ml/kg per day, respectively.  Nor will we exceed the 
8-week limit of 9.5 ml/kg or 550 ml for children or adults, respectively. Nursing 
staff will monitor blood-drawing volumes. If blood limits are an issue, testing will 
be prioritized by the investigators. Safety laboratory tests will take priority over 
investigational testing. Not obtaining a test due to blood limit prioritization will not 
be considered a protocol deviation.  If a patient is concurrently enrolled in 
another protocol, the total blood volume collected across all protocols for 
research will not exceed the above limit.
7.5 Audiological Evaluation
For the hearing test the patient will wear headphones or soft foam earplugs. 
Tones and words that vary in loudness will be played over the earphones and the 
patient will be asked to respond to the sounds. This testing lasts approximately 
15 minutes and involves minimal discomfort. Acoustic reflex measurement allows 
the audiologist to further examine the integrity of the acoustic reflex arc, which 
relies on functional integrity of the middle ear system, inner ear, seventh and 
eighth cranial nerves and auditory pathways in the lower brainstem. For this test, 
very brief, somewhat loud tones are presented to each ear. In a normal-hearing 
ear, the stapedius muscle in the middle ear contracts in response to loud sounds 
presented at levels of about 70-100 dB HL (decibels hearing level). In this test, 
the audiologist presents tones at these levels and determines whether there is an 
acoustic reflex and what level of sound is required to produce the reflex. This is a 
standard audiologic test. The audiologic evaluation will also include 
measurement of auditory evoked potentials. For this testing the patients will wear 
either headphones or soft, foam earplugs. Four electrodes will be taped to the 
patient’s head and the electrical response to sound will be recorded. This testing 
lasts approximately 30 minutes. This testing involves minimal discomfort and no 
risk.
7.6 Sedation
Sedation for study procedures may be performed at the discretion of the 
research team in consultation with the patient/guardians and anesthesiology. The 
medical and anesthesia clearance may determine that the patient is not fit for 
sedation during study procedures due to pre-existing medical conditions that 
would cause this elective procedure to be riskier. If that is the case, and sedation 
is necessary, the patient will be excluded from the study. 
The major risk associated with sedation is respiratory collapse. To minimize this 
possible complication, sedation will be performed by an NIH Clinical Center 


39
anesthesiologist. Facilities for maintenance of a patient airway, artificial 
ventilation, and circulatory resuscitation will be immediately available and ready 
for use. The anesthesiologist will also select the anesthetic agent used based on 
their clinical judgment. Criteria used in making this judgment include patient age, 
size, history of reflux, history of difficult airway management, and overall medical 
status. Another risk of sedation is aspiration. Intubation decreases the risk of 
aspiration and may be used if in the opinion of the anesthesiologist that it is 
indicated. Death is a rare complication of sedation when performed by a licensed 
anesthesiologist under controlled conditions.
Exposure to repeated and prolonged anesthesia in young children may affect 
neurocognitive development. Sedation in young children will be assessed on an 
individual basis, and efforts made to consolidate evaluations and procedures 
optimally done under sedations to minimize the anesthesia time.
7.7 Radiation Exposure
Radiation exposure due to participation in this study comes from the baseline 
Chest X-ray.  The estimated total body exposure is 0.007 cSv.  
This exposure is below the NIH Radiation Safety committee guidelines of 5 cSv 
per year for adults.  This exposure is below the NIH Radiation Safety committee 
guidelines of 0.5 cSv per year for individuals under 18 years of age.  The risk of 
this radiation exposure has to be weighed against the severity of this disease and 
the potential direct benefit of this therapy.     
Female participants will be asked to inform any study coordinators, nurses and 
the x-ray technologist if there is any possibility that they are pregnant.
The average person in the US receives a radiation exposure of 0.3 rem per year 
from natural sources, such as the sun, cosmic radiation, and the earth's air and 
soil. If the patient/guardian would like more information about radiation, he/she 
may ask the investigator for a copy of the pamphlet, An Introduction to Radiation 
for NIH Research Subjects. 
The source will be a chest X-ray that will be obtained on the first admission and 
this will serve as a baseline study should pulmonary symptoms be observed 
during the study.  
There is no discomfort and minimal exposure to radiation when obtaining a CXR.   
The CXR is one of the lowest radiation exposure medical examinations 
performed today. The radiation dose from this CXR is about 0.007 cSv.   
While there is no direct evidence that the amount of exposure received from 
participating in this study is harmful, there is indirect evidence it may not be 
completely safe. There may be a very slight increase in the risk of cancer. The 


40
participant/guardian will inform one of the doctors if he/she has had any radiation 
exposure in the past year, either from other research studies or from medical 
tests or care, so the doctors can make sure that the subject will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology 
departments, cardiac catheterization, and fluoroscopy as well as nuclear 
medicine scans in which radioactive materials were injected into the subject’s 
body. If the participant is pregnant or breast feeding, she may not participate in 
this research study. It is best to avoid radiation exposure to unborn or nursing 
children since they are more sensitive to radiation than adults.
7.8 Liver/Spleen Ultrasound and Liver Fibroscan
The risks of an abdominal ultrasound or transient elastography (Fibroscan) are 
limited to mild discomfort of the technicians pressing the probe against the 
abdominal wall.     
7.9 Future Research and Other Testing
Other blood, cellular, urine or CSF biomarkers may be assessed. At the 
discretion of the investigator, blood, urine, and CSF may be collected and saved 
for future research. The blood, urine, CSF, and derivatives thereof (e.g., 
exosomes, peripheral B-cells, ribonucleic acid (RNA) or deoxyribonucleic acid 
(DNA)), collected under this protocol, can be stored for future research not 
specifically outlined in this protocol. Such research could involve, but is not 
limited to, proteomic, genomic, biochemical, metabolomic, and molecular 
analysis of these samples. Data collected under this protocol may be used for 
future research.  Future research using these samples and data will relate to 
Niemann-Pick disease or other projects specifically approved by an Institutional 
Review Board.  Priority will go to studies related to Niemann-Pick disease. This 
research may occur at the NIH or at outside laboratories. If sent to outside 
laboratories samples will be coded and patient identifiers will be removed. If 
biospecimens are sent to a clinical laboratory for testing, identifiers will not be 
removed, and the result will become part of the NIH medical record. For patients 
also enrolled in the ongoing Natural History Study (06-CH-0186), biospecimens 
collected during admissions for this protocol can be used for research specified 
in that protocol. Sample volume safety limits will take into account both protocols.
Data collected under this protocol may be used in future studies.
  
Data collected under this protocol and the Natural History study may be 
exchanged if a participant is enrolled in both studies. Upon closure of this 
protocol, all data and biomaterials will transfer to 06-CH-0186.
7.10 Lumbar Puncture


41
There are several potential risks associated with an LP. About a third of adults 
report a headache after a LP. The frequency is lower in children. This can be 
made less by lying flat in bed and taking medications such as Tylenol. Although 
rare, bleeding may occur near the puncture site or in the deep tissue around it. 
Which may cause; pain, loss of sensation in the feet, loss of bowel or bladder 
control, and numbness, cramping, or weakness in the arms, hands, or legs. 
There is a risk of causing a serious infection in the CSF known as meningitis. To 
prevent this, the LP will be done using sterile techniques and instruments. A rare 
but serious complication of a LP, if it is done when the pressure inside the head 
is higher than normal (such as when a brain tumor is present), is known as 
medullary herniation which can result in death. Increased intracranial pressure is 
very unlikely to be present. The LP will not be done if there are any clinical 
indications of increased intracranial pressure, a skin infection in the lower back 
area, or bone malformation of the lower back (including severe scoliosis) which 
would make a LP difficult. We will do the LP monthly for drug administration. CSF 
will be collected and saved each time we do an LP.  The LP will be performed 
under sedation if the participant is unable to cooperate with the procedure while 
awake.  
8. Subject Safety Monitoring
8.1 Monitoring of Adverse Event Data  
The investigators have primary responsibility for the ongoing monitoring of 
adverse events.  Adverse events will be summarized and reported to the NICHD 
IRB.  This study will use a medical monitor. The study is not blinded, of relatively 
short duration and involves a small number of subjects that can be adequately 
assessed through simple comparison, thus a DSMC is not required.  
8.2 Review of Safety and Tolerability
The evaluation of a dose for an individual will be reviewed by the Principal 
Investigator and research team. See Table 1.
8.2.1 Tolerability Determinations
Adverse events will be assessed using CTCAE version 5.0.  Safety and 
tolerability of VTS-270 will be determined as presented in table 1 except for 
respiratory and audiological complications.
High frequency hearing loss is a known symptom of NPC1 and ototoxicity is a 
known complication of IT VTS-270 administration. Audiological changes will not 
be considered to be related to IV VTS-270 in subjects receiving IT VTS-270 


42
unless the changes exceed or are qualitatively different than those expected 
based upon our experience with IT VTS-270.        
Post-dose fatigue and ataxia is a known complication of IT VTS-270 
administration. These symptoms will not be considered related to IV VTS-270 in 
subjects receiving IT VTS-270 unless they are qualitatively different than those 
expected for the individual.    
8.2.1 Review of Respiratory Compromise
The study will be discontinued if two subjects demonstrate respiratory 
compromise associated with drug infusion at 500 mg/kg dose. If two subjects 
demonstrate respiratory compromise associated with drug infusion in cohort 
three (1500 mg/kg group), dosing for all subjects in this cohort will be decreased 
to 1000 mg/kg/d. If two subjects demonstrate respiratory compromise associated 
with drug infusion in cohort two (1000 mg/kg), consideration will be given to 
reducing dosing for cohorts two and three depending upon the total trial 
experience. This latter decision will be made in consultation with the FDA and 
IRB.    
We will consider respiratory compromise to be one of the following:
1.  Sustained tachypnea for 30 minutes or dyspnea during drug infusion or 
within 2 hours post infusion that is likely related to drug administration. 
The 
individual subject will be withdrawn, or the dose decreased.
2. Decreased SaO2 (<90%) during drug infusion or within 2 hours post 
infusion that is likely related to drug administration.  The individual subject 
will be withdrawn, or the dose decreased.
3. Repeat CXR demonstrating pulmonary infiltrates likely related to drug 
administration. If the etiology of pulmonary infiltrates is not known, the 
dose may be repeated and a subsequent CXR obtained. If the subsequent CXR 
demonstrates increased pulmonary infiltrates, subject will be withdrawn, or 
the dose decreased.   
 
 
8.2.2 Review of High Frequency Hearing Loss
 
High frequency hearing loss is considered an expected complication of VTS-270 
administration. Evaluation will be confounded by potential concomitant 
administration of intrathecal VTS-270. No changes to this protocol will be made 
unless the degree of hearing loss exceeds that typically observed in our Phase 
1/2a intrathecal HP-β-CD trial (13-CH-0001).   


43
8.3 Data Safety Monitoring Board
This protocol does not meet the criteria as outlined in the NIH HRPP SOP 17 for 
data to be submitted to a data safety monitoring committee. The IRB will be 
consulted concerning dose reductions and subject withdrawal.  
8.4 Withdrawal of Patients from the Study
Participants can withdraw from the study at any time for any reason. 
Patients/guardians/parents will be informed that they have the right to withdraw 
from the study at any time for any reason without prejudice to their medical care. 
However, to receive care at the NIH CC, patients must be enrolled on a research 
protocol. The Natural History Study provides an alternative to this protocol. 
Patients who are withdrawn from the study either by their choice or investigator 
action will be notified and provided with recommended follow-up instructions in 
writing.   
Patients may be withdrawn from the study for any of the following reasons:
Patient/parent/guardian request
Patient/parent/guardian is unwilling or unable to comply with the protocol
Medical reason, at the discretion of the Investigators 
Occurrence of the following:  
a. any Grade 3 AE (per NCI’s CTCAE) possibly or definitely related to 
study drug
b. any Grade 4 toxicity
c. any subject with Grade 3 pulmonary complications or evidence of 
renal injury
d. determination that the limit of safety and/or tolerability has been 
reached


44
Table 1.  Decision Table for Evaluating the Safety and Tolerability of IV 
VTS-270 in 
Individual Patients (respiratory and audiological excluded)
Safety Profile of Individual Patient 
Safety Decisions*
A
No AEs and no SAEs or Any number 
of CTCAE Grade 1 drug-related AEs;
≤ 1 CTCAE Grade 2 drug-related AE; 
or
Repeat the current dose
B
2 CTCAE Grade 2 drug-related AEs (or 
Repeat the current dose, 
Study 
a 
lower 
dose 
(if 
applicable)
C
≥ 3 CTCAE Grade 2 drug-related AEs or
≥ 1 drug-related SAE
Study 
a 
lower 
dose, 
or 
withdraw the patient
and
Evaluate the risk/benefit profile 
for this dose for other patients
D
Any CTCAE Grade 3 drug related AE; 
Any CTCAE Grade 4 AE; 
Determination that the limit of safety 
and/or tolerability has been reached 
Withdraw the patient 
and
Evaluate the risk/benefit profile 
in other patients for the dose 
resulting in Grade 3 toxicity 
 and 
Discontinue 
study 
if 
two 
patients develop the same 
Grade 3 toxicity or if any patient 
develops a Grade 4 toxicity 
Guardians or consenting participant may request discontinuation of study 
medication.  In this case although study treatment will cease immediately, end of 
study evaluations may be completed. 
The reasons for patient withdrawal will be recorded in the patient’s CRF. 
For a withdrawal due to a safety issue, patients will be followed until the safety 
issue is resolved or returns to baseline level. Additionally, any appropriate 
referrals will be made as needed. Referrals may involve an institution other than 
the NIH CC.  
Expenses due to research related injuries will be handled per NIH policy.   
A participant may withdraw or be withdrawn from the IT VTS-270 aspect of this 
protocol and continue with the IV VTS-270 trial.  Participants can not withdraw 
from the IV VTS-270 trial and continue to receive IT VTS-270.  If investigators 
withdraw a participant from the IV VTS-270 trial due to a safety concern, the 


45
patient may continue to receive monthly IT VTS-270 under this protocol for up to 
15 months.      
Any usable data from withdrawn patients will be included in safety and efficacy 
evaluations. Patient withdrawn from the IV aspect of this protocol may be 
replaced. 
8.5   Discontinuation or Temporary Suspension of the Study
The Principal Investigator may terminate this study at any time for safety or 
administrative reasons. The Principal Investigator will terminate the study if the 
occurrence of AEs or other findings suggests an unacceptable risk to the health 
of the subjects. The study will be stopped if two subjects develop the same 
Grade 3 adverse event (unless related to disease progression of NPC), or if any 
patient that develops a Grade 4 adverse event, regardless of whether the event 
is determined to be related to the study drug (unless the AEs are of an accidental 
nature that could not be reasonably attributable to VTS-270 or related to disease 
progression of NPC). 
9. Outcome Measures
9.1 Primary outcome measures
The primary clinical outcome measure for this trial will be to delineate safety and 
tolerability of intravenous VTS-270 in NPC1 participants.  Adverse events, as 
delineated in section 8, will be used to determine safety and tolerability. 
The primary biochemical outcome measure for this trial will be reduction of the 
plasma cholestane-3β,5α,6β-triol level (ng/ml).  
9.2.  Secondary outcome measures
The secondary clinical outcome measure for this trial will be reduced liver size 
(cm3) or stiffness (kPa).
The secondary biochemical outcome measures for this trial will be reduction of 
serum transaminase levels (AST, ALT) or improved AST/ALT ratio.  AST and 
ALT will be reported in U/L.
9.3.  Exploratory outcome measures


46
Evaluation of potential biomarkers (Section 4.6.10) will be considered 
exploratory. Outcome measures related to IT administration are considered 
exploratory  
10. Statistical Analysis Plan
The primary clinical outcome of this study is to assess the safety and tolerability 
of intravenous VTS-270 in subjects with Niemann-Pick Disease, type C1.
Assessment of safety and tolerability will be made by evaluation of summary 
statistics of adverse events and unanticipated problems.  Adverse events and 
tolerability are defined in section 8 and will be summarized for each dose level. 
We hypothesize that the total number of drug-related adverse events will not 
increase with dose level and we will not observe an increase in the number of a 
specific type of drug-related adverse event increase with dose level.  
A dose will be considered tolerated if not more than one participant in a dose 
cohort requires either dose reduction or withdrawal from the protocol due to a 
drug-related issue.   
The primary biochemical outcome of this study is to assess the potential efficacy 
of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick 
Disease, type C1 as measured by reduction in plasma cholestane-3β,5α,6β-triol, 
an NPC1-specific pharmacodynamic biomarker.
Plasma cholestane-3β,5α,6β-triol, a biomarker that is elevated >97% of NPC1 
subjects, is largely generated in the liver and therefore provides a biochemical 
measure of oxidizable lysosomal unesterified cholesterol in liver tissue (6, 20).  
We hypothesize that there will be a significant reduction in the last treated 
plasma cholestane-3β,5α,6β-triol concentration relative to baseline in each of the 
three dose cohorts.   
Limited data is available to estimate the power of this study. The mean and 
standard deviation of plasma cholestane-3β,5α,6β-triol levels for 109 NPC1 
patients and 89 controls were 80.3 ± 77 and 11.5 ± 3.3  ng/ml, respectively [7]. 
Due to the large variability among NPC1 patients, data will need to be normalized 
to the individuals baseline value. Serial plasma cholestane-3β,5α,6β-triol 
concentrations were measured in two NPC1 subjects over four years, during 
which period IV HP-β-CD treatment was initiated under an individual expanded 
use Investigation New Drug application.  Baseline plasma cholestane-3β,5α,6β-
triol concentrations for these two subjects were 60.7 and 53.5 ng/ml (normal 
<24.5 ng/ml).  Plasma cholestane-3β,5α,6β-triol concentrations were reduced to 


47
29.8 and 18.1 ng/ml after 8-12 months of IV HPβCD.  Expressed as a 
percentage, mean reduction was 58.54 ± 10.79 
percent.  
Setting the baseline at 100%, standard deviation at 
11%, type one error at 0.05, for a two-tailed 
comparison the following table provides the number 
of subjects would be needed to achieve 90%, 80% 
and 70% power for a reduction of mean cholestane-3β,5α,6β-triol level to 90, 80 
or 70 percent of baseline.  Thus, we expect 80% power to detect a 20% 
reduction in mean cholestane-3β,5α,6β-triol levels using cohorts of 5 participants.  
A major purpose of this trial is to obtain pilot data on potential clinical outcome 
measures and biomarkers to identify outcome measures that appear to respond 
to therapy and to inform power calculations for a subsequent trial focused on 
establishing therapeutic efficacy. Thus, secondary and exploratory outcome 
measures will be evaluated independently.   
For group comparisons, such as comparing mean values of primary outcome 
measurements, the statistical significance of differences in mean values will be 
determined by a two-tailed single-factor ANOVA or Student’s t test. To perform 
correlations, such as for comparison of primary/secondary outcome data with 
NIH severity scale values or clinical assessments, data will be analyzed using 
Pearson and Spearman correlations, as appropriate. A p value of 0.05 or less will 
be considered significant and p values between 0.05 and 0.10 will be considered 
a trend. Multiple comparisons will be corrected by appropriate post-hoc analysis.  
11. Human Subjects Protection
11.1 Institutional Review Board
This protocol will be reviewed and approved by the Eunice Kennedy Shriver 
National Institute of Child Health and Human Development (NICHD) Institutional 
Review Board (IRB). The IRB will meet all FDA requirements governing IRBs 
(Code of Federal Regulations (CFR), Title 21, Part 56).
11.2 Ethical Conduct of the Study
The investigator will conduct this study in compliance with Intramural NIH policy
and FDA regulations.


48
11.3 Subject Selection
Patients will be diagnosed as having NPC1 based on criteria specified in Section 
3.5. For potential subjects for whom a definitive diagnosis is not available, the 
primary care physician may assist in obtaining these results before enrolling the 
patient to this study.
Patients currently enrolled in the Natural History Study or individuals who have 
contacted the Investigator/Sponsor for information about NPC1 studies will be 
recruited for this study. Enrollment will be optional and electing not to enroll will 
not affect participation in the Natural History Study. Patients will be recruited 
through parent support organizations such as, but not limited, to National 
Niemann-Pick Disease Foundation (NNPDF), Ara Parseghian Medical Research 
Foundation (APMRF), Dana's Angels Research Trust (DART), Support of 
Accelerated Research for Niemann-Pick Type C (SOAR-NPC), and Fight NPC. 
Information about this study will be posted on ClinicalTrials.gov. 
11.3 Gender and Ethnic/Racial Background
Patients of any gender and ethnic/racial background will be eligible for this study. 
NPC1 is an autosomal recessive disorder, thus gender distribution is expected to 
be equal. NPC1 is a panethnic disorder, but several genetic isolates, due to 
founder effects, exist. These include Acadians in Nova Scotia, Hispanics in parts 
of Colorado and New Mexico, Costa Rico and a Bedouin Group in Israel. It is 
expected that the patient’s ethnic/racial demographics will reflect disease 
demographics. The small size of this study could result in random skewing of the 
expected distribution for either gender or ethnic/racial background. 
This is a study involving a small sample size from a limited patient population 
with a rare disease. Patients will be screened to determine if they are eligible to 
participate in the trial prior to enrollment. Selection bias will be minimized as 
much as possible by screening all interested NPC1 patients until the maximum 
accrual number has been met.
11.4 Research Involving Children
We will obtain written informed consent from the parents /guardian(s) who 
accompany the child to the NIH Clinical Center (CC). If possible, consent will be 
obtained from both parents/guardians. If the second parent is unable to attend 
the visit, the second parent will be consented via telephone or another electronic 
process. If the parents are divorced and share custody we will obtain consent 
from both parents. A witness to the consent process will be present at the 
location of the individual obtaining consent.  The signed consent must be sent to 


49
the research team by fax, post, or other forms of electronic transmission. 
According to 45 CFR 46. 408 when one parent is deceased, unknown, 
incompetent or not reasonably available, or when only one parent has legal 
responsibility for the care and custody of the child, the permission of one parent 
suffices.
A screening consent may be used to allow for serum testing to establish 
chronicity of the liver disease.  This may be obtained by telephone and obtained 
by any member of the research team.  Only one parent/guardian signature will be 
required for the screening consent.  
  
Due to the age range included in this study and possibility of cognitive 
impairment, obtaining assent may not be possible. The protocol will be explained 
in an age/cognitive appropriate manner.  Verbal assent will be obtained from 
participants 7 years of age or older, unless precluded by the cognitive status of 
the child as assessed by the investigators. This verbal assent will be indicated on 
the consent document signature page by a parent or guardian. 
For individuals who are capable of providing consent, we will re-consent at the 
first NIH visit after their 18th birthday.  For cognitively impaired individuals who 
are unable to provide consent, we will consult the NIH Ability to Consent 
Assessment Team (ACAT) to determine if the guardian/parent may continue to 
provide consent. 
For individuals who are not being followed on an active NIH protocol, data and 
biomaterials will be used consistent with the prior consent. This will also be 
applicable for the period of time between a subject turning 18 and a subsequent 
NIH admission.   
With regards to the waiver of re-consent:
1.  The research constitutes no more than minimal risk since it involves 
preexisting data and biomaterials.
2.  The rights and welfare of the subjects will not be adversely affected.
3.  Obtaining re-consent from individuals who no longer being followed at 
the NIH is not practical. Direct interaction and in some cases ethics 
consultation is required to establish competency with our patient 
population.  
4.  Whenever appropriate, subjects will be provided with any additional 
information that becomes available.   
This study is consistent with 45 CFR 46.405. Specifically, the research involves 
greater than minimal risk but presents the prospect of direct benefit to the 
individual child involved in the research. Given that NPC1 is a progressive, lethal 
neurological disorder, with no FDA approved therapy, the risks in this protocol 
are commensurate with the disease process. The preclinical data in animal 


50
models suggest that the risk is justified by the potential benefit should this drug 
prove to be efficacious in humans. 
11.5 Research Involving Cognitively Impaired Patients
Because NPC1 is a progressive neurological disorder, some adult patients may 
not have the cognitive ability to provide informed consent. In this case, a parent 
or legal guardian may consent for the patient. If a patient presents to NIH and the 
ability to consent cannot be easily deduced, the NIH Ability to Consent 
Assessment Team (ACAT) will be consulted.  The ACAT team will determine if 
the guardian/parent may provide consent.
Because a consenting patient could become cognitively impaired after providing 
initial informed consent, at the time of first admission, the Investigator will request 
that the patient enact a Durable Power of Attorney for Health Care Decisions to 
guide continuation should they become cognitively impaired. 
Guardians of a cognitively impaired patient can withdraw consent for any part of 
this protocol at any time. 
 
11.6 Other vulnerable subjects
11.6.1 Pregnant women 
Pregnant women will be excluded due to use of an investigational drug and 
limited knowledge of the risks to the fetus.
11.6.2 Prisoners 
Prisoners will not be excluded. Should this situation arise, the IRB, OHSRP and 
the NIH Ethics team will be consulted, and the protocol amended accordingly.    
11.6.3 NIH Staff
We do not anticipate enrolling NIH staff but neither NIH staff nor their dependents 
will be excluded.  Exclusion would not be appropriate given the rarity of the 
disease, expertise of the NIH research team and potential benefits that are not 
available elsewhere. We will ensure that appropriate safeguards are in place per 
SOP 14F if the situation arises.  
 
11.7 Justification for sensitive procedures
Not applicable
11.8 Training of investigators


51
The Principal Investigator has verified that all individuals working on this protocol 
required to take HRPP training under OHSRP Policy 201 have completed all 
required training.  
12. Anticipated Benefit
The treatment has the potential to provide a direct benefit to the patient by 
reducing the effect of the underlying disease. The complete natural history of 
liver disease in NPC1 has not been defined. This is primarily due to early death 
secondary to neurological disease.  As therapies are developed that slow 
neurological disease progression, it is likely that other aspects of the disease will 
become apparent. Chronic liver disease in NPC1, like chronic liver disease due 
to other etiologies, can lead to development of hepatocellular carcinoma.  
This study will improve understanding of the safety and potential efficacy effects 
of administering IV VTS-270 in patients with NPC1. It also will provide us with 
information related to liver disease and biomarkers that will be of use in the 
development of other therapies. Participants and families may directly benefit 
from knowing that they are helping to increase our understanding of this 
devastating disease and participating in the development of potential therapies 
that may help others in the future.   
Participants may directly benefit from having disease specialists directly involved 
in their medical care.
No financial compensation will be offered to patients, guardians, or families. 
Travel, lodging, and per diem expenses will be covered per NICHD and NIH 
policy.
13. Classification of Risk 
13.1 Consenting adults
This study should be classified as more than minimal risk. The phone screening 
aspect of the protocol is not greater than minimal risk.
13.2 For adults unable to provide consent


52
Research involving greater than minimal risk but presenting the prospect of direct 
benefit to the individual.  The phone screening aspect of the protocol is not 
greater than minimal risk.
13.3 For children
45CFR46.405 Research involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual child.  The phone screening aspect of 
the protocol should be classified as 45CFR46.404 Research not involving greater 
than minimal risk.
13.4 Overall risk benefit consideration
NPC1 is a lethal disease with significant morbidity.  Currently there are no 
approved therapies. The risks of this study are reasonable in relation to the 
potential benefit.   
14. Consent Documents and Process
14.1 Consent process
Written informed consent will be obtained from patients or guardians as 
applicable to the specific situation prior to any intervention under this protocol. 
The informed consent form (ICF), as specified by the NIH IRB, must follow the 
Protection of Human Subjects regulations listed in the CFR, Title 21, Part 50. 
Verbal or written screening for inclusion/exclusion criteria can be conducted prior 
to obtaining informed consent. Investigators may assist families in meeting 
eligibility requirements related to miglustat and dietary supplements prior to 
enrollment.  Investigators may assist in obtaining laboratory testing to determine 
if a potential participant is likely to meet inclusion criteria related to serum 
transaminase levels.  
Screening tests (such as NPC1 mutation analysis or blood chemistry testing) or 
evaluations may be conducted under other NICHD IRB approved protocols. Data 
collected under protocol 06-CH-0186 may be used for determining eligibility 
requirements.
The background of the proposed study and the benefits and risks of the 
procedures and study will be explained to the subjects. Either the Principal 
Investigator or a designated Associate Investigator will obtain consent. The 
original signed and dated informed consent will be placed into subject’s NIH 
Clinical Center medical record. A copy will be given to the patient/guardian. 


53
See sections 11.4 and 11.5 regarding consent/assent process in children and 
cognitively impaired adults.  
14.2 Non-English–Speaking Participants
If a non-English speaking participant is eligible for enrollment, the participant will 
be provided with the CC Short Written Consent Form for Non-English-Speaking 
Research Participants in the participant’s native language and a verbal 
explanation of the purpose, procedures and risks of the study as described in 
MAS Policy M77-2, NIH HRPP SOP 12 and 45 CFR 46.117(b)(2). The IRB-
approved English consent form will serve as basis for the verbal explanation of 
the study. The investigator will obtain an interpreter unless the investigator is 
fluent in the prospective participant’s language. The interpreter will be someone 
who is independent of the participant (i.e., not a family member). Interpretation 
servicesprovided by the CC will be used. The interpreters will interpret the IRB-
approved English consent form and facilitate discussion between the participant 
and investigator.
The IRB-approved English consent form will be signed by the investigator 
obtaining consent and a witness to the oral presentation. The CC Short Written 
Consent Form will be signed by the participant and a witness who observed the 
presentation of information. The interpreter may sign the consent document as 
the witness and, in this case, will note “Interpreter” under the signature line. A 
copy of both signed forms will be provided to the participant to take home. The 
investigator obtaining consent will document the consent process in the 
participant’s medical record, including the name of the interpreter.
We request prospective IRB approval of the use of the short form for up to a 
maximum of 5 separate encounters in a given language and will notify the IRB at 
the time of continuing review of the frequency of the use of the Short Form. 
Should we reach the threshold of 5, we will notify the IRB of the need for an 
additional use of the Short Form and that we will have that consent document 
translated into the given inherent language.  
14.3.  Consent documents
Adult patient/Guardian for impaired adult or child
Minor assent
Intrathecal Consent
Screening Consent
15. Data and Safety Monitoring
15.1 Safety Monitoring


54
This is an unblinded trial, thus it can be monitored by the Principal Investigators 
in conjunction with Associate Investigators.  The Principal Investigator is 
responsible for all aspects of the study.  Regular, typically weekly, meetings will 
be held by the research staff to review status of all subjects, potential issues and 
possible adverse events.
This protocol does not meet the criteria as outlined in the NIH HRPP SOP 17 for 
data to be submitted to a data safety monitoring committee.  
15.2 Data Monitoring 
The research team will be responsible for monitoring data.   The Principal 
Investigator is responsible for data integrity.  Although all members of the 
research team will participate in data collections and review, Kisha Jenkins RN is 
the designated lead who will review data for accuracy and completeness.   
15.3 IRB and FDA documentation
   
Protocol documentation related to IRB and FDA will be maintained in IRIS until 
NIH transfers all protocols to a centralized system 
16. Quality Assurance
Quality assurance and quality control systems with written SOPs will be 
implemented and maintained to ensure this trial will be conducted and data will 
be generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements.
NICHD Office of the Clinical Director will perform quality assurance audits of this 
protocol consistent with applicable policy.
NICHD Office of the Clinical Director will contract for outside quality assurance 
audit of this protocol consistent with applicable policy.     
17. Reporting of Unanticipated Problems, Adverse Events and 
Protocol Deviations
17.1 Definitions
Adverse event:  An adverse event (AE) means any untoward medical 
occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 


55
Suspected adverse reaction:  This is defined as any AE for which there is a 
reasonable possibility that the drug caused the AE. For the purposes of IND 
safety reporting, ‘‘reasonable possibility’’ means there is evidence to suggest a 
causal relationship between the drug and the AE. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any AE caused by a drug.
Life-Threatening AE or Life-Threatening Suspected Adverse Reaction: An 
AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the view 
of the Investigator/Sponsor, its occurrence places the patient at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.
Serious Adverse Event or Serious Suspected Adverse Reaction:  An AE or 
suspected adverse reaction is considered ‘‘serious’’ if, in the view of the 
Investigator/Sponsor, it results in any of the following outcomes: 
1.  Death
2.  A life-threatening adverse event
3.  Inpatient hospitalization or prolongation of hospitalization
4.  A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions
5.  A congenital anomaly/birth defect
Unexpected AE or Unexpected Suspected Adverse Reaction: An AE or 
suspected adverse reaction is considered “unexpected” if it is not listed in the 
protocol or consent, or is not listed at the specificity or severity that has been 
observed. 
17.2 Adverse Event Classification
Relationship to Investigational Drug: The following two classifications should 
be used when evaluating the relationship of AEs and serious adverse events 
(SAEs) to the investigational drug:
1. Unrelated: no temporal association or definitely due to an alternative etiology 
2. Unlikely Related: no clear temporal association or good evidence for a more 
likely alternative etiology
3. Possibly Related: temporal association, evidence exists for alternative etiology
4. Likely Related: temporal association follows a suspected response pattern 
(based on similar agents), a more likely alternative etiology unlikely 


56
5. Definitely Related: clear temporal association follows a known response 
pattern, clear evidence to suggest a causal relationship, there is no alternative 
etiology.
17.3 Severity of an Adverse Event
Severity will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (Published: 27 
November 2017). 
17.4 Investigator Reporting
Reportable events will be tracked and submitted to the IRB as outlined in policy 
801.  
Relatedness to the research of all serious adverse events will be determined by 
the PI in consultation with the SD. 
Deaths will be reported to the Scientific Director within 7 days after the PI first 
learns of the event. 
17.5 Documentation of Adverse Events
Patients will be evaluated and interviewed to identify AEs during the course of 
the study. AEs may also be identified through clinical and neurological 
examinations, laboratory tests, etc. Any events occurring prior to dosing will be 
recorded on the Medical History CRF. Events occurring after administration of 
the first dose of study medication will be recorded on the AE CRF. AE that occur 
up to and including 30 days after administration of the last dose of study drug 
must be reported. 
All AEs spontaneously reported by the patient or in response to a question from 
study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the Adverse Event Form for that visit. 
Any clinically relevant deterioration in laboratory assessments or other clinical 
findings is considered an AE and must be recorded on the AE CRF, unless 
otherwise stated in the protocol. AE information recorded on AE CRFs will be 
entered into the database on an ongoing basis. 
For SAEs, a Serious Adverse Event Form must also be completed with as much 
information as possible and submitted in the time frame described below. When 
new significant information is obtained as well as when the outcome of an event 
is known, the Investigator should record the information on a new SAE form. If 
the patient was hospitalized, a copy of the discharge summary and any other 


57
relevant hospital records (e.g. admission report, laboratory test results, etc., must 
be included as part of the patient medical file).
 
All AEs considered to be related to study medication and all SAEs will be 
followed until resolved or until stable. 
17.6 Non-Reportable Events
The following data will be collected but the following will not be reported to the 
NICHD IRB as adverse events.
 
1.  Findings present at initial evaluation.
2. Abnormal laboratory tests that have no clinical consequence.
3. Abnormal clinical tests in which the clinical response would be 
considered standard care (such as iron supplementation of iron 
deficiency anemia) and are unlikely to be related to the protocol.
4. Problems listed in Table 2 unless increase in frequency is noted.
17.7 Protocol Deviations
The following anticipated minor deviations in the conduct of the protocol will not 
be reported to the NCIHD IRB unless they occur at a rate greater than that which 
is anticipated to occur (frequency will be assessed over ten protocol admissions).
Expected 
Frequency
Inability to obtain a blood or urine sample 
     20%
Technical issues preventing analysis of a blood 
   sample (e.g. hemolysis)
     20%
Procedure or sample not obtained at specified time
     20%
Admission occurring outside of the defined time range
     20%
Not obtaining a sample/data related to an exploratory endpoint will not be 
considered a deviation.   
18. Alternatives to Participation 
There are no approved therapies for NPC1.  Potential participants have the 
option of requesting HPβCD under an expanded access IND or participating in 
clinical trials that are not associated with the NIH.    


58
All NPC1 patients remain eligible for enrollment or continued participation in our 
Natural History protocol (06-CH-0186).    
19. Privacy
Research activities will be conducted in a manner to protect privacy to the extent 
possible.  
Table 2.  Adverse events associated with NPC1


59
Category
Adverse Event
Eyes
Ptosis
Abnormal eye movements (including vertical supranuclear gaze palsy 
and abnormalities of both vertical and horizontal eye movements)
Audiologic
Progressive high frequency hearing loss
Abnormalities in Behavioral Hearing tests and Auditory Brain Stem
Responses
HEENT
 
Oromotor/Speech 
Dysarthria
Dysphagia, choking/gagging on food or saliva
Copious secretions/drooling
Aspiration
Aspiration pneumonia
Respiratory
Sleep apnea 
Hepatomegaly
Elevated liver enzymes
Splenomegaly
Gastrostomy tube related to dysphasia
Bladder/bowel incontinence
Diarrhea 
Gastrointestinal/ Genitourinary
Constipation
Lymphatic
Enlarged tonsils and adenoids
Epistaxis
Thrombocytopenia and prolonged PT/PTT
Hematologic
Decreased serum iron, % saturation (not typically associated 
with low MCV)
Hyperreflexia, clonus
Musculoskeletal/Extremities
Motor impairment
Gross motor ataxia; impaired ambulation, balance, 
Coordination; decreased muscular strength; muscle contractures
Fine motor ataxia, tremor
Seizures
Cognitive Impairment: 
Learning difficulty, long/short term memory loss 
Sleep Disruptions:
Gelastic cataplexy
Narcolepsy
Sleep schedule inversion
Neurological
Fatigue, daytime sleepiness
Mood swings, diagnosis of major depressive disorder, bipolar 
disorder, schizophrenia 
Psychiatric/Behavioral
ADD/ADHD diagnosis (not more common than in general pediatric
population)
ADD: attention deficit disorder; ADHD: attention deficit hyperactivity disorder; HEENT: head, eyes, ears, 
nose, throat; MCV: mean corpuscular volume


60
20. Confidentiality
20.1 Research Data and Medical Records
To maintain patient privacy, all CRFs, study drug accountability records, study 
reports, and communications will identify the patient by the assigned patient 
number. The Investigator will grant monitor(s) and auditor(s) from the Sponsor or 
its designee and regulatory authority(ies) access to the patient’s original medical 
records for verification of data gathered on the CRFs and to audit the data 
collection process. The patient’s confidentiality will be maintained and will not be 
made publicly available to the extent permitted by the applicable laws and 
regulations.
Research data will be maintained on password protected computers.  Laptops 
containing clinical information will be encrypted per NIH policy.  Hard copy 
patient records will be maintained in secured files/offices.   
Participants/guardians will be notified that registration information, results, and 
other information about this study will be submitted to ClinicalTrials.gov, a 
publicly available trial registry database; however, protected health information of 
individual patients will not be used.
20.2 Stored samples
The NICHD Biorepository will be used to store samples.  Samples will be coded. 
Working aliquots and samples sent to collaborators will be coded.  Samples sent 
to a clinical, CLIA certified laboratory will be labeled with patient identifiers and 
the report will become part of the participants NIH medical record.   
21. Conflict of Interest
NIH guidelines on conflict of interest will be distributed to all investigators.  
Dr. Forbes D. Porter has been awarded or has filed patent application related to 
the identification and use of biomarkers in Niemann-Pick disease type C.  Some 
of these biomarkers will be tested in this protocol.  Additional patent applications 
may be filed by institutions involved in this study that relate to the treatment or 
monitoring of therapy for NPC1.  
Dr. Forbes D. Porter and NICHD have a Cooperative Research Agreement with 
Vtesse, Inc for the development of intrathecal VTS-270. Vtesse, Inc. has been 
acquired by Sucampo which has now been acquired by Mallinckrodt. Dr. Porter is 
a Co-Principal Investigator for the Vtesse, Inc. Sponsored Phase 2b/3 study of 


61
intrathecal VTS-270. Dr. Porter does not receive any compensation from Vtesse, 
Sucampo or Mallinckrodt.  
Mallinckrodt will provide the VTS-270 for this study and may provide additional 
support to facilitate completion of this study.  Mallinckrodt may use data obtained 
from this study to develop VTS-270 as a commercial product.  Personal 
identifiers will not be supplied to Mallinckrodt.  This CRADA has been reviewed 
by NIH ethics.  Other formal agreements, such as a confidentiality, material 
transfer or clinical  trial agreements, may be established between NICHD and 
Mallinckrodt to facilitate this trial.  All agreements will be reviewed by NIH ethics 
per policy.
Collaborating or associate investigators who are not part of the NIH may have 
funding or consulting relationships with pharmaceutical companies developing 
therapies for NPC1. Although these collaborating or associate investigators 
provide invaluable input, they are not responsible for the implementation of this 
protocol at the NIH Clinical Center. Although members of the team may interact 
with pharmaceutical companies as part of their official duties, NIH investigators 
do not receive financial compensation or have personal financial holdings (above 
the limits set by the NIH) with pharmaceutical companies.
This protocol is supported by an Opportunities for Collaborative Research at the 
NIH Clinical Center U01 grant (U01 HD090845). The extramural principal 
investigator is Dr. Daniel S. Ory, Washington University.   The intramural 
principal investigator is Dr. Forbes D. Porter, NICHD.  
22. Technology Transfer
We will establish a material transfer agreements and notify the NICHD IRB 
consistent with current applicable NIH DIR policy. 
Material transfer agreements with commercial entities will be submitted as 
amendments to this protocol prior to implementation.   
23. Research and Travel Compensation 
No financial compensation will be offered to patients, guardians, or families. 
Travel, lodging, and per diem expenses will be covered per NICHD and NIH 
policy.
NIH employees or staff who participate during work hours must have permission 
from their supervisor.


62
24. References
1.
Ory, D.S., et al., Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases 
neurological disease progression in Niemann-Pick disease, type C1: a non-
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Attachment 1:  Schedule of Events


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