Study of VTS-270 (2-hydroxypropyl-β-cyclodextrin) to Treat Niemann-Pick Type C1 (NPC1) Disease

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

Study Description

Brief Summary:

This study evaluates the efficacy and safety of 2-hydroxypropyl-β-cyclodextrin (VTS-270) in patients with neurologic manifestations of Niemann-Pick Type C1 (NPC1) Disease. Approximately two-thirds of patients will receive the study drug, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), while the remaining study participants will receive sham control.

Condition or disease	Intervention/treatment	Phase
Niemann-Pick Disease, Type C	Drug: VTS-270; Drug: Sham Procedure Control	Phase 2; Phase 3

Detailed Description:

Non-clinical studies and a Phase 1 clinical trial suggest that intrathecal administration of 2-hydroxypropyl- β-cyclodextrin (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 is a multicenter, multinational, prospective, randomized, double-blind, sham-controlled, 3-part, efficacy and safety trial of VTS-270, administered by the lumbar intrathecal route (IT) every 2 weeks, with a planned enrollment of approximately 51 subjects with NPC1 disease. The study will be conducted in three parts: Parts A, B, and C.

Part A will evaluate 3 different dose levels of VTS-270 in 9 subjects and 3 sham control subjects to determine the dose level for Parts B and C.

Part B will evaluate the safety and efficacy of the dose selected from Part A compared to sham control in 51 subjects, including the 12 subjects from Part A.

Part C will be an open-label extension phase of the study to subjects who either complete Part B or are subjects in Part B who have met rescue therapy criteria.

Subjects in Part C will receive treatment with VTS-270 until the product is licensed or the program is terminated.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	51 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
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
Actual Study Start Date :	October 2015
Actual Primary Completion Date :	March 28, 2018
Estimated Study Completion Date :	September 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: VTS-270; Part A: Three (3) different VTS-270 lumbar intrathecal doses (900 mg, 1200 mg, and 1800 mg) administered IT every 2 weeks for 8 weeks in 9 subjects; 3 subjects will receive sham treatment. Dose for Part B to be selected for the remainder of the study. Part B: Approximately 51 subjects, including 12 from Part A, will receive lumbar intrathecal infusions of VTS-270 or sham (randomized 2:1) every 2 weeks for a total of 52 weeks. Part C: Open-label extension with IT treatment every 2 weeks.; All subjects (sham and drug-treated) with clinically defined worsening following > 6 months of treatment in Part B will be eligible to enter Part C.; All subjects who complete Part B will be eligible to enter Part C.	Drug: VTS-270; Lumber intrathecal infusion of VTS-270 (dose to be selected after Part A); Other Names: 2-hydroxypropyl-β-cyclodextrin; Cyclodextrin
Sham Comparator: Sham Procedure Control; Sixteen (16) subjects, including 3 from Part A.	Drug: Sham Procedure Control; No experimental drug administered to patients. All intrathecal administrations are simulated.; Other Name: Sham group

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Clinician and Caregiver Clinical Global Impression of Change [ Time Frame: 52 weeks ]
   The CGIC will be evaluated using a 7-point Likert scale.
2. Time to get up and go test [ Time Frame: 52 weeks ]
3. 9-hole peg test [ Time Frame: 52 weeks ]
4. Percentage of patients with clinical worsening [ Time Frame: from week 26 through week 52 based on first dose being week 1 ]
5. European Quality of Life-5 Dimensions Quality of Life Rating (EQ-5D QoL) [ Time Frame: 52 weeks ]

Other Outcome Measures:

1. 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.
2. Plasma protein biomarkers [ Time Frame: 52 weeks ]
   Plasma samples will be collected and stored for possible biomarker analysis

Eligibility Criteria

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Ages Eligible for Study:	4 Years to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Locations

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United States, California
Children's Hospital of Orange County
Orange, California, United States, 92868
University of California San Francisco
San Francisco, California, United States, 94143
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Maryland
National Institute of Child Health and Human Development at NIH
Bethesda, Maryland, United States, 20878
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
United States, Pennsylvania
Lehigh Valley Health Network
Allentown, Pennsylvania, United States, 18103
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Dell Children's Medical Center of Central Texas
Austin, Texas, United States, 78723
Australia, Victoria
Monash Medical Centre
Clayton, Victoria, Australia, 3168
Royal Melbourne Hospital
Parkville, Victoria, Australia, 3050
France
CHU Paris Est - Hospital d'Enfants Armand-Trousseau
Paris, Cadex 12, France, 75 571
Germany
Ruhr University, St. Josefs-Hospital
Bochum, Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Mainz, Germany
Spain
Hospital Universitario del Valle Hebron
Barcelona, Spain, 08035
Turkey
Gazi Universitesi Araştırma ve Uygulama Hastanesi
Ankara, Turkey
Hacettepe Universitesi Hastanesi
Ankara, Turkey
United Kingdom
Birmingham Children's Hospital
Birmingham, United Kingdom, B4 6NH
Great Ormond Street Hospital
London, United Kingdom, WC1N 3JH

Sponsors and Collaborators

Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company

More Information

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Responsible Party:	Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company
ClinicalTrials.gov Identifier:	NCT02534844 History of Changes
Other Study ID Numbers:	VTS301
First Posted:	August 28, 2015
Last Update Posted:	March 27, 2019
Last Verified:	March 2019

Keywords provided by Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company:

Niemann-Pick Type C1 (NPC1) Disease; neurologic disease; gross motor dysfunction; fine motor dysfunction; dysphagia	swallowing problems; cognitive dysfunction; gait abnormalities; pediatrics

Additional relevant MeSH terms:

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Pick Disease of the Brain; Aphasia, Primary Progressive; Frontotemporal Dementia; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Frontotemporal Lobar Degeneration; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Aphasia; Speech Disorders	Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Histiocytosis, Non-Langerhans-Cell; Histiocytosis