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    Summary
    EudraCT Number:2015-002548-15
    Sponsor's Protocol Code Number:VTS301
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2015-002548-15
    A.3Full title of the trial
    A Phase 2b/3 Prospective, Randomized, Double-blind, Sham-controlled Trial of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Niemann-Pick Type C1 Disease
    A.4.1Sponsor's protocol code numberVTS301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorVtesse LLC, a Mallinckrodt Pharmaceutical Company
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportVtesse LLC, a Mallinckrodt Pharmaceutical Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVtesse LLC, a Mallinckrodt Pharmaceutical Company
    B.5.2Functional name of contact pointAlbert Leung, PhD
    B.5.3 Address:
    B.5.3.1Street Address90 Washington Valley Road
    B.5.3.2Town/ cityBedminster
    B.5.3.3Post codeNJ 07921
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 908-256-3889
    B.5.6E-mailalbert.leung@mnk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1124
    D.3 Description of the IMP
    D.3.1Product nameVTS-270
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrathecal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHP-β-CD
    D.3.9.1CAS number 128446-35-5
    D.3.9.2Current sponsor codeHP-β-CD
    D.3.9.3Other descriptive name2-HYDROXYPROPYL-BETA-CYCLODEXTRIN
    D.3.9.4EV Substance CodeSUB21143
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease
    E.1.1.1Medical condition in easily understood language
    Niemann-Pick Type C1 (NPC1) Disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Study Part A: The primary study objective was to select the dose of VTS-270 to be used in Study Part B and Part C. Dose selection criteria included safety and tolerability including a thorough audiologic evaluation. Preliminary efficacy data was provided to the Dose Selection Committee (DSC) to assist, if necessary, in dose selection.

    Study Part B: The primary study objective was to evaluate, in a double-blind sham-controlled design, the progression of the neurologic manifestations of NPC1 disease following 52 weeks of treatment for subjects treated with VTS-270 compared to sham control, using the following assessments:
    •The Neimann Pick Type C Severity Scale (NPC-SS) composite which consists of the sum of 4 components of the NPC-SS: ambulation, fine motor, cognition, and swallowing.
    •The blinded Clinician-Clinical-Global Impression of Change (CGIC)

    Study Part C: The primary study objective is to evaluate the long-term safety, tolerability, and efficacy of VTS 270.
    E.2.2Secondary objectives of the trial
    Study Part A: There were no secondary objectives.

    Study Part B: The secondary objectives were divided into 2 categories: Key Secondary Objectives and Other Secondary Objectives.
    The key secondary objective for Study Part B was to evaluate the progression of the neurologic manifestations of NPC1 disease using the total NPC-SS score, excluding the hearing domain and auditory brainstem response (ABR) modifier results, following 52 weeks of treatment for subjects treated with VTS-270 compared to sham controls and the Caregiver CGIC.

    Study Part C:
    The secondary study objectives are to:
    1. Assess the safety and tolerability of the B. Braun Celsite Spinal Access Port utilized to administer VTS-270 (device safety and tolerability substudy).
    2. Assess the plasma and cerebrospinal fluid (CSF) PK of VTS-270 concentrations in subjects receiving the 900 mg dose of VTS-270 via the B. Braun Celsite Spinal Access Port (device PK substudy).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    (1)Part C European Site-Specific Device Safety and Tolerability Substudy and (2) European Site-Specific Device PK Substudy.
    The both sub-studies are included into the main Protocol v11.0 dated 24-Aug-2018.

    Objectives for substudy (1):
    Assess the safety and tolerability of the B. Braun Celsite Spinal Access Port utilized to administer VTS-270 in approximately 6 subjects who are currently enrolled in VTS301 Part C.

    Objectives for substudy (2):
    Assess the plasma and CSF PK of VTS-270 and trough HP-β-CD concentration in subjects receiving the 900 mg dose of VTS-270 via the B. Braun Celsite Spinal Access Port.
    E.3Principal inclusion criteria
    Study Parts A and B – not applicable as Part A and B are completed.
    Study Part C – NO NEW SUBJECTS ARE ALLOWED TO ENTER THE STUDY AS OF 20 JANUARY 2021
    Inclusion Criteria:
    1. Subject has completed Study Part B, meets the criteria for dose reduction for a second time or meets the criteria for the rescue option
    OR
    2. Subject is a current participant in the NIH phase 1/2a open-label study and:
    a. Subject agrees to convert from the dose of VTS-270 currently receiving as a subject in the NIH phase 1/2a protocol to the dose chosen for Parts B and C of this study, 900 mg.
    b. Subject agrees to convert from the monthly dosing regimen used in the NIH phase 1/2a protocol to an every 2-week dosing regimen.
    c. In instances where NIH phase 1/2a subjects eligible to enroll into Study Part C are unable to convert from their current NIH phase 1/2a dose or monthly regimen, the investigator must receive prior written authorization from the sponsor for the subject to enter Part C of the study on an amended dose and/or regimen.
    OR
    3. Subject has received prior written authorization from Vtesse to enroll directly into Study Part C.
    4. Females of childbearing 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. Acceptable methods of contraception include barrier method with spermicide, intrauterine device, steroidal contraceptive in conjunction with a barrier method, abstinence, or same-sex partner.
    5. Subject or parent/guardian must provide written informed consent to participate in the study. In addition to parental consent, assent to participate must also be sought from minor children.

    Subject Inclusion Criteria for European Site-specific Device Safety and Tolerability Substudy – Not applicable – enrollment in the Device Substudy concluded Aug 2018.

    Subject Inclusion Criteria for the European Site-specific Device Pharmacokinetic (PK) Substudy – Not applicable – no subject consented to participate in the PK Substudy.
    E.4Principal exclusion criteria
    Study Parts A and B – not applicable as Part A and B are completed.
    Study Part C – NO NEW SUBJECTS ARE ALLOWED TO ENTER THE STUDY AS OF 20 JANUARY 2021

    Subject Exclusion Criteria for the European Site-specific Device Safety and Tolerability Substudy – Not applicable - enrollment in the Device Substudy concluded Aug 2018.
    E.5 End points
    E.5.1Primary end point(s)
    Study Part A/B is complete.
    Study Part C: as of 20 January 2021 no efficacy analyses will be performed.
    - The change from baseline to each assessment in a composite outcome that is the sum of the ambulation, cognition, fine motor, and swallowing components of the NPC-SS.
    - The change from baseline to each assessment in total NPC-SS with the hearing domain and auditory brainstem response (ABR) modifiers removed.
    - Proportion of responders (defined as no change or improvement on NPC-SS total score with hearing domain and ABR modifiers removed) at each assessment.
    - Proportion of Blinded Clinician-Clinical Global Impression of Change (CGIC) (defined as a score of no change, minimally improved, moderately improved, or markedly improved) at each assessment compared to baseline.
    - Summary of AEs, concomitant medications, physical examinations, audiologic examination, and clinical laboratories.
    - Change from baseline in the EQ-5D-3L questionnaire at each assessment.
    - Change from baseline to each assessment in each of the 9 clinical domains of the NPC-SS.
    - Change from baseline to each assessment in the total NPC-SS with hearing domain and ABR modifier included.
    - Time to one 1-point increase (worsening) in NPC-SS composite score.
    - The composite NPC-SS mean annualized rate of change (slope) from baseline to each assessment
    E.5.1.1Timepoint(s) of evaluation of this end point
    Study Part C: Treatment with VTS-270 should be discontinued as soon as possible; it will be permitted for up to an additional 9 months (20 October 2021), in consideration of the need to determine a transition plan. The potential extension of treatment is contingent upon re-consent of the subject and approval by their applicable EC and health authority.
    After 21 June 2021, subjects may continue to receive IT adrabetadex, only in case:
    -they appear to be benefiting from treatment based on investigator’s assessment, AND
    -they are aware of the risks associated with adrabetadex, including hearing loss, and understand that no significant differences were seen between patients treated with adrabetadex and sham-treated patients on any efficacy measures in this randomized, controlled trial.
    E.5.2Secondary end point(s)
    Study Part A/B: Not applicable as these analyses are complete.

    Study Part C: After 20 January 2021, efficacy endpoints for Study Part C will not be reported.
    • The change from baseline to each assessment in a composite outcome that is the sum of the ambulation, cognition, fine motor, and swallowing components of the NPC-SS
    • The change from baseline to each assessment in total NPC-SS with the hearing domain and ABR modifiers removed
    • Proportion of responders (defined as no change or improvement on NPC-SS total score with hearing domain and ABR modifiers removed) at each assessment
    • Proportion of Blinded Clinician-CGIC responders (defined as a score of no change, minimally improved, moderately improved, or markedly improved) at each assessment compared to baseline
    • Summary of AEs, concomitant medications, physical examinations, audiologic examination, and clinical laboratories
    • Change from baseline in the EQ-5D-3L questionnaire at each assessment
    • Change from baseline to each assessment in each of the 9 clinical domains of the NPC-SS
    • Change from baseline to each assessment in the total NPC-SS with hearing domain and ABR modifier included
    • Time to one point increase (worsening) in NPC-SS composite score
    • The composite NPC-SS mean annualized rate of change (slope) from baseline to each assessment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Study Part C: Treatment with VTS-270 should be discontinued as soon as possible; it will be permitted for up to an additional 9 months (20 October 2021), in consideration of the need to determine a transition plan. The potential extension of treatment is contingent upon re-consent of the subject and approval by their applicable EC and health authority.
    After 21 June 2021, subjects may continue to receive IT adrabetadex, only in case:
    -they appear to be benefiting from treatment based on investigator’s assessment, AND
    -they are aware of the risks associated with adrabetadex, including hearing loss, and understand that no significant differences were seen between patients treated with adrabetadex and sham-treated patients on any efficacy measures in this randomized, controlled trial.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Study Part C (Substudy): Safety and tolerability of the B. Braun Celsite Access Port System and Pharmacokinetics-Substudy
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Study Parts A and B of the trial are sham-controlled. Study Part C is open labelled.
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Turkey
    United States
    France
    Germany
    Italy
    Spain
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 35
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 16
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 51
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Study Part C will be an open-label extension phase of the study. Study Part A and B and NIH phase 1/2a subjects who transition into Study Part C will receive treatment with VTS-270 until
    • The Investigator considers VTS-270 to no longer be beneficial to the subject
    • The development program is discontinued.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-04-11
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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