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: January 13, 2021
• Sponsor: Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company
• Information provided by (Responsible Party): Mallinckrodt ( Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company )

Tracking Information

• First Submitted Date: August 18, 2015
• First Posted Date: August 28, 2015
• Last Update Posted Date: January 13, 2021
• Actual Study Start Date: October 2015
• Estimated Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2020)

• Part A: Number of participants with adverse events (AE) [ Time Frame: within 8 weeks ]
• Part A: Composite Niemann Pick Type C Severity Scale (NPC-SS) at Week 8 [ Time Frame: Week 8 ]
  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.
• Part A: Blinded Clinician Global Impression of Change (Clinician-CGIC) at Week 8 [ Time Frame: at Week 8 ]
  The Clinician-CGIC will be conducted at the beginning of the 8-week visit prior to all other procedures and assessments. After the screening (baseline) assessment, the blinded rater will have no access to or knowledge of treatment assignment, clinical and laboratory AEs, laboratory tests, and any of the other assessments. The Clinician-CGIC is evaluated using a 7-point Likert scale ranging from 1 (marked improvement from screening) to 7 (marked worsening from screening), will be assessed Week 8 for Part A. The same rater should conduct the Clinician-CGIC at all visits for a given participant throughout the entire trial.
• Part B: Composite Niemann Pick Type C Severity Scale (NPC-SS) During Part B [ Time Frame: at 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.
• Part B: Blinded Clinician-CGIC [ Time Frame: within 76 weeks ]
  The Clinician-CGIC, evaluated using a 7-point Likert scale ranging from 1 (marked improvement) from screening to 7 (marked worsening from screening), will be assessed at Weeks 16, 24, 32, 40, 46, and 52 in Part B, plus at Follow-up Weeks 63 and 76 in Part B for subjects who elect not to participate in Part C.
• Part C: Blinded Clinician-CGIC [ Time Frame: anticipated within 6 years of study start ]
  For Part C, the Clinician-CGIC will be conducted every 6 months, at the end of study visit or end of treatment, and at follow-up visits 2 and 3, using a 7-point Likert scale ranging from 1 (marked improvement from screening) to 7 (marked worsening from screening).

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: February 12, 2020)

• Part B: Clinician and Caregiver Global Impression of Change [ Time Frame: 52 weeks ]
• Part B: Time to get up and go test [ Time Frame: 52 weeks ]
• Part B: 9-hole peg test [ Time Frame: 52 weeks ]
• Part B: Percentage of patients with clinical worsening [ Time Frame: from week 26 through week 52 based on first dose being week 1 ]
• Part B: European Quality of Life-5 Dimensions Quality of Life Rating (EQ-5D QoL) [ Time Frame: 52 weeks ]

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

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 Part A and B, two out of every three patients will receive the study drug. The doctor will give the third patient an injection with nothing in it (sham control).

In Part C, all participants will receive study drug.

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.

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

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

Study Design

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

In Parts A and B interventions will be administered in parallel. All participants will become a single group for Part C,

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: VTS-270
  Lumbar intrathecal infusion of VTS-270
  Other Names:

  • 2-hydroxypropyl-β-cyclodextrin
  • Cyclodextrin
• Other: Sham
  No experimental drug is administered to patients. All intrathecal administrations are simulated by skin prick.
  Other Name: Procedure Control

Study Arms

• Experimental: Part A- 900 mg VTS-270
  Participants receive 900 milligram (mg) of VTS-270 administered by the lumbar intrathecal (IT) route every 2 weeks.
  Intervention: Drug: VTS-270
• Experimental: Part A- 1200 mg VTS-270
  Participants receive 1200 mg of VTS-270 administered by the lumbar IT route every 2 weeks.
  Intervention: Drug: VTS-270
• Experimental: Part A- 1800 mg VTS-270
  Participants receive 1800 mg of VTS-270 administered by the lumbar IT route every 2 weeks.
  Intervention: Drug: VTS-270
• Part A- Sham
  Participants receive 1 to 2 skin pricks with a needle.
  Intervention: Other: Sham
• Experimental: Part B- 900 mg VTS-270
  Participants receive 900 mg of VTS-270 administered by the lumbar IT route every 2 weeks.
  Intervention: Drug: VTS-270
• Part B- Sham
  Participants receive 1 to 2 skin pricks with a needle.
  Intervention: Other: Sham
• Experimental: Part C- 900 mg VTS-270
  Participants receive 900 mg of VTS-270 administered by the lumbar IT route every 2 weeks.
  Intervention: Drug: VTS-270

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: August 27, 2015): 51
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 30, 2021
• Estimated Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

Parts A and B:

1. Onset of neurological symptoms prior to 15 years of age.

2. Confirmed diagnosis of NPC1 determined by either:

   • Two NPC1 mutations;
   • Positive filipin staining and at least one NPC1 mutation;
   • c. 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. Subject or parent/guardian must provide written informed consent and assent (for minors).
4. Ability to undergo a lumbar puncture (LP) and IT drug administration under conscious sedation or general anesthesia.
5. An NPC Clinical Severity Scale Score of 1 through 4, inclusive, in two or more of the following on the NPC Severity Scale components: ambulation, fine motor skills, or swallowing and a score of 0 through 4 on the cognition component.
6. Total NPC Clinical Severity Scale Score of 10 or greater.
7. If taking miglustat, must have been on a stable dose for past 3 months and be willing to remain on a stable dose.
8. 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 anti epileptic medication during the 3 months prior to screening without change in dose in regimen up to and including Study Day 0.
9. Agree to discontinue all non-prescription supplements such as Coenzyme Q10, curcumin, cinnamon, fish oil supplements, high dose vitamin D (>500 milli-International unit (mIU)/day), acetylleucine, or gingko biloba at least 1 month prior to first dose (Study Day 0).
10. Agree to discontinue any other investigational treatments for NPC including vorinostat or arimoclomol at least 3 months prior to first dose (Study Day 0).
11. Females of child-bearing 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.

Part C:

1. Subject has completed Part B, or meets the criteria for the Rescue Option.

Key Exclusion Criteria:

1. Exclusion criteria as assessed by NPC Clinical Severity Scale:

   • Unable to walk, wheelchair dependent (ambulation NPC score=5)
   • Needs a nasogastric tube to overcome swallowing difficulties (swallowing NPC score=5) Note: Nasogastric or gastric tube use for supplemental feeding or medication administration is permitted and will not exclude a subject from the trial.
   • Severe dysmetria (fine motor NPC score=5)
   • Minimal cognitive function (cognition NPC score=5).
2. Body weight < 15 kg.
3. 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. Note: Any prior IT administration of HP-β-CD will exclude a subject from enrollment.
4. Subjects on 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.
5. History of hypersensitivity reactions to any product containing 2-hydroxypropyl-β-cyclodextrin (HP-β-CD).
6. Spinal deformity that could impact the ability to perform a lumbar puncture.
7. Skin infection in the lumbar region within 2 months of study entry.
8. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 X 10^9/L.
9. Thrombocytopenia (platelet count of less than 75 X 10^9/L).
10. 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. Status epilepticus occurring within 3 months of screening and/or seizure frequency that cannot be quantified.
12. Evidence of obstructive hydrocephalus or normal pressure hydrocephalus.
13. Recent use of anticoagulants [in past 2 weeks prior to first dose (Study Day 0); re: lumbar puncture safety].
14. Subjects unable to comply with the study procedures or with 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; 2015-002548-15 ( EudraCT Number ); Approved 01-Aug-2019 ( Other Identifier: Singapore SG-HSA ); 16-QUI-17 ( Registry Identifier: Turkey MoH ID ); 45278/0001/001-0004 ( Other Identifier: MHRA )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Mallinckrodt ( Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company )
• Study Sponsor: Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Team Leader; Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company

• PRS Account: Mallinckrodt
• Verification Date: January 2021