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    Summary
    EudraCT Number:2015-005761-23
    Sponsor's Protocol Code Number:CTD-TCNPC-201
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-08-03
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-005761-23
    A.3Full title of the trial
    A Phase I/II study to evaluate the safety and pharmacokinetics of intravenous Trappsol Cyclo (HP-β-CD) in patients with Niemann-Pick disease type C (NPC-1) and the pharmacodynamic effects of treatment upon markers of cholesterol metabolism and clinical outcomes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II study to evaluate Trappsol Cyclo (hydroxypropyl-β-cyclodextrin) in patients with Niemann-Pick disease type C (NPC-1) to assess what the drug does to the body, and what the body does to the drug, and the side effects and benefits experienced by patients
    A.4.1Sponsor's protocol code numberCTD-TCNPC-201
    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 SponsorCyclo Therapeutics, Inc.
    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 supportCyclo Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCyclo Therapeutics, Inc.
    B.5.2Functional name of contact pointCSO & SVPMA
    B.5.3 Address:
    B.5.3.1Street Address6714 NW 16th Street, Suite B
    B.5.3.2Town/ cityGainesville
    B.5.3.3Post codeFL 32653
    B.5.3.4CountryUnited States
    B.5.6E-mailsharon.hrynkow@cyclodex.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/3/11/895
    D.3 Description of the IMP
    D.3.1Product nameTrappsol Cyclo
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNhydroxypropyl-beta-cyclodextrin
    D.3.9.1CAS number 128446-35-5
    D.3.9.2Current sponsor codeTrappsol Cyclo
    D.3.9.3Other descriptive namehydroxypropyl-beta-cyclodextrin
    D.3.10 Strength
    D.3.10.1Concentration unit % (W/V) percent weight/volume
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    Niemann-Pick disease type C
    E.1.1.1Medical condition in easily understood language
    A rare, genetically inherited and neurologically progressive disease in which fatty substances accumulate in the brain and other major organs
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029403
    E.1.2Term Niemann-Pick disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Stage 1
    • To compare the plasma pharmacokinetics of hydroxypropyl-β-cyclodextrin following 3 different single doses of intravenous Trappsol Cyclo in patients with NPC-1

    Stage 2
    • To evaluate the efficacy and tolerability of 3 different doses of Trappsol Cyclo in the management of clinical manifestations of NPC-1
    E.2.2Secondary objectives of the trial
    Stage 1
    • To investigate the effect of 3 different doses of intravenous Trappsol Cyclo in patients upon serum and lymphocytic markers of cholesterol metabolism in patients with NPC-1
    • To evaluate hydroxypropyl-β-cyclodextrin concentrations in cerebrospinal fluid following intravenous administration of Trappsol Cyclo in patients with NPC-1

    Stage 2
    • To investigate the effect of 3 different doses of intravenous Trappsol Cyclo upon serum and lymphocytic markers of cholesterol metabolism in patients with NPC-1
    • To evaluate the impact of treatment upon measures of neurological function including ataxia, cognitive impairment, fine motor skills and saccadic eye movements in patients with NPC-1
    • To evaluate the impact of treatment upon behavioural aspects of NPC-1 disease
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Confirmed diagnosis of NPC-1 defined as one of the following:
    a) Two NPC-1 mutations on genotyping
    b) One NPC-1 mutation and positive filipin staining (current or prior)
    c) Vertical supranuclear gaze palsy [VSNGP] plus either ≥ one NPC-1 mutation or positive filipin staining and no NPC-2 mutations
    2. NIH NPC Severity Score <30 and with no more than 4 individual domains with a score ≥ 3.
    3. Age range: 2 years upwards
    a) Inclusion of the first three paediatric patients will be restricted to individuals aged ≥ 5 years. Once the first three paediatric patients have safely completed stage 1, study entry will be open to all ages ≥2 years as per the protocol.
    4. Negative pregnancy test for females of child bearing potential
    5. Written, informed consent
    E.4Principal exclusion criteria
    1. The presence of NPC-2 mutations on genotyping
    2. Previous receipt of cyclodextrin therapy
    3. Lanksy score < 50 if aged ≤16 or Karnofsky score < 40 if aged > 16.
    4. Inability to comply with the proposed protocol assessments
    5. Concurrent treatment with any type of cholesterol lowering agents such as statins, fibrates, ezetimibe
    6. Concurrent medical conditions representing a contraindication to any of the study medications
    7. Stage 3 chronic kidney disease (CKD) or worse as indicated by an eGFR < 60 mL/min/1.73 m2. In patients aged ≤ 18 years, eGFR is calculated according to the Schwartz equation (ref: Schwartz GJ & Work DF) and in patients aged > 18 years eGFR is calculated using the MDRD equation
    8. Clinical evidence of acute liver disease including symptoms of jaundice or right upper quadrant pain or international normalised ratio (INR) >1. 8
    9. Involvement in another interventional clinical trial within the previous 6 months from screening
    10. Weight >100 kg
    11. Females of childbearing potential who are not willing to use a method of highly effective
    contraception (hormonal contraception, intrauterine device, intrauterine hormone-releasing system,
    bilateral tubal occlusion, vasectomised partner, or true abstinence) during the study and the followup
    period. True abstinence can only be in line with the preferred and usual lifestyle of the subject.
    Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration
    of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
    12. Females who are breastfeeding
    E.5 End points
    E.5.1Primary end point(s)
    Stage 1
    • Plasma concentrations of HP-β-CD during and following infusion to evaluate Tmax, Cmax, volume of distribution and elimination half-life (at 0, 2, 4, 6 and 8 hours after the start of infusion and 30 minutes, 1, 2, 4, 8 and 12 hours after the end of the infusion)

    Stage 2
    • Change from baseline in global impression of disease severity at 48 weeks
    • The proportion of patients at 48 weeks with a reduction from baseline of at least one point in two or more domains of the NIH NPC severity scale
    E.5.1.1Timepoint(s) of evaluation of this end point
    See Section E.5.1.
    In addition, interim analysis will be performed
    E.5.2Secondary end point(s)
    Stage 1
    • Change from baseline in serum cholesterol precursors (lanosterol, lathosterol, desmosterol) and cholesterol metabolites/bile acid precursors (4b-, 24S-, 25-, 27- hydroxycholesterol) (days 2, 3, 5, 8, and 15 post-dose in Stage 1)
    • Change from baseline in markers of lipid trafficking in peripheral blood mononuclear cells (PBMCs) (at day 15 post-dose in Stage 1)
    • CSF concentrations of HP-β-CD at 4, 8 and 12 hours following the start of the intravenous administration. In paediatric patients the number of samples may be reduced at the discretion of the Investigator to one post dose sample taken approximately within 1 hour after the end of the infusion. (Stage 1)
    • AEs, laboratory abnormalities, time to withdrawal due to AE (every visit)

    Stage 2
    • Change from baseline in serum cholesterol precursors (lanosterol, lathosterol, desmosterol) and cholesterol metabolites/bile acid precursors (4b-, 24S-, 25-, 27- hydroxycholesterol) (4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 weeks)
    • Change from baseline in markers of lipid trafficking in peripheral blood mononuclear cells (PBMCs) (12, 24, 36 and 48 weeks)
    • Change from baseline in NIH NPC severity scale at 12, 24, 36 and 48 weeks
    • Change from baseline in individual NIH NPC scale domains at 12, 24, 36 and 48 weeks
    • Change from baseline in neurologic symptoms at 12, 24, 36 and 48 weeks
    - ataxia (using the Scale for the assessment and rating of ataxia [SARA] scale)*
    - cognitive impairment (using the Mini-Mental State Evaluation score [MMSE])*
    - saccadic eye movements
    - fine motor skills (using the bead threading test)*
    *In patients where age and cognitive function allow
    • Change from baseline in hepatic, splenic and renal morphology (abdominal ultrasound) at 24 and 48 weeks
    • Change from baseline in quality of life using the PedsQL (Pediatric Quality of Life Inventory) at 12, 24, 36 and 48 weeks
    • AEs, laboratory abnormalities, time to withdrawal due to AE (every visit)
    • Auditory acuity assessment (weeks 12, 24, 36, 48 and follow-up)
    E.5.2.1Timepoint(s) of evaluation of this end point
    See Section E.5.2
    In addition, interim analysis will be performed
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Trappsol Cyclo has previously been administered in a compassionate use/named patient programme.
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Yes
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Pharmacist is unblinded to dose.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    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: 6
    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: 3
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The nature of the disease under study means that some potential adult participants may have impaired capacity to make informed consent decisions or the participants may be too young to provide informed assent.
    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 6
    F.4.2.2In the whole clinical trial 11
    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)
    Patients who complete the study treatment will be offered the opportunity to continue receiving IMP either through a follow on protocol or on an individual treatment basis as appropriate.
    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 Decision2016-09-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-26
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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