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

• ClinicalTrials.gov Identifier: NCT02534844
• Recruitment Status: Active, not recruiting
• First Posted: August 28, 2015
• Last Update Posted: July 29, 2021
• Sponsor: Mandos LLC
• Information provided by (Responsible Party): Mandos LLC

Tracking Information

• First Submitted Date: August 18, 2015
• First Posted Date: August 28, 2015
• Last Update Posted Date: July 29, 2021
• Actual Study Start Date: October 2015
• Estimated Primary Completion Date: October 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2021)

• Parts A/B: Composite Niemann Pick Type C Severity Scale (NPC-SS) [ Time Frame: Baseline, Week 52 ]
  Each of four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The highest (worst) possible score is 20.
• Parts A/ B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) [ Time Frame: Week 52 ]
  The study doctor rates his impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7).

Original Primary Outcome Measures (submitted: August 27, 2015)

NPC Clinical Severity Score [ Time Frame: 52 weeks ]

Data for NPC score rating will be provided to a centralized independent blinded rater who will analyze all NPC information for all subjects and assign the NPC Clinical Severity Score.

Current Secondary Outcome Measures (submitted: June 29, 2021)

• Parts A/B: NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response) at Baseline and Week 52 [ Time Frame: Baseline, Week 52 ]
  Each of four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The highest (worst) possible score is 20. The hearing domain and auditory brainstem response modifiers will be removed from the total NPC-SS total score for this measure.
• Parts A/ B: Number of Participants Classified as Responders by Their Caregiver at Week 52 [ Time Frame: Week 52 ]
  Caregiver rates the global impression of change at Week 52. Participants who receive the caregiver's rating of no change, minimally improved, moderately approved, or markedly improved will be classified as responders. The number of participants classified as responders will be recorded.

Original Secondary Outcome Measures (submitted: August 27, 2015)

• Clinician and Caregiver Clinical Global Impression of Change [ Time Frame: 52 weeks ]
  The CGIC will be evaluated using a 7-point Likert scale.
• Time to get up and go test [ Time Frame: 52 weeks ]
• 9-hole peg test [ Time Frame: 52 weeks ]
• Percentage of patients with clinical worsening [ Time Frame: from week 26 through week 52 based on first dose being week 1 ]
• European Quality of Life-5 Dimensions Quality of Life Rating (EQ-5D QoL) [ Time Frame: 52 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: August 27, 2015)

• Cerebrospinal fluid (CSF) biomarkers [ Time Frame: 52 weeks ]
  CSF will be collected from subjects receiving study drug and will be stored for possible biomarker analysis.
• Plasma protein biomarkers [ Time Frame: 52 weeks ]
  Plasma samples will be collected and stored for possible biomarker analysis

Descriptive Information

• Brief Title: VTS-270 to Treat Niemann-Pick Type C1 (NPC1) Disease
• Official Title: 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

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).

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

In Parts A/B (see other registration for Part C description)

Masking: Double (Care Provider, Investigator)
Masking Description:

While it is a double-blind trial, the participant and outcomes assessor will be blinded, as well as the Care Provider and Investigator.

Primary Purpose: Treatment

• Condition: Niemann-Pick Disease, Type C

Intervention

• Drug: Parts A/B: Adrabetadex
  900 - 1800 milligram (mg) of adrabetadex administered every 2 weeks via lumbar intrathecal infusion
  Other Names:

  • 2-hydroxypropyl-β-cyclodextrin
  • Cyclodextrin
  • VTS-270
  • Adrabetadex
• Other: Parts A/B: Sham Control
  No experimental drug is administered to patients - intrathecal administrations are simulated by skin prick
  Other Names:

  • Procedure Control
  • Skin prick

Study Arms

• Experimental: Parts A/B: Sham Control
  Participants receive no study drug
  Intervention: Other: Parts A/B: Sham Control
• Parts A/B: Adrabetadex
  Participants receive adrabetadex
  Intervention: Drug: Parts A/B: Adrabetadex

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 27, 2015): 51
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2021
• Estimated Primary Completion Date: October 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

Parts A/B:

1. Had onset of neurological symptoms prior to 15 years of age

2. Has confirmed diagnosis of NPC1 determined by either:

   1. two NPC1 mutations
   2. positive filipin staining and at least one NPC1 mutation
   3. 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
3. Adult participant or parent/guardian has provided written informed consent, with assent collected from minors of appropriate age
4. Is able to undergo a lumbar puncture (LP) and IT drug administration under conscious sedation or general anesthesia
5. 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
6. Has a total NPC Clinical Severity Scale Score of 10 or greater
7. If taking miglustat, must have been on a stable dose for past 6-8 weeks and be willing to remain on a stable dose
8. If participant has seizures, they have been adequately controlled for 3 months without changing dose or regimen
9. Has agreed to discontinue all non-prescription supplements at least 1 month prior to first dose (Study Day 0)
10. 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)
11. 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:

1. Has exclusion criteria as assessed by NPC Clinical Severity Scale:

   1. Unable to walk, wheelchair dependent (ambulation NPC score=5)
   2. Has need for a nasogastric tube to overcome swallowing difficulties (swallowing NPC score=5) unless used for supplemental feeding or administering medication
   3. severe dysmetria (fine motor score =5) or
   4. minimal cognitive function (cognition NPC score=5)
2. Weighs less than 15 kg
3. 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
4. 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
5. Has a history of hypersensitivity reactions to any product containing HP-β-CD
6. Has a spinal deformity that could impact the ability to perform a lumbar puncture
7. Has had a skin infection in the lumbar region within 2 months of study entry
8. Has neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 X 10^9/L
9. Has thrombocytopenia (platelet count of less than 75 X 10^9/L)
10. 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
11. Has had status epilepticus occurring within 3 months of screening and/or seizure frequency that cannot be quantified
12. Has evidence of either obstructive hydrocephalus or normal pressure hydrocephalus
13. Has recently used anticoagulants [in past 2 weeks prior to first dose (Study Day 0); re: lumbar puncture safety].
14. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Germany, New Zealand, Singapore, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT02534844
• Other Study ID Numbers: VTS301 (Parts A/B); 2015-002548-15 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Summary aggregate (basic) results (including adverse events information) and the study protocol are made available on clinicaltrials.gov (NCT02534844) when required by regulation. Individual de-identified patient data will not be disclosed. Requests for additional information should be directed to the company at medinfo@mnk.com.

• Current Responsible Party: Mandos LLC
• Original Responsible Party: Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company [Disabled]
• Current Study Sponsor: Mandos LLC
• Original Study Sponsor: Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company [Disabled]
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Study Lead; Mandos LLC

• PRS Account: Mandos LLC
• Verification Date: July 2021