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    Clinical Trial Results:
    A Phase I/II study to evaluate the safety and pharmacokinetics of intravenous Trappsol® Cyclo™ (HP-Beta-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

    Summary
    EudraCT number
    		 2015-005761-23
    Trial protocol
    		 GB   SE   IT  
    Global end of trial date
    03 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2022
    First version publication date
    23 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTD-TCNPC-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02912793
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cyclo Therapeutics, Inc.
    Sponsor organisation address
    6714 NW 16th Street, Suite B, Gainesville, United States, FL 32653
    Public contact
    Lise Kjems, MD PhD, CMO, Cyclo Therapeutics, Inc., lise.kjems@cyclodex.com
    Scientific contact
    Lise Kjems, MD PhD, CMO, Cyclo Therapeutics, Inc., lise.kjems@cyclodex.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Stage 1 • To compare the plasma pharmacokinetics of hydroxypropyl-β-cyclodextrin following three different single doses of intravenous Trappsol® in patients with NPC-1 Stage 2 • To evaluate the efficacy and tolerability of three different doses of Trappsol® in the management of clinical manifestations of NPC-1
    Protection of trial subjects
    This study was conducted in full conformance with the International Conference on Harmonisation (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki (October 2013), or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. Safety of the subjects was safeguarded through safety data review throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Israel: 6
    Worldwide total number of subjects
    12
    EEA total number of subjects
    1
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient in on 20th Jun 2017 and last patient out on 3rd Mar 2021. All patients recruited to hospital clinics.

    Pre-assignment
    Screening details
    		 13 patients were screened for up to 28 days before entry. One patient was excluded due to screen failure.

    Pre-assignment period milestones
    Number of subjects started
    		 13 [1]
    Number of subjects completed
    		 12

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Failed screening: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 13 patients were screened for up to 28 days before entry. One patient was excluded due to screen failure.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    Study drug was prepared by an on-site pharmacist; therefore, the blind for the Principal Investigator, site personnel and patient could be maintained. PK bioanalytical personnel and drug accountability monitors were unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trappsol® Cyclo™ IV 1500 mg/kg
    Arm description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trappsol® Cyclo™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks at a dose of 1500 mg/kg.

    Arm title
    		 Trappsol® Cyclo™ IV 2000 mg/kg
    Arm description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trappsol® Cyclo™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks at a dose of 2000 mg/kg.

    Arm title
    		 Trappsol® Cyclo™ IV 2500 mg/kg
    Arm description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trappsol® Cyclo™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks at a dose of 2500 mg/kg.

    Number of subjects in period 1
    		Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Started
    5
    4
    3
    Completed
    2
    4
    3
    Not completed
    3
    0
    0
         Consent withdrawn by subject
    1
    -
    -
         Physician decision
    1
    -
    -
         Unable to travel due to Covid restrictions
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trappsol® Cyclo™ IV 1500 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.

    Reporting group title
    Trappsol® Cyclo™ IV 2000 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.

    Reporting group title
    Trappsol® Cyclo™ IV 2500 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks

    Reporting group values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg Total
    Number of subjects
    		 5 4 3 12
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 3 3 2 8
        Adolescents (12-17 years)
    		 1 0 0 1
        Adults (18-64 years)
    		 1 1 1 3
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 12.2 (2 to 34) 13.5 (2 to 39) 10.7 (3 to 21) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 1 5
        Male
    		 2 3 2 7
    Race
    Units: Subjects
        White
    		 4 4 3 11
        Black/African
    		 1 0 0 1
    Weight
    Units: Kg
        arithmetic mean (full range (min-max))
    		 25 (11 to 58) 34.5 (13 to 68) 30.0 (15 to 45) -
    17-Domain Niemann-Pick disease Type C-Clinical Severity Scale
    Units: Points on scale 0-61
        arithmetic mean (standard deviation)
    		 21.0 ± 9.25 15.5 ± 7.42 17.7 ± 5.69 -

    End points

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    End points reporting groups
    Reporting group title
    Trappsol® Cyclo™ IV 1500 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.

    Reporting group title
    Trappsol® Cyclo™ IV 2000 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.

    Reporting group title
    Trappsol® Cyclo™ IV 2500 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks

    Subject analysis set title
    Across the dose range
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who were assigned to a treatment regimen (randomized, even if not dosed) constituted the ITT population. The ITT population was analyzed using the treatment assigned in the randomization schedule even if a patient was dosed incorrectly.

    Primary: To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (Cmax)

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    End point title
    		 To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (Cmax) [1]
    End point description
    To evaluate plasma PK of Trappsol® by comparison of Maximum Concentration (Cmax ) of the three doses.
    End point type
    Primary
    End point timeframe
    0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappsol® and 0.5,1,2,4,8 & 12 h after the end of the infusion
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analysis was not performed for this PK endpoint. Descriptive statistics are included.
    End point values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Number of subjects analysed
    5
    3 [2]
    3
    Units: ng/ml
        arithmetic mean (standard deviation)
    1272600 ± 489692
    1856667 ± 803140
    1920000 ± 121655
    Notes
    [2] - Sample missing for 1 patient
    No statistical analyses for this end point

    Primary: To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (Tmax)

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    End point title
    		 To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (Tmax) [3]
    End point description
    To evaluate plasma PK of Trappsol® by comparison of time to maximum concentration (tmax) of the three doses
    End point type
    Primary
    End point timeframe
    0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappsol® and 0.5,1,2,4,8 & 12 h after the end of the infusion
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analysis was not performed for this PK endpoint. Descriptive statistics are included.
    End point values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Number of subjects analysed
    5
    3
    3
    Units: hours
        arithmetic mean (standard deviation)
    5.66 ± 1.7
    6.7 ± 1.16
    6.02 ± 0.03
    No statistical analyses for this end point

    Primary: To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (Vd)

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    End point title
    		 To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (Vd) [4]
    End point description
    To evaluate plasma PK of Trappsol® by comparison of volume of distribution (Vd) of the three doses
    End point type
    Primary
    End point timeframe
    0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappsol® and 0.5,1,2,4,8 & 12 h after the end of the infusion
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analysis was not performed for this PK endpoint. Descriptive statistics are included.
    End point values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Number of subjects analysed
    5
    3
    3
    Units: ml/kg
        median (standard deviation)
    426 ± 168
    399 ± 193
    412 ± 107
    No statistical analyses for this end point

    Primary: To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (T1/2)

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    End point title
    		 To Evaluate the Plasma Pharmacokinetics of 3 Doses of Trappsol® by Measurement of Plasma Levels (T1/2) [5]
    End point description
    Plasma elimination half-life (T1/2)
    End point type
    Primary
    End point timeframe
    0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappsol® and 0.5,1,2,4,8 & 12 h after the end of the infusion
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analysis was not performed for this PK endpoint. Descriptive statistics are included.
    End point values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Number of subjects analysed
    5
    3
    3
    Units: Hours
        arithmetic mean (standard deviation)
    2.01 ± 0.27
    1.63 ± 0.15
    1.81 ± 0.259
    No statistical analyses for this end point

    Primary: To Evaluate the Cerebrospinal fluid (CSF) Pharmacokinetics of 3 Doses of Trappsol® (Concentration of HP-β-CD in the CSF)

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    End point title
    		 To Evaluate the Cerebrospinal fluid (CSF) Pharmacokinetics of 3 Doses of Trappsol® (Concentration of HP-β-CD in the CSF) [6]
    End point description
    To evaluate Concentration of HP-β-CD in the CSF of the three doses of Trappsol®
    End point type
    Primary
    End point timeframe
    8 hour after start of 1st Infusion
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analysis was not performed for this PK endpoint. Descriptive statistics are included.
    End point values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Number of subjects analysed
    2
    4
    2
    Units: ng/mL
        arithmetic mean (full range (min-max))
    232600 (22200 to 443000)
    22225 (0 to 48800)
    184400 (16800 to 352000)
    No statistical analyses for this end point

    Primary: To Evaluate CSF to Plasma ratio of 3 doses of Trappsol®

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    End point title
    		 To Evaluate CSF to Plasma ratio of 3 doses of Trappsol® [7]
    End point description
    The mean ratio of CSF HP-β-CD concentration to plasma HP-β-CD concentration in the three reporting groups
    End point type
    Primary
    End point timeframe
    0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappsol® and 0.5,1,2,4,8 & 12 h after the end of the infusion
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analysis was not performed for this PK endpoint. Descriptive statistics are included.
    End point values
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Number of subjects analysed
    3 [8]
    4 [9]
    3 [10]
    Units: Ratio
        arithmetic mean (standard deviation)
    0.215 ± 0.353
    0.0608 ± 0.124
    0.196 ± 0.157
    Notes
    [8] - 7 samples from 3 participants
    [9] - 8 samples from 4 participants
    [10] - 4 samples from 3 participants
    No statistical analyses for this end point

    Secondary: To Evaluate the Effect of Treatment on Plasma Biomarkers of NPC disease

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    End point title
    		 To Evaluate the Effect of Treatment on Plasma Biomarkers of NPC disease
    End point description
    Niemann-Pick disease type C (NPC-1)
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Across the dose range
    Number of subjects analysed
    2
    Units: % Change from baseline
    arithmetic mean (standard deviation)
        Lysosphingomyelin 509
    61.3 ± 17.7
    No statistical analyses for this end point

    Secondary: To Evaluate the Effect of Treatment on Biomarkers of Cholesterol Metabolism (Serum Lathosterol, 27-hydroxycholesterol, 24S-hydroxycholesterol)

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    End point title
    		 To Evaluate the Effect of Treatment on Biomarkers of Cholesterol Metabolism (Serum Lathosterol, 27-hydroxycholesterol, 24S-hydroxycholesterol)
    End point description
    End point type
    Secondary
    End point timeframe
    Various times post dosing (Day 3 post dose)
    End point values
    		 Across the dose range
    Number of subjects analysed
    7
    Units: Mean % of baseline
    arithmetic mean (standard deviation)
        Lathosterol
    59.11 ± 13.45
        27-hydroxycholesterol
    199.19 ± 45.69
        24S-hydroxycholesterol
    117.9 ± 6.74
    No statistical analyses for this end point

    Secondary: To Evaluate the Effect of Treatment on Biomarkers of Cholesterol Metabolism (LDL and HDL cholesterol)

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    End point title
    		 To Evaluate the Effect of Treatment on Biomarkers of Cholesterol Metabolism (LDL and HDL cholesterol)
    End point description
    End point type
    Secondary
    End point timeframe
    Various times post dosing (Day 3 post dose)
    End point values
    		 Across the dose range
    Number of subjects analysed
    12
    Units: Mmol/L
    arithmetic mean (standard deviation)
        LDL cholesterol
    4.06 ± 0.83
        HDL cholesterol
    1.35 ± 0.24
    No statistical analyses for this end point

    Secondary: To Evaluate the Effect of Treatment on CSF Biomarkers of NPC disease

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    End point title
    		 To Evaluate the Effect of Treatment on CSF Biomarkers of NPC disease
    End point description
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Across the dose range
    Number of subjects analysed
    2
    Units: % baseline
    arithmetic mean (full range (min-max))
        CSF Tau
    48.83 (28.11 to 69.56)
    No statistical analyses for this end point

    Secondary: To Evaluate the Effect of Treatment on NIH NPC severity scale 17

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    End point title
    		 To Evaluate the Effect of Treatment on NIH NPC severity scale 17
    End point description
    NIH NPC severity scale (NCSS) (17 item) and Clinical Global Impression (CGI-I)
    End point type
    Secondary
    End point timeframe
    NIH NPC severity scale Week 48, CGI Week 12 and Week 48
    End point values
    		 Across the dose range
    Number of subjects analysed
    12 [11]
    Units: Mean Score
    arithmetic mean (standard deviation)
        NCSS Mean total score
    17.3 ± 5.97
        CGI-I Mean score w 12
    2.9 ± 0.89
        CGI-I Mean score End of study
    2.7 ± 1.0
    Notes
    [11] - 11 subjects analysed for CGI-I mean score
    No statistical analyses for this end point

    Other pre-specified: To Evaluate the Effect of Treatment on Liver and Spleen Morphology

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    End point title
    		 To Evaluate the Effect of Treatment on Liver and Spleen Morphology
    End point description
    Measure of organ length by ultrasound
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to end of study
    End point values
    		 Across the dose range
    Number of subjects analysed
    8 [12]
    Units: Cm
    arithmetic mean (standard deviation)
        Change in liver size
    -0.198 ± 1.235
        Change in spleen size
    -1.22 ± 1.415
    Notes
    [12] - 6 subjects analysed for change in spleen size
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were continuously monitored throughout the study from signing of the ICF until the last follow-up assessment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Trappsol® Cyclo™ IV 1500 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.

    Reporting group title
    Trappsol® Cyclo™ IV 2000 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks.

    Reporting group title
    Trappsol® Cyclo™ IV 2500 mg/kg
    Reporting group description
    		 HP-β-CD was administered as Trappsol® Cyclo™ 25% (250 mg/mL) diluted with normal saline as needed up to a set volume by slow IV infusion over a period of 8 to 9 hours every 2 weeks

    Serious adverse events
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    2 / 3 (66.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza/Influenza B
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Trappsol® Cyclo™ IV 1500 mg/kg Trappsol® Cyclo™ IV 2000 mg/kg Trappsol® Cyclo™ IV 2500 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    3 / 3 (100.00%)
         occurrences all number
    1
    0
    5
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    2
    Peripheral Swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Catheter Site Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Catheter Site Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Gait Disturbance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 4 (25.00%)
    2 / 3 (66.67%)
         occurrences all number
    3
    2
    7
    Rhinorrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Tonsillar Hypertrophy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Mood swings
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Acoustic Stimulation Tests Abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    6
    0
    Blood Cholesterol Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Body Temperature Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    High Density Lipoprotein Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Low Density Lipoprotein Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Weight Decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    3
    Fall
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    2
    Gastrostomy Tube Site Complication
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    5
    Head Injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Post Lumbar Puncture Syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural Pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Pericardial Effusion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    3
    Cataplexy
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    2
    Cerebrospinal Fluid Leakage
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Ataxia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Dyskinesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Petit Mal Epilepsy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    0
    4
    Restless Legs Syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Speech Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Cerumen Impaction
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 4 (75.00%)
    2 / 3 (66.67%)
         occurrences all number
    3
    4
    5
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    3 / 3 (100.00%)
         occurrences all number
    1
    3
    6
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Abdominal Distension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Frequent Bowel Movements
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    0
    Pigmentation Lip
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    1
    1
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    Swelling face
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Muscle twitching
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 4 (25.00%)
    2 / 3 (66.67%)
         occurrences all number
    4
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    2 / 3 (66.67%)
         occurrences all number
    1
    2
    3
    Rhinitis
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    4
    6
    Tonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Viral Infection
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Anal Fungal Infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2016
    Version 2.0 Removal of VFSE; correction to Figure 1 Study Schematic; correction of NCCS to NCSS; AE causality changed from yes/no to unlikely, possibly, probably; neurology testing and PBMCs added to Day 1 in Table of Assessments
    06 Sep 2016
    Version 2.1 Expanded definition of effective contraception in exclusion criterion 11; exclusion criterion 12 added breastfeeding females; discontinuation criteria for CTCAE G3 ototoxicity and CTCAE G3 renal failure added; change of "expected adverse events" to observed and SUSAR requirements added; emergency unblinding process added
    18 Oct 2016
    Version 3.0, Protocol amendment 1 Updated as per SA1
    09 May 2018
    Version 4.0, Protocol amendment 2 All NSA2 and SA2 changes added
    21 Nov 2019
    Version 5.0, Protocol amendment 3 SWE - Addition of interim analysis; change to EU representative; IB version 4.0; change of company name from CTD Holdings to Cyclo Therapeutics, Inc.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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