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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02534844
Recruitment Status : Active, not recruiting
First Posted : August 28, 2015
Last Update Posted : August 24, 2020
Sponsor:
Information provided by (Responsible Party):
Mallinckrodt ( Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company )

Tracking Information
First Submitted Date  ICMJE August 18, 2015
First Posted Date  ICMJE August 28, 2015
Last Update Posted Date August 24, 2020
Actual Study Start Date  ICMJE October 2015
Estimated Primary Completion Date September 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE VTS-270 to Treat Niemann-Pick Type C1 (NPC1) Disease
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE 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  ICMJE Niemann-Pick Disease, Type C
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: August 27, 2015)
51
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2021
Estimated Primary Completion Date September 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   France,   Germany,   New Zealand,   Singapore,   Spain,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02534844
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Mallinckrodt ( Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company )
Study Sponsor  ICMJE Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Team Leader Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company
PRS Account Mallinckrodt
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP