Conditions: Niemann-Pick Disease, Type C
Keywords: Niemann-Pick Type C1 (NPC1) Disease neurologic disease gross motor dysfunction fine motor dysfunction dysphagia swallowing problems cognitive dysfunction gait abnormalities pediatrics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
Due to different study designs, the sponsor separated Part C into a separate registration (NCT04958642), leaving Parts A/B here in NCT02534844.

This study is to find out how safe and effective VTS-270 is for patients with Niemann-Pick Type C1 (NPC1) disease who have neurologic symptoms (listed under Keywords).

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

In Part C, all participants will receive study drug, as described in the Part C registration record.

Start date for this record is the first day a participant was enrolled in Parts A/B. The trial is actually continuing until the last primary outcome measure of safety data are collected from Part C participants. The last primary outcome measure of safety, along with final adverse events results will be posted in the separate Part C registration record.

Detailed description:
Non-clinical studies and a Phase 1 clinical trial suggest that intrathecal administration of VTS-270 in patients with neurologic manifestations of Niemann-Pick Type C1 (NPC1) disease has the potential to slow the rate of progression of their neurologic disease.

Niemann-Pick Type C1 (NPC1) disease is a rare, neurodegenerative, inherited, autosomal recessive lysosomal lipid storage disorder primarily in children and teenagers. The disease is characterized by the inability to properly metabolize cholesterol and other lipids within the cell due to mutations in the NPC1 gene, causing unesterified cholesterol to accumulate in the brain, liver and spleen.

This study plans to enroll about 51 participants with NPC1 disease. It will be conducted in three parts: Parts A, B, and C.

* Part A will evaluate 3 different dose levels of VTS-270 in 12 participants to determine the dose level for Parts B and C.
* In Part B, 39 more participants will join the original 12 to evaluate the safety and effectiveness of the dose selected from Part A compared to sham control.
* Part C will be an open-label extension phase of the study for Part B participants who either complete Part B or have met rescue therapy criteria, as well as participants entering Part C from other trials.

Participants in Part C will receive treatment with VTS-270 until the product is licensed or the program is terminated (anticipated within 5 years).

Final results will be posted in the Part C registration record (NCT04958642).

Arms:
arm 1: Participants receive no study drug arm 2: Participants receive adrabetadex

Interventions: intervention 1: Parts A/B: Adrabetadex intervention 2: Parts A/B: Sham Control
Intervention descriptions: intervention 1: 900 - 1800 milligram (mg) of adrabetadex administered every 2 weeks via lumbar intrathecal infusion intervention 2: No experimental drug is administered to participants - intrathecal administrations are simulated by skin prick

Protocol document:
Prot_000.pdf: 
Vtesse, Inc. a Mallinckrodt Pharmaceutical Company 
Clinical Research 
Protocol 
 
Version 2.0 
Protocol Synopsis for Parts A/B 
Full protocol to be disclosed with Part C Results 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham-Controlled Trial 
of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic 
Manifestations of Niemann-Pick Type C1 (NPC1) Disease 
Protocol Number: 
VTS301 
Version Number: 
– Version 2.0 
Version Date: 
18 October 2019 
Investigational Product: 
VTS-270 (specific and well-characterized mixture of 
2-hydroxypropyl-β-cyclodextrin [HP-β-CD])
IND Number: 
 
EudraCT Number: 
2015-002548-15 
Development Phase: 
2b/3 
Sponsor: 
Vtesse, Inc a Mallinckrodt Pharmaceutical Company 
1425 US Route 206 
Bedminster, NJ 07921 
Co-Principal Investigator: 
Name: 
 Telephone: 
 
Fax: 
 
E-mail: 
Co-Principal Investigator 
Name: 
 Telephone: 
 
Fax: 
 
E-mail: 
 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document may not be 
disclosed unless federal or state law or regulations require such disclosure. Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who have a need to know, with the 
obligation not to further disseminate this information. 
NCT #NCT02534844


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 17 of 136 
Confidential and Proprietary 
5.
PROTOCOL SYNOPSIS
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
Sponsor 
Vtesse, Inc a Mallinckrodt Pharmaceutical Company 
1425 US Route 206 
Bedminster, NJ 07921 
Number of Sites 
Approximately 24 sites worldwide 
Study Design 
This is a multicenter, multinational, prospective, randomized, double-blind, sham-controlled, 
3-part, efficacy and safety trial of VTS-270 administered by the lumbar intrathecal (IT) route
every 2 weeks, with a planned enrollment of approximately 51 subjects (in Parts A and B)
with Niemann-Pick type C1 (NPC1) disease. The study will be conducted in 3 parts: Parts A,
B, and C.
Part A evaluated 3 different dose levels of VTS-270 versus sham control, administered as 4 
lumbar IT injections every 2 weeks, to determine the dose level for Parts B and C. A total of 
12 subjects were enrolled and have completed Part A. 
Part B will evaluate the safety and efficacy of the dose selected from Part A, 900 mg, 
compared with sham control in approximately 51 subjects, including the 12 subjects from 
Part A. Subjects will receive treatment with VTS-270 for up to 52 weeks (inclusive of Part 
A). Subjects who elect not to continue with Part C will have 26 weeks of follow-up. 
Part C will be an open-label extension phase of the study. Subjects who complete Part B, 
meet the criteria for dose reduction for a second time, or meet the rescue therapy criteria after 
6 months of participation in Part B are eligible to participate in Part C. Subjects who are 
currently active in the National Institutes of Health (NIH) phase 1 study (Protocol 13-CH- 
0001) will also be eligible to participate upon completion of their participation in the phase 1 
study. Additionally, subjects who have received prior written authorization from Vtesse to 
enroll directly into Part C are eligible to participate. Part A and B subjects who transition into 
Part C will receive treatment with VTS-270 until the investigator considers VTS-270 to no 
longer be beneficial, VTS-270 receives marketing authorization, or the development program 
is discontinued. NIH phase 1/2a subjects who transition into Part C will receive treatment 
with VTS-270 until the investigator considers VTS-270 to no longer be beneficial to the 
subject, VTS-270 receives marketing authorization, or the development program is 
discontinued. 
A European site-specific substudy will be conducted as part of the Part C study. This 
substudy will assess the safety and tolerability of the B. Braun Celsite® Spinal Access Port 
System (hereafter generally referred to as the “device”) for the administration of VTS-270 
every 2 weeks. The device is CE marked in Europe and consists of a subdermal access port 
connected to a catheter that is positioned in the lumbar IT space. Given that VTS-270 does 
not penetrate the blood-brain barrier and requires IT administration, the ability to administer 
VTS-270 via the device will obviate the need for biweekly lumbar punctures (LPs), as well as 
anesthesia, thereby removing a significant burden for subjects and site personnel. In this 
device safety and tolerability substudy, approximately 6 eligible Part C subjects who have 
received at least 3 lumbar IT doses (900 mg VTS-270) in Part C will undergo baseline 
assessments approximately 3 days prior to implantation of the device (same day as their last 
administration of VTS-270 via LP). The device will be implanted in the hospital, and the 
subject will remain in the hospital for 2 additional days post implantation. During the 3-day 
confinement period (Day 1 surgery, Days 2 and 3), subjects will be given intravenous (IV) 
antibiotics, which are part of the routine implantation procedure. 
Subjects entering the European site-specific device safety and tolerability substudy will 
continue on their Part C schedule of assessments but will have additional device safety 


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 18 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
evaluations. After a minimum of 2 weeks after placement of the device and confirmation of 
catheter patency, subjects will receive their VTS-270 dose via device infusion. Dosing will 
continue every 2 weeks for a total of 9 doses via the device. Specific evaluations will be 
conducted during the treatment period to assess device safety. These visits, designated Visit 
D1 through Visit D9, will occur at the same time as the subject’s Part C schedule. Where 
there is duplication of assessments with the Part C schedule, only 1 assessment will be 
conducted. Following 9 device infusions of VTS-270 and the specific device safety 
assessments conducted during the treatment period, subjects will either enter the device 
pharmacokinetic (PK) substudy described below or will remain in the main Part C study and 
continue to receive VTS-270 via the device to evaluate its long-term safety and tolerability. 
A European site-specific device PK substudy will also be conducted and include 
approximately 6 eligible subjects under Part C of the VTS301 study. Eligible subjects will 
have completed the device safety and tolerability substudy, i.e., received 9 consecutive doses 
of 900 mg VTS-270 via the device. In addition, after 6 subjects have completed the device 
safety and tolerability substudy, subjects in the main Part C study who are on a stable dose of 
900 mg VTS-270 via LP and eligible for device insertion will be eligible to participate in the 
European site-specific device PK substudy. During a single dosing session using the device, 
blood and CSF samples will be collected just before VTS-270 infusion and 1, 2, 4, 6, 8, 
approximately 24, and approximately 30 hours after infusion. The 30-hour time point should 
be at least 6 hours after the 24 hour time point. Subjects who enter the device PK substudy 
from the main Part C study must receive at least 3 device infusions of 900 mg VTS-270 
before PK assessments are performed. Following the full PK assessment visit, subjects will 
continue in the main Part C study and have CSF samples collected for measurement of trough 
2-hydroxypropyl-β-cyclodextrin (HP-β-CD) concentration prior to each subsequent device
infusion of VTS-270.
Dose Reduction 
The following are guidelines for which dose reduction on an individual subject basis is 
allowed in Part B: 
Subjects who, in the opinion of the investigator, experience a drug-related adverse event (AE) 
after any blinded IT treatment that is considered clinically relevant and impactful to the 
subject’s function may have their dose reduced to 600 mg per IT administration for 
subsequent IT dosing intervals following discussion with the unblinded medical monitor. If, 
following dose reduction to 600 mg, a subject continues to experience AEs as described 
above, the subject’s dose may be further reduced to 400 mg per IT administration for 
subsequent dosing intervals following discussion with the unblinded medical monitor. 
If, following dose reduction to 400 mg, a subject continues to experience a drug-related 
clinically relevant AE, the dose is NOT to be reduced further and the subject is to be 
discontinued from Part B of the study, being given the option to transition into Part C at a 
lower dose, based on discussion with the unblinded medical monitor and on a case-by-case 
basis. 
During Part C, the same guidelines apply for dose reduction, with each subject for whom dose 
reduction is considered being individually reviewed with the medical monitor. 
Dose 
Re-Escalation 
Under specific circumstances, and after discussion with and approval by the medical monitor, 
an investigator may be allowed to re-escalate the dose for an individual study subject in Part 
C. If a subject has had his/her dose reduced and is in Part C on a tolerable dose, the subject
may be dose titrated back up (e.g., from 400 mg to 600 mg and from 600 mg to 900 mg) to a
tolerable dose as determined by the investigator.
Rescue Option 
Subjects who are enrolled in Part B and manifest significant disease progression according to 
predefined clinical criteria after 26 weeks or more of treatment will have the option to enter 


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 19 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
Part C. The blinded medical monitor will notify the blinded Rescue Option Criteria 
Committee (ROCC). Alternatively, a blinded site clinician may contact the blinded medical 
monitor to request a blinded ROCC review if he/she feels the disease symptoms have 
progressed substantially since the beginning of the trial. If a subject still meets criteria for 
predefined worsening at the confirmatory visit, the ROCC will make a recommendation as to 
whether the subject has the option to enter the open-label extension study or to withdraw from 
the program. 
Primary Objective 
Part A: 
The primary study objective in Part A was to select the dose of VTS-270 to be used in Part B 
and Part C. Dose selection criteria included safety and tolerability including a thorough 
audiologic evaluation. Preliminary efficacy data was provided to the Dose Selection 
Committee (DSC) to assist, if necessary, in dose selection. 
Part B: 
The primary study objective in Part B is to evaluate, in a double-blind sham-controlled 
design, the progression of the neurologic manifestations of NPC1 disease following 52 weeks 
of treatment for subjects treated with VTS-270 compared to sham control, using the following 
assessments: 
•
The NPC-SS composite which consists of the sum of 4 components of the
Niemann Pick Type C Severity Scale (NPC-SS): ambulation, fine motor,
cognition, and swallowing.
•
The blinded Clinician-Global Impression of Change (CGIC)
Part C: 
The primary study objective in Part C is to evaluate the long-term safety, tolerability, and 
efficacy of VTS-270. 
Secondary 
Objectives 
Part A: 
There are no secondary objectives for Part A. 
Part B: 
The secondary objectives for Part B are divided into 2 categories: key secondary objective 
and other secondary objectives. 
The key secondary objective for Part B is to evaluate the progression of the neurologic 
manifestations of NPC1 disease using the total NPC-SS score, excluding the hearing domain 
and auditory brainstem response (ABR) modifier results, following 52 weeks of treatment for 
subjects treated with VTS-270 compared to sham controls and the Caregiver CGIC. 
Other secondary objectives are to: 
1.
Evaluate the Safety and Tolerability of VTS-270 Administered IT Via LP Every
2 Weeks, Compared to Sham Control
2.
Assess Quality of Life Using the EQ-5D-3L Following 52 Weeks of Treatment
for Subjects Treated for 52 Weeks with VTS-270 Compared to Sham Controls
3.
Further Assess the Efficacy of VTS-270 on Treating the Neurologic Symptoms
of NPC1 by Comparing Subjects Treated for 52 Weeks with VTS-270
Compared to Sham Control on:
•
Subjects Who Required Rescue Following At Least 6 Months of Treatment
•
the 9 Major Domains of the NPC-SS
•
the Total NPC-SS Score (Hearing Domain and ABR Modifier Included)
•
Time to a One Point Increase (Worsening) on the NPC-SS Composite Score


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 20 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
•
the Annualized Rate of Change (Slope) of The NPC-SS Composite
•
Timed Up And Go (TUG) Test
•
9-Hole Peg Test
Part C: 
The secondary study objectives in Part C are to: 
1.
Assess the safety and tolerability of the B. Braun Celsite Spinal Access Port
utilized to administer VTS-270 (device safety and tolerability substudy).
2.
Assess the plasma and CSF PK of VTS-270 and trough HP-β-CD concentration
in subjects receiving the 900 mg dose of VTS-270 via the B. Braun Celsite
Spinal Access Port (device PK substudy).
Exploratory 
Objectives 
Part A: 
There are no exploratory objectives for Part A. 
Part B: 
The exploratory study objectives in Part B are to: 
•
Collect cerebrospinal fluid (CSF), urine, and plasma samples from the subjects
receiving study drug, and urine and plasma samples from subjects randomized
to sham control, will be collected at prespecified intervals and stored for
exploratory biomarker analyses.
•
Further evaluate the efficacy of VTS-270 on treating the neurologic symptoms
of NPC1 by comparing subjects treated with VTS-270 compared to sham
control on:
1.
The composite NPC-SS in completers.
2.
The composite NPC-SS outcome assuming data missing at random using a
standard multiple imputation model
3.
The composite NPC-SS using a pattern mixture model
4.
Assigning individual subject changes (+1 if improved, 0 if unchanged, or -
1 if worse relative to baseline)
Part C: 
There are no exploratory objectives for Part C. 
Number of 
Subjects 
Approximately 51 in Parts A and B. 
Part C may enroll more than 51 subjects. 
Approximately 6 in the device safety and tolerability and device PK substudies. 
Subject Selection 
Criteria 
Parts A and B 
Inclusion Criteria: 
Subjects must meet the following criteria to be included: 
1.
Male or female subjects, 4 to 21 years of age at time of screening, with onset of
neurological symptoms prior to 15 years of age.
2.
Diagnosis of NPC1 determined by one of the following:
a. Two NPC1 mutations;
b. Positive filipin staining or oxysterol testing and at least one NPC1 mutation;
c. Vertical supranuclear gaze palsy (VSNGP) in combination with either:
i.
One NPC1 mutation, or
ii.
Positive filipin staining or oxysterol levels consistent with NPC1
disease and no NPC2 mutations.


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 21 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
3.
Subject or parent/guardian must provide written informed consent to participate
in the study. In addition to parental consent, assent to participate must also be
sought from minor children.
4.
Ability to undergo a LP and IT drug administration under monitored anesthesia
care (conscious sedation) or if medically necessary, general anesthesia.
5.
An NPC-SS score of 0 through 4, inclusive, on the cognition component, and 1
through 4 in two or more of the following components: ambulation, fine motor
skills, or swallowing.
6.
Total NPC-SS score of 10 or greater.
7.
Subjects with adequately controlled seizures may qualify for enrollment.
Subjects with a history of seizures should have a stable pattern of seizure
activity and be on a stable dose and regimen of antiepileptic medication during
the 3 months prior to screening without change in dose or regimen up to and
including Study Day 0.
8.
If taking miglustat, must have been on a stable dose for the past 6 to 8 weeks
and be willing to remain on a stable dose for the duration of participation in
Parts A and B of the study. Alternatively, subjects may elect to discontinue
miglustat use and be eligible for trial entry after undergoing a minimum 6-week
washout period prior to Study Day 0.
9.
Agree to discontinue all nonprescription supplements such as coenzyme Q10,
curcumin, cinnamon, fish oil supplements, high-dose vitamin D
(> 500 mIU/day), N-acetylcysteine, acetylleucine, or gingko biloba at least
1 month prior to first dose (Study Day 0). Note: Daily administration of an age- 
appropriate multivitamin is allowed.
10. Agree to discontinue any other investigational treatments for NPC including, for
example, vorinostat or arimoclomol at least 3 months prior to first dose (Study
Day 0).
11. Females of childbearing potential (not surgically sterile) must use a medically
acceptable method of contraception and must agree to continue use of this
method for the duration of the study and for 30 days after participation in the
study. Acceptable methods of contraception include barrier method with
spermicide, intrauterine device, steroidal contraceptive in conjunction with a
barrier method, or abstinence.
12. Subject or caregiver must possess the ability, per the investigator, to understand
and comply with protocol requirements including clinical outcome
measurements and instructions for the entire duration of the study.
13. Caregiver, parent, guardian or responsible adult must be able and willing to
accompany the subject to study visits.
Exclusion Criteria: 
Subjects meeting any of the following criteria are to be excluded: 
1.
Exclusion criteria as assessed by NPC-SS:
a.
Unable to walk, wheelchair dependent (ambulation score = 5).
b.
Needs a nasogastric tube or gastric tube for all feedings (swallowing score
= 5). Note: Nasogastric or gastric tube use for supplemental feeding or
medication administration is permitted and will not exclude a subject from
this trial.
c.
Severe dysmetria (fine motor score = 5).
d.
Minimal cognitive function (cognition score = 5).
2.
Body weight < 15 kg.


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 22 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
3.
Prior treatment with IV 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for NPC1
disease, unless the subject has undergone a minimum 3-month washout period
prior to Study Day 0. Note: Any prior IT administration of HP-β-CD for the
treatment of NPC1 disease will exclude a subject from enrollment. Treatment of
other medical conditions with drug preparations containing HP-β-CD as an
excipient (inactive ingredient) is acceptable and will not exclude a subject from
immediate entry into this trial (no washout period required).
4.
Status epilepticus occurring within 3 months of screening and/or seizure
frequency that cannot be quantified.
5.
Subjects on typical or atypical antipsychotics for treatment of psychosis. Note:
Use of antipsychotic medication for treatment of other disorders (e.g., attention
deficit hyperactivity disorder) will not exclude a subject from this trial.
6.
History of hypersensitivity reactions to any product containing HP-β-CD.
7.
Prior treatment with any other investigational product within 3 months prior to
first dose (Study Day 0).
8.
Female subjects who are pregnant or nursing.
9.
Subjects with suspected infection of the central nervous system (CNS) or any
systemic infection.
10. Spinal deformity that could impact the ability to perform a LP.
11. Skin infection in the lumbar region within 2 months of study entry.
12. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 ×
109/L.
13. Thrombocytopenia (platelet count less than 75 × 109/L).
14. Activated partial thromboplastin time (aPTT) or prothrombin time (PT)
prolonged by greater than 1.5 times the upper limit of normal (ULN) or known
history of a bleeding disorder.
15. Evidence of obstructive hydrocephalus or normal pressure hydrocephalus.
16. Recent use of anticoagulants (in past 2 weeks prior to first dose [Study Day 0]).
17. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater
than 4 times the ULN.
18. Anemia: hemoglobin more than 2 standard deviations below normal for age and
gender.
19. Estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73m2 calculated
using the modified Schwartz formula (2009) for subjects aged 6 through
17 years old or using the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula for subjects aged 18 years or older.
20. Active pulmonary disease, oxygen requirement, or clinically significant history
of decreased blood oxygen saturation, pulmonary therapy, or requiring active
suction.
21. Subjects who, in the opinion of the investigator, are unable to comply with the
protocol or have medical conditions that would potentially increase the risk of
participation.
22. Life expectancy less than 1 year.
Part C 
Inclusion Criteria: 
1. Subject has completed Part B, meets the criteria for dose reduction for a second
time or meets the criteria for the rescue option
OR


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 23 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
2.
Subject is a current participant in the NIH phase 1/2a open-label study and:
a.
Subject agrees to convert from the dose of VTS-270 currently receiving as a
subject in the NIH phase 1/2a protocol to the dose chosen for Parts B and C
of this study, 900 mg;
b.
Subject agrees to convert from the monthly dosing regimen used in the NIH
phase 1/2a protocol to an every 2-week dosing regimen.
c.
In instances where NIH phase 1/2a subjects eligible to enroll into Part C are
unable to convert from their current NIH phase 1/2a dose or monthly
regimen, the investigator must receive prior written authorization from the
sponsor for the subject to enter Part C of the study on an amended dose
and/or regimen.
OR
3.
Subject has received prior written authorization from Vtesse to enroll directly
into Part C.
4.
Females of childbearing potential (not surgically sterile) must use a medically
acceptable method of contraception and must agree to continue use of this
method for the duration of the study and for 30 days after participation in the
study. Acceptable methods of contraception include barrier method with
spermicide, intrauterine device, steroidal contraceptive in conjunction with a
barrier method, abstinence, or same-sex partner.
5.
Subject or parent/guardian must provide written informed consent to participate
in the study. In addition to parental consent, assent to participate must also be
sought from minor children.
Subject Inclusion Criteria for European Site-Specific Device Safety and Tolerability 
Substudy 
The European site-specific device safety and tolerability substudy will evaluate 
approximately 6 subjects who are currently enrolled in VTS301 Part C. 
A subject must meet all the following inclusion criteria to be eligible to enroll in the 
substudy: 
1.
Subject must be enrolled in Study VTS301 Part C.
2.
Subject must have received a minimum of 3 doses of VTS-270 (900 mg each) in
Part C of Protocol VTS301 (frequency of every 2 weeks) and be on a stable
dose to be eligible for device placement.
3.
Subject or parent/guardian must provide written informed consent to participate
in the study. In addition to parental consent, assent to participate must also be
sought from minor children.
4.
Females of childbearing potential (not surgically sterile) must use a medically
acceptable method of contraception and must agree to continue use of this
method for the duration of the study and for 30 days after participation in the
study. Acceptable methods of contraception include barrier method with
spermicide, intrauterine device, steroidal contraceptive in conjunction with a
barrier method, abstinence, or same-sex partner.
5.
Subject or caregiver must possess the ability, in the judgment of the
investigator, to understand and comply with protocol requirements, including
clinical outcome measurements and instructions, for the entire duration of the
study.
6.
Caregiver, parent, guardian, or responsible adult must be able and willing to
accompany the subject to study visits.


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 24 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
Subject Exclusion Criteria for the European Site-Specific Device Safety and Tolerability 
Substudy 
The presence of any of the following excludes a subject from substudy enrollment: 
1.
Musculoskeletal/spinal abnormality or other anatomic abnormality identified by
symptoms, history, physical/neurological examination, and/or imaging studies
that would impact placement and patency of the device (port and catheter).
2.
Skin infection in the lumbar or abdominal region within 3 months prior to
device placement.
3.
Subjects who, in the opinion of the investigator, are unable to comply with the
protocol or have disease severity or medical conditions that would potentially
increase the risk of participation or confound study results.
4.
Subjects with suspected or confirmed infection of the CNS or any systemic
infection.
5.
Absolute neutrophil count less than 1.5 × 109/L.
6.
Platelet count less than 100 × 109/L.
7.
aPTT or PT greater than 1.5 times the ULN or known history of a bleeding
disorder.
8.
Requirement for anticoagulation therapy.
9.
Evidence of obstructive hydrocephalus or normal pressure hydrocephalus based
on symptoms, history, and physical/neurological examination, or elevated
intracranial pressure (ICP; opening ICP > 25.0 cm H2O).
10. AST or ALT greater than 4 times the ULN, or total bilirubin greater than 2
times ULN.
11. Anemia: hemoglobin more than 2 standard deviations below normal for age and
gender.
12. eGFR less than 60 mL/minute/1.73 m2 calculated using the modified Schwartz
formula (2009) for subjects aged 4 through 17 years or using the CKD-EPI
formula for subjects aged 18 years or older.
13. Active pulmonary disease, oxygen requirement, or clinically significant history
of decreased blood oxygen saturation, pulmonary therapy, or requiring active
suction.
14. Hypersensitivity to any materials contained in the device port or catheter.
15. Subjects with a CNS shunt.
16. Prior radiation therapy to the area for device placement.
17. Expected need for magnetic resonance imaging during participation in the study,
with exception of the following allowable conditions for safe scanning
immediately after device placement:
a.
Static magnetic field of 3 Tesla and 1.5 Tesla
b.
Maximum spatial gradient magnetic field of 710 Gauss/cm or less
c.
Maximum whole body averaged specific absorption rate of 2.9 W/kg for 15
minutes of scanning
Subject Inclusion Criteria for the European Site-Specific Device Pharmacokinetic (PK) 
Substudy 
A subject must meet the following inclusion criteria to be eligible to enroll in the device PK 
substudy: 
1. Subject has completed the device safety and tolerability substudy and received 9
consecutive doses of 900 mg VTS-270 via the device


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 25 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
Or 
2.
After 6 subjects have completed the device safety and tolerability substudy,
subjects in the main Part C study who are receiving a stable dose of 900 mg
VTS-270 via LP and are eligible for device implantation per the above
eligibility criteria for the device safety and tolerability substudy.
3.
Subject or parent/guardian must provide written informed consent to participate
in the study. In addition to parental consent, assent to participate must also be
sought from minor children.
Test and Control 
Product, Dose, 
and Route of 
Administration 
VTS-270 will be provided in appropriately labeled vials, formulated as a 200 mg/mL 
injectable solution. An unblinded pharmacist/designee at each investigational site will be 
responsible for dispensing or preparing the assigned dosage of 900 mg for administration in 
4.5 mL. In the case of dose reduction, the 600 mg dose is administered in 3 mL and the 400 
mg dose is administered in 2 mL. 
VTS-270 Administration via Lumbar Puncture and Sham Lumbar Puncture 
In Part A, VTS-270 administration via LP and sham will be performed every 2 weeks for 4 
administrations. In Part B, VTS-270 administration via LP and sham will be performed every 
2 weeks for 52 weeks. In Part C, VTS-270 will be administered via LP or the device every 2 
weeks. Instructions for administration via the device are presented in the following 
subsection. 
The LP and/or sham is to be performed under monitored anesthesia care (conscious sedation) 
with an appropriate oral or IV agent and performed by an unblinded study physician. General 
anesthesia will be allowed on a case-by-case basis, following discussion with the medical 
monitor, in those subjects for whom a medical condition necessitates it. 
Parents/caregivers will not be present in the room during lumbar IT or sham treatment. Thus, 
the subject and the parent will be blinded to treatment, the former a consequence of 
anesthesia. 
The sham procedure will consist of 1 to 2 small needle pricks on the lower back at the 
location where the LP and IT injection is normally made. The needle(s) will break the skin 
but no lumbar puncture or needle insertion will occur. The needle prick(s) will be covered 
with the same bandage that is used to cover the IT injection normally, thus simulating the 
appearance of an IT LP injection. To maintain the blind, a similar type of anesthesia, 
sedation, or minimal sedation (e.g., a low dose of an anxiolytic) should be used for the sham 
procedure as for the subject receiving study drug, following institutional procedures. The 
subject will be kept in the procedure room for approximately 30 minutes, simulating the same 
amount of time that subjects administered study drug are kept for administration procedure. 
VTS-270 will be administered as an IT slow bolus (1 to 2 minutes, depending on the volume 
administered) LP injection (maximum rate of administration = 4.5 mL/minute). The volume 
of the injection is determined by the dose group. Prior to the VTS-270 injection, a volume of 
CSF fluid approximately equal to the VTS-270 dose is to be removed. Anesthesia or sedation 
will be used for the IT dosing procedure, following institutional guidelines and procedures. 
All subjects, sham and study drug, are required to lie flat with feet elevated for 30 to 45 
minutes following dosing. For the 3 days following each procedure, subjects in both the sham 
and active treatment groups are to avoid acoustic overstimulation and minimize exposure to 
loud noises, e.g., headphones for music or video games. 
Device Administration (European Site-Specific Device Safety and Tolerability Substudy, 
Part C) 


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 26 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
VTS-270 administration via the device will be conducted every 2 weeks. There are no 
adjustments for weight or subject age. The device area will be prepared for sterile 
manipulation following standard site procedures. Cerebrospinal fluid will be withdrawn 
through the port of the device. The first 1 mL will be discarded, and then at least 3 mL will be 
collected for clinical laboratory tests (approximately 2 mL) and VTS-270 concentration 
(approximately 1-2 mL). The volume of CSF to be removed should be approximately equal to 
that being administered. VTS-270 will be administered as a slow bolus over 1 to 2 minutes 
with a maximum rate of infusion of 4.5 mL/minute. Non-coring needles adapted for use with 
the device should be used. Normal hypodermic needles will damage the port septum and may 
cause leakage of the system or blockage due to small silicone particles from the septum. 
Subjects are to receive the same dose of VTS-270 administered during Study VTS301 Part C 
by IT LP. 
Following the infusion of VTS-270, the system should be flushed with 1.5 mL of 
preservative-free 0.9% saline solution. For 30 to 45 minutes following dosing, subjects should 
lie flat with feet elevated. 
Duration of 
Subject 
Participation and 
Duration of Study 
Parts A and B 
Total duration of subject participation in Parts A and/or B will be approximately 58 weeks, to 
include a screening period of up to 45 days (maximum), and 52 weeks of serial IT injections 
or sham control procedures given on a 2-week cycle. An additional 26 weeks of post- 
treatment follow-up will be included for any subject who elects not to participate in Part C, 
for a total of 84 weeks. 
Below is a summary of the duration of Part A and B: 
•
Up to 45 days screening
•
Up to 8 weeks in Part A 
•
Up to 52 weeks of dosing, inclusive of the 8 weeks for subjects from Part A, for
subjects enrolled in Part B.
•
Up to 26 weeks of follow-up for Part B subjects who elect not to participate in
Part C.
Part C 
Part C is an open-label extension. The total duration of subject participation is until the 
investigator considers VTS-270 to no longer be beneficial to the subject, VTS-270 receives 
marketing authorization, or the development program is discontinued. 
Efficacy Evaluations 
Primary Endpoint 
Part B: 
The co-primary efficacy analysis will be based on: 
•
Change from baseline in NPC-SS composite score at Week 52 in the group
treated with VTS-270 vs. the sham control group.
•
Blinded Clinician CGIC at Week 52 in the group treated with VTS-270 vs the
sham control group.
Secondary 
Endpoints 
Part B: 
The secondary outcomes for Part B are divided into 2 categories: Key secondary outcome and 
other secondary outcomes. 
The key secondary endpoints are 
•
Change from baseline at Week 52 in the total NPC–SS score with the hearing
domain and ABR modifiers removed in the group treated with VTS-270 vs. the
sham control group.


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 27 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
•
Proportion of Caregiver CGIC responders (defined as a score of no change,
minimally improved, moderately improved or markedly improved) at Week 52
in the group treated with VTS-270 vs. the sham control group.
Other (non-key) secondary endpoints: 
•
Summary of AEs, concomitant medications, physical examinations, audiologic
examination, and clinical laboratories
•
Change from baseline in the EQ-5D-3L questionnaire at Week 52
•
Proportion of subjects in each group, treated for at least 6 months who qualified
for the rescue option.
•
Change from baseline to Week 52 in each of the 9 clinical domains of the NPC- 
SS
•
Change from baseline to Week 52 in the total NPC-SS with hearing domain and
ABR modifier included
•
Time to one point increase (worsening) in NPC-SS composite score
•
The composite NPC-SS mean annualized rate of change (slope) from baseline to
Week 52
•
Change from baseline in the TUG test at Week 52
•
Change from baseline in the 9-hole peg test at Week 52
Part C: 
•
The change from baseline to each assessment in a composite outcome that is the
sum of the ambulation, cognition, fine motor, and swallowing components of
the NPC-SS
•
The change from baseline to each assessment in total NPC-SS with the hearing
domain and ABR modifiers removed
•
Proportion of responders (defined as no change or improvement on NPC-SS
total score with hearing domain and ABR modifiers removed) at each
assessment
•
Proportion of Blinded Clinician-CGIC responders (defined as a score of no
change, minimally improved, moderately improved, or markedly improved) at
each assessment compared to baseline
•
Summary of AEs, concomitant medications, physical examinations, audiologic
examination, and clinical laboratories
•
Change from baseline in the EQ-5D-3L questionnaire at each assessment
•
Change from baseline to each assessment in each of the 9 clinical domains of
the NPC-SS
•
Change from baseline to each assessment in the total NPC-SS with hearing
domain and ABR modifier included
•
Time to one point increase (worsening) in NPC-SS composite score
The composite NPC-SS mean annualized rate of change (slope) from baseline
to each assessment
Other Evaluations 
•
CSF, urine, and plasma protein (e.g., calbindin D) biomarkers
•
CSF and plasma sterol biomarkers
•
Gene and protein expression
Safety Evaluations 
•
AEs
•
Audiologic testing


VTS-270 Solution for Injection 
Protocol VTS-270-301 
 
Page 28 of 136 
Confidential and Proprietary 
Title 
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham- Controlled Trial of VTS-270 
(2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann- 
Pick Type C1 (NPC1) Disease 
•
Clinical laboratory tests (hematology, chemistry, coagulation, urinalysis)
•
Vital signs
•
Physical and neurological examinations
•
Electrocardiograms (ECGs)
•
Wound check / port and catheter track check for device safety and tolerability
•
Intracranial pressure via LP for subjects with device
•
CSF routine laboratory tests for subjects with device
Statistics 
Primary Analysis 
Plan 
Analysis populations: 
The intent-to-treat (ITT) population will include all randomized subjects categorized by their 
randomized treatment assignment. The modified intent-to-treat (mITT) population will 
consist of all randomized subjects who received at least one dose of VTS-270 infusion or 
sham control. The primary population for the primary efficacy assessment will be the mITT. 
The per-protocol (PP) population will consist of all randomized subjects who had no major 
protocol deviation that would have had an impact on the primary outcome and who received 
at least 75% of their scheduled VTS-270 IT administrations. The safety population will also 
consist of all randomized subjects who receive at least one dose of VTS-270 or sham control. 
The European site-specific device safety population will consist of all subjects who receive at 
least 1 dose of VTS-270 via the device. The PK population will consist of subjects enrolled in 
the device PK substudy and whose plasma and/or CSF drug concentrations will provide at 
least 1 of the PK parameters of interest. Subjects in the PK population will be used for all PK 
data summaries. 
Primary outcome measure: 
The co-primary efficacy endpoints are the change from baseline in NPC-SS composite score 
(sum of the ambulation, cognition, fine motor, and swallowing components of the NPC-SS) at 
Week 52 and the blinded Clinician CGIC at Week 52. 
The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and 
swallowing domains of the NPC-SS. For the primary efficacy analysis, any missing Week 52 
assessments will be imputed. Subjects who take the rescue option will be considered 
dropouts and will need to have their missing Week 52 assessment imputed. 
The Clinician CGIC is a 7-point Likert scale. The scale requires assessment of change from a 
baseline level of disease activity, with anchors ranging from markedly improved, moderately 
improved, and minimally improved to no change and corresponding worsening (minimally, 
moderately, markedly). The analysis of the blinded Clinician CGIC at Week 52 will be 
conducted using the nonparametric Van Elteren method to test for the treatment effect using 
study part as a blocking variable. Average ranks will be assigned when there are ties within a 
block. Missing Week 52 assessments will be imputed. 
Analysis of secondary endpoints: 
The following key secondary endpoints comparing subjects treated with VTS-270 with the 
sham controls will be analyzed using a hierarchical testing, serial gatekeeping strategy based 
on the mITT population. 
•
The change from baseline to Week 52 in total NPC-SS with the hearing domain
and ABR modifiers removed.
•
Proportion of Caregiver CGIC responders (defined as a score of no change,
minimally improved, moderately improved or markedly improved) at Week 52.

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




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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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 
Intracranial pressure (ICP) via LP 
Device implant procedure data will be listed.     
 


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


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


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


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


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


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


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


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


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


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j The collection period of adverse events will begin after informed consent is obtained and end after procedures for the final study visit have completed. 
 


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


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


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Exhibit 6. Study Part C schedule of assessments (Week 54 through Week 182) 
 


VTS301: STATISTICAL ANALYSIS PLAN 
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Exhibit 7. Part C European Site-specific Device Safety and Tolerability Substudy Schedule of Assessments 


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