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

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ClinicalTrials.gov Identifier: NCT02534844
Recruitment Status : Recruiting
First Posted : August 28, 2015
Last Update Posted : November 7, 2018
Sponsor:
Information provided by (Responsible Party):
Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company

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 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
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019


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




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



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02534844


Contacts
Contact: Susan VanMeter, MD 240.278.6860 susan.vanmeter@mnk.com
Contact: Karrie Hilsinger, B.S. 908-238-6448 Karrie.hilsinger@mnkc.om

Locations
United States, California
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Raymond Wang, MD    714-509-8852    rawang@choc.org   
Contact: Nina Movsesyan    1-714-509-3008    nmovsesyan@choc.org   
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Renata Gallagher, MD    415-476-3572    renata.gallagher@ucsf.edu   
Contact: Nora Darago    1-415-476-6997    nora.darago@ucsf.edu   
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Elizabeth Berry-Kravis, MD PhD    312-942-4036    Elizabeth_Berry-Kravis@rush.edu   
Contact: Jamie A Chin    1-312-942-4036    Jamie_A_Chin@rush.edu   
United States, Maryland
National Institute of Child Health and Human Development at NIH Recruiting
Bethesda, Maryland, United States, 20878
Contact: Forbes D Porter, M.D., Ph.D.    301-435-4432    fdporter@mail.nih.gov   
Contact: Nicole Farhat, NP    301-594-1765    nicole.farhat@nih.gov   
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Olaf Bodamer, MD, PhD, FAAP, FACMG    1 857-218-5544    olaf.bodamer@childrens.harvard.edu   
Contact: Sophia Kon    1 617-919-1399    sophia.kon@childrens.harvard.edu   
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467
Contact: Paul Levy, MD    718-741-2323    plevy@montefiore.org   
Contact: Jessica Fishetti       jfischetti@montefiore.org   
United States, Pennsylvania
Lehigh Valley Health Network Recruiting
Allentown, Pennsylvania, United States, 18103
Contact: Sameh Morkous, MD    610-402-9543    sameh.morkous@lvhn.org   
Contact: Sagan Loburak    610-402-8447    sagan_M.Loburak@lvhn.org   
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Can Ficicioglu, MD    215-590-1000    Ficicioglu@email.chop.edu   
Contact: Alicia Hurnton    1-267-425-2174    HURNTONA@email.chop.edu   
United States, Texas
Dell Children's Medical Center of Central Texas Recruiting
Austin, Texas, United States, 78723
Contact: James Gibson, MD    512-628-1840    JBGibson@seton.org   
Contact: Theresa Viduya, MSN, RN, RNBC    512-324-9999 ext 87081    tsviduya@seton.org   
Australia, Victoria
Monash Medical Centre Recruiting
Clayton, Victoria, Australia, 3168
Contact: Michael Fahey, A/Prof    +61 3 9594 3499    Michael.Fahey@monash.edu   
Contact: Marie Backstrom    +61 9594 1487    marie.backstrom@monashhealth.org   
Royal Melbourne Hospital Recruiting
Parkville, Victoria, Australia, 3050
Contact: Mark Walterfang, A/Prof    + 61 3 9342 8750    mark.walterfang@mh.org.au   
Contact: Sean Hosking    +61 3 9342 4657    sean.hosking@mh.org.au   
France
CHU Paris Est - Hospital d'Enfants Armand-Trousseau Recruiting
Paris, Cadex 12, France, 75 571
Contact: Benedicte Heron, MD    (0)1 44 73 66 93    benedicte.heron@trs.aphp.fr   
Contact: Samira Zebiche    (0)1 40 87 52 86    samira.zebiche@bjn.aphp.fr   
Germany
Ruhr University, St. Josefs-Hospital Recruiting
Bochum, Germany
Contact: Nesrin Karabul, MD    +49 176 551 295 38    n.karabul@klinikum-bochum.de   
Contact: Sandra Böger    +49 234 509 2809    s.boeger@klinikum-bochum.de   
Universitätsmedizin der Johannes Gutenberg-Universität Mainz Recruiting
Mainz, Germany
Contact: Julia Hennermann, Univ. Prof. Dr. med.    +49 (0) 6131 17 5754    julia.hennermann@unimedizin-mainz.de   
Contact: Petra Kleinhans    +49 (0) 6131 17 4579    petra.kleinhans@unimedizin-mainz.de   
Spain
Hospital Universitario del Valle Hebron Recruiting
Barcelona, Spain, 08035
Contact: Miereia Del Toro Riera, Dra.    +34 93 489 31 56    mdeltoro@vhebron.net   
Contact: Carla Aguilar Blancafort    +34 93 274 67 20    carla.aguilar@vhr.org   
Turkey
Gazi Universitesi Araştırma ve Uygulama Hastanesi Recruiting
Ankara, Turkey
Contact: Fatih Ezgü, Prof. Dr.    00905326853697    fezgu@gazi.edu.tr   
Contact: Deniz Koca    0090 549 610 12 85    deniz.koca@medex-smo.com   
Hacettepe Universitesi Hastanesi Recruiting
Ankara, Turkey
Contact: Meral Topçu, Prof. Dr.    00905323657282    mtopcu@hacettepe.edu.tr   
Contact: Yonca Kanal    0090 549 610 12 84    yonca.kanal@medex-smo.com   
United Kingdom
Birmingham Children's Hospital Recruiting
Birmingham, United Kingdom, B4 6NH
Contact: Suresh Vijay, MD, Consultant IMD    44 (0) 1213339907    suresh.vijay@bch.nhs.uk   
Contact: Alice Stewart    44 (0) 1213339954    alice.stewart@bch.nhs.uk   
Great Ormond Street Hospital Recruiting
London, United Kingdom, WC1N 3JH
Contact: Paul Gissen, PhD, MRCPCH    +44(0)2078297989    p.gissen@ucl.ac.uk   
Contact: Stephanie Tingley    +44(0)2074056892    Stephanie.Tingley@gosh.nhs.uk   
Sponsors and Collaborators
Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company

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    Key Record Dates
Last Update Posted: November 7, 2018
Last Verified: November 2018

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:
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