VTS-270 to Treat Niemann-Pick Type C1 (NPC1) Disease

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham-Controlled 3-Part Trial of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects With Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease

Conditions
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Niemann-Pick Disease, Type C

Intervention / Treatment
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* Drug: Parts A/B: Adrabetadex
* Other: Parts A/B: Sham Control


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Parts A/B: Had onset of neurological symptoms prior to 15 years of age Has confirmed diagnosis of NPC1 determined by either: two NPC1 mutations positive filipin staining and at least one NPC1 mutation vertical supranuclear gaze palsy (VSNGP) in combination with either: one NPC1 mutation, OR positive filipin staining or oxysterol levels consistent with NPC disease and no Niemann-Pick Type C2 (NPC2) Disease mutations Adult participant or parent/guardian has provided written informed consent, with assent collected from minors of appropriate age Is able to undergo a lumbar puncture (LP) and IT drug administration under conscious sedation or general anesthesia Has an NPC Clinical Severity Scale Score of 1 through 4, inclusive, in two or more of the following components: ambulation, fine motor skills, or swallowing; and has a score of 0 through 4 on the cognition component Has a total NPC Clinical Severity Scale Score of 10 or greater If taking miglustat, must have been on a stable dose for past 6-8 weeks and be willing to remain on a stable dose If participant has seizures, they have been adequately controlled for 3 months without changing dose or regimen Has agreed to discontinue all non-prescription supplements at least 1 month prior to first dose (Study Day 0) Has agreed to discontinue any other investigational treatments for NPC including vorinostat or arimoclomol at least 3 months prior to first dose (Study Day 0) If of child-bearing potential (not surgically sterile), agrees to use a medically acceptable method continuously, until at least 30 days after participation in the study Key Exclusion Criteria: Has exclusion criteria as assessed by NPC Clinical Severity Scale: Unable to walk, wheelchair dependent (ambulation NPC score=5) Has need for a nasogastric tube to overcome swallowing difficulties (swallowing NPC score=5) unless used for supplemental feeding or administering medication severe dysmetria (fine motor score =5) or minimal cognitive function (cognition NPC score=5) Weighs less than 15 kg Has had prior treatment with intravenous 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, or has had any prior intrathecal (IT) administration of HP-β-CD Is taking antipsychotics for treatment of psychosis; use of antipsychotic medication for treatment of other disorders (e.g., Attention Deficit Hyperactivity Disorder) will not exclude participation in this trial Has a history of hypersensitivity reactions to any product containing HP-β-CD Has a spinal deformity that could impact the ability to perform a lumbar puncture Has had a skin infection in the lumbar region within 2 months of study entry Has neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 X 10^9/L Has thrombocytopenia (platelet count of less than 75 X 10^9/L) Has activated partial thromboplastin time (aPTT) or prothrombin time (PT) prolonged by > 1.5 times the upper limit of normal (ULN) or known history of a bleeding disorder Has had status epilepticus occurring within 3 months of screening and/or seizure frequency that cannot be quantified Has evidence of either obstructive hydrocephalus or normal pressure hydrocephalus Has recently used anticoagulants [in past 2 weeks prior to first dose (Study Day 0); re: lumbar puncture safety]. Is unable to comply with the study procedures or has a clinical disease or laboratory abnormality that in the opinion of the investigator would potentially increase the risk of participation

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In Parts A/B (see other registration for Part C description)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Parts A/B: Sham Control<br>Participants receive no study drug | Other: Parts A/B: Sham Control<br>* No experimental drug is administered to participants - intrathecal administrations are simulated by skin prick<br>* Other names: Skin prick;|
| Other: Parts A/B: Adrabetadex<br>Participants receive adrabetadex | Drug: Parts A/B: Adrabetadex<br>* 900 - 1800 milligram (mg) of adrabetadex administered every 2 weeks via lumbar intrathecal infusion<br>* Other names: Adrabetadex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score | The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. | Baseline, Week 52 | 
| Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | 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 Investigator rates his/her impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7). | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR]) | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. The hearing domain and auditory brainstem response modifiers are removed from the total NPC-SS total score for this measure. A Likert-like scale is used to assign the remaining 8 major domain scores of 0 to 5 (better to worse). The total score was the sum of individual component scores which ranges from 0 (best) to 40 (worst), with higher scores indicating more severe clinical impairment. | Baseline, Week 52 | 
| Parts A/ B: Number of Participants Classified as CGIC Responders at Week 52 | 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 Investigator rates his/her impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7). CGIC Responders are defined as participants who received the caregiver's rating of no change, minimally improved, moderately improved, or markedly improved from baseline to Week 52. | Week 52 | 
| Parts A/B: Number of Participants Classified as Responders on NPC-SS Total Score (Excluding Hearing and ABR) at Week 52 | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. The hearing domain and ABR modifiers are removed from the total NPC-SS total score for this measure. A Likert-like scale is used to assign the remaining 8 major domain scores of 0 to 5 (better to worse). The total score was the sum of individual components scores which ranges from 0 (best) to 40 (worst), with higher scores indicating more severe clinical impairment. Responders on NPC-SS Total Score are defined as participants with no change or improvement on NPC-SS total score from baseline to Week 52. | Week 52 | 
| Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52 | The EQ-5D-3L assessment is a self-reported, simple, descriptive system measuring 5 dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. A vertical VAS allows the participants to indicate their health state that day, and ranges from 0 (worst imaginable) to 100 (best imaginable), with higher scores indicating better health state. | Baseline, Week 52 | 
| Parts A/B: Number of Participants Treated for at Least 6 Months Who Qualified for the Rescue Option | Participants who manifested significant disease progression according to predefined clinical criteria after treatment of 26 weeks or more had the option to rescue. Number of participants who qualified for the rescue option following a minimum of 26 weeks of treatment were analyzed. | Baseline up to Week 26 | 
| Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. A Likert-like scale is used to assign to each domain score of 0 to 5 (better to worse) with higher scores indicating more severe clinical impairment. | Baseline, Week 52 | 
| Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included) | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. A Likert-like scale is used to assign to each domain score of 0 to 5 (better to worse). The total score was the sum of individual components scores which ranges from 0 (best) to 45 (worst), with higher scores indicating more severe clinical impairment. | Baseline, Week 52 | 
| Parts A/B: Time to One Point Increase (Worsening) in NPC-SS Composite Score | The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. The product-limit survival analysis method is used to estimate the time to one point increase (worsening) in NPC-SS composite score. Time to worsening in NPC-SS Composite Score defined as the interval from study drug administration to a one point increase in the NPC-SS composite score. If a subject discontinued from the study prior to Week 52, then the subject was censored at time of discontinuation. If a subject completed the Week 52 visit, then the subject was censored at the time of last study visit. | Baseline up to Week 52 | 
| Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52 | The TUG is a test of balance and risk for falls. This test measures the time taken by a participant to walk 3 meters starting from a sitting position and it ends when the participant is seated again. | Baseline, Week 52 | 
| Parts A/B: Change From Baseline in the 9-Hole Peg Test at Week 52 | The 9-Hole Peg Test is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. | Baseline, Week 52 | 
| Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | A TEAE is defined as an adverse event (AE) with onset on or after start of study Drug. An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 52 | 
| Parts A/B: Change From Baseline to Week 52 in Mean Annualized Rate of Change (Slope) of NPC-SS Composite Score | The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. The Annualized rate of change (Slope) is calculated as 365.25 *([measurement at post-baseline visit - measurement at baseline]/[date of post-baseline visit - date of baseline visit + 1]). | Baseline, Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Niemann-Pick Type C1 (NPC1) Disease, neurologic disease, gross motor dysfunction, fine motor dysfunction, dysphagia, swallowing problems, cognitive dysfunction, gait abnormalities, pediatrics