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    Clinical Trial Results:
    A Phase I-II, Randomised, Double-Blind, Placebo Controlled, Safety and Tolerability Study of Intermittent Bilateral Intraputamenal Cerebral Dopamine Neurotrophic Factor (CDNF) Infusions Administered via an Investigational Drug Delivery System to Patients with Idiopathic Parkinson’s Disease (PD) of Moderate Severity.

    Summary
    EudraCT number
    2015-004175-73
    Trial protocol
    FI  
    Global end of trial date
    19 Dec 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    05 May 2021
    First version publication date
    05 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HP-CD-CL-2002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03295786
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Herantis Pharma Plc
    Sponsor organisation address
    Bertel Jungin Aukio 1, Espoo, Finland, 02600
    Public contact
    Project Director, Herantis Pharma Plc, 358 401585669, sigrid.booms@herantis.com
    Scientific contact
    Project Director, Herantis Pharma Plc, 358 401585669, sigrid.booms@herantis.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
    18 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the safety and tolerability of - the investigational medicinal product administered as monthly intermittent bilateral intraputamenal CDNF infusions, and, - the investigational medical device for the intended use and within the intended patient population during device implantation and follow-up, including the test infusion procedure. To demonstrate the accuracy of investigational device as implantation accuracy to the target site during implantation surgery.
    Protection of trial subjects
    The evening before any off-medication assessments, patients were to stay overnight at the clinic or patient-hotel for safety reasons. In some cases the patient was allowed to stay overnight at home without medication, if their caregiver could bring the patient to the clinic the next morning. Patients were allowed to take their normal anti-Parkinson medication prior to DAT-PET imaging, to prevent them from having painful cramps while in the scanner. After the first and second treatment dosing, patients were monitored for safety for 24 hours. After any subsequent treatment dosing, patients were advised not to drive or operate machines for 24 hours.
    Background therapy
    Patients were allowed to continue to use their anti-Parkinson's medication as prescribed.
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Finland: 7
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    11
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient first visit of the study was in Sweden on 03 October 2017. The first patient first visit in Finland was on 20 February 2018, after the DSMB recommended to open two more sites for recruitment and surgery in Finland and Sweden. The last patient recruited in Sweden was on 19 November 2018 and in Finland on 27 February 2019.

    Pre-assignment
    Screening details
    Altogether 26 patients were screened of which 19 patients were eligible, but two patients withdrew their consent prior to surgery and randomisation. Three patients met some of the psychiatric exclusion criteria, and three other patients had medical conditions making them unsuitable for inclusion. One patient's motor state was not advanced enough.

    Period 1
    Period 1 title
    Screening
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    patients would be randomised after surgery, meeting the post-surgery inclusion criteria and none of the exclusion criteria.

    Arms
    Arm title
    Eligibility screening
    Arm description
    Screening for eligibility to undergo surgery for implantation of drug delivery system.
    Arm type
    Eligibility screening

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Eligibility screening
    Started
    17
    Completed
    17
    Period 2
    Period 2 title
    Surgery, Baseline and Treatment period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Vehicle
    Arm description
    artificial cerebrospinal fluid is used as the vehicle.
    Arm type
    Placebo

    Investigational medicinal product name
    artificial cerebrospinal fluid
    Investigational medicinal product code
    Other name
    vehicle
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intracerebral use
    Dosage and administration details
    4x 480 micro litre was infused intracerebrally via an implanted drug delivery system.

    Arm title
    CDNF mid-dose
    Arm description
    CDNF formulated in artificial cerebrospinal fluid to a final concentration of 0.25 mg/mL
    Arm type
    Experimental

    Investigational medicinal product name
    CDNF
    Investigational medicinal product code
    CDNF
    Other name
    rhCDNF
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intracerebral use
    Dosage and administration details
    4x 400 microlitres of CDNF solution for infusion was infusion via an implanted drug delivery system. The IMP was flushed out by infusing 4x 80 micrometers of artificial cerebrospinal fluid at the end of each infusion.

    Arm title
    CDNF high-dose
    Arm description
    CDNF formulated in artificial cerebrospinal fluid to a final concentration of 0.75 mg/mL.
    Arm type
    Experimental

    Investigational medicinal product name
    CDNF
    Investigational medicinal product code
    CDNF
    Other name
    rhCDNF
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intracerebral use
    Dosage and administration details
    4x 400 microlitres of CDNF solution for infusion was infusion via an implanted drug delivery system. The IMP was flushed out by infusing 4x 80 micrometers of artificial cerebrospinal fluid at the end of each infusion.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the screening and surgery period. Baseline assessments for the drug are done 1 week before first dosing, ie. approximately 7 weeks after surgical implantation of the drug delivery system.
    Number of subjects in period 2
    Vehicle CDNF mid-dose CDNF high-dose
    Started
    6
    6
    5
    Completed
    5
    5
    5
    Not completed
    1
    1
    0
         Adverse event, non-fatal
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vehicle
    Reporting group description
    artificial cerebrospinal fluid is used as the vehicle.

    Reporting group title
    CDNF mid-dose
    Reporting group description
    CDNF formulated in artificial cerebrospinal fluid to a final concentration of 0.25 mg/mL

    Reporting group title
    CDNF high-dose
    Reporting group description
    CDNF formulated in artificial cerebrospinal fluid to a final concentration of 0.75 mg/mL.

    Reporting group values
    Vehicle CDNF mid-dose CDNF high-dose Total
    Number of subjects
    6 6 5 17
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Mean age of the patients who underwent surgery and thereafter randomised to the treatment group.
    Units: years
        arithmetic mean (standard deviation)
    63.8 ± 6.4 63.2 ± 8.9 57.8 ± 6.7 -
    Gender categorical
    Units: Subjects
        Female
    1 3 1 5
        Male
    5 3 4 12
    Subject analysis sets

    Subject analysis set title
    Vehicle screening
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Surgical Analysis Set (FSAS) for analysis of device objectives from the day of surgery onwards.

    Subject analysis set title
    CDNF mid-dose
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Surgical Analysis Set (FSAS) for analysis of device objectives from the day of surgery onwards.

    Subject analysis set title
    CDNF high-dose
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Surgical Analysis Set (FSAS) for analysis of device objectives from the day of surgery onwards.

    Subject analysis sets values
    Vehicle screening CDNF mid-dose CDNF high-dose
    Number of subjects
    6
    6
    5
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Mean age of the patients who underwent surgery and thereafter randomised to the treatment group.
    Units: years
        arithmetic mean (standard deviation)
    63.8 ± 6.4
    63.2 ± 8.9
    57.8 ± 6.7
    Gender categorical
    Units: Subjects
        Female
    1
    3
    1
        Male
    5
    3
    4

    End points

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    End points reporting groups
    Reporting group title
    Eligibility screening
    Reporting group description
    Screening for eligibility to undergo surgery for implantation of drug delivery system.
    Reporting group title
    Vehicle
    Reporting group description
    artificial cerebrospinal fluid is used as the vehicle.

    Reporting group title
    CDNF mid-dose
    Reporting group description
    CDNF formulated in artificial cerebrospinal fluid to a final concentration of 0.25 mg/mL

    Reporting group title
    CDNF high-dose
    Reporting group description
    CDNF formulated in artificial cerebrospinal fluid to a final concentration of 0.75 mg/mL.

    Subject analysis set title
    Vehicle screening
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Surgical Analysis Set (FSAS) for analysis of device objectives from the day of surgery onwards.

    Subject analysis set title
    CDNF mid-dose
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Surgical Analysis Set (FSAS) for analysis of device objectives from the day of surgery onwards.

    Subject analysis set title
    CDNF high-dose
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Surgical Analysis Set (FSAS) for analysis of device objectives from the day of surgery onwards.

    Primary: Beck Depression Inventory II (BDI-II)

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    End point title
    Beck Depression Inventory II (BDI-II) [1]
    End point description
    Mean change; as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    Baseline (Week -1) to End-of-Study (Week 24)
    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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        arithmetic mean (standard deviation)
    0.0 ± 2.12
    -0.20 ± 2.68
    4.60 ± 5.18
    No statistical analyses for this end point

    Primary: questionnaire for impulsive-compulsive disorder in Parkinson’s disease rating scale (QUIP_RS)

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    End point title
    questionnaire for impulsive-compulsive disorder in Parkinson’s disease rating scale (QUIP_RS) [2]
    End point description
    Mean change; as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    Baseline (Week -1) to End-of-Study (Week 24)
    Notes
    [2] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: total score
        arithmetic mean (standard deviation)
    2.75 ± 4.19
    -2.50 ± 4.95
    5.00 ± 5.66
    No statistical analyses for this end point

    Primary: Montreal Cognitive Assessment (MoCA)

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    End point title
    Montreal Cognitive Assessment (MoCA) [3]
    End point description
    Mean change; as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    Baseline (Week -1) to End-of- Study (Week 24)
    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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        least squares mean (standard deviation)
    0.00 ± 1.87
    0.60 ± 1.52
    0.40 ± 2.61
    No statistical analyses for this end point

    Primary: Physical Examination – Abnormal with clinical relevance

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    End point title
    Physical Examination – Abnormal with clinical relevance [4]
    End point description
    Shift number of patients with abnormal measurements with clinical relevance; as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    Baseline (Week -1) to End-of-Study (Week 24)
    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: safety endpoint, descriptive statistics
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5 [5]
    5 [6]
    5
    Units: normal - abnormal no CR - abnormal CR
    number (not applicable)
        Abdomen – Baseline
    0
    0
    0
        Abdomen – Week 24
    0
    0
    0
        Cardiovascular – Baseline
    0
    0
    0
        Cardiovascular – Week 24
    0
    0
    0
        Chest and lungs – Baseline
    0
    0
    0
        Chest and lungs – Week 24
    0
    0
    0
        General inspection / Upper extremitis – Baseline
    0
    0
    0
        General inspection / Upper extremitis – Week 24
    0
    1
    1
        Head,eyes,ears,nose,throat,lymph nodes – Baseline
    0
    0
    0
        Head,eyes,ears,nose,throat,lymph nodes – Week 24
    0
    0
    0
        Lower extremities – Baseline
    0
    1
    0
        Lower extremities – Week 24
    1
    0
    0
        Neck, shoulders and back – Baseline
    0
    1
    0
        Neck, shoulders and back – Week 24
    0
    1
    1
    Notes
    [5] - Only patients with a baseline value and End of Study (Week 24) value are represented in this table.
    [6] - Only patients with a baseline value and End of Study (Week 24) value are represented in this table.
    No statistical analyses for this end point

    Primary: Vital Signs - diastolic/systolic blood pressure, pulse rate, temperature, weight

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    End point title
    Vital Signs - diastolic/systolic blood pressure, pulse rate, temperature, weight [7]
    End point description
    as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    at End-of-Study (Week 24)
    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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: mmHg, bpm, degrees Celsius, kg
    least squares mean (standard deviation)
        Diastolic blood pressure
    77.40 ± 7.50
    79.80 ± 8.29
    77.40 ± 9.63
        Systolic blood pressure
    149.40 ± 143.00
    123.80 ± 123.00
    127.40 ± 124.00
        Pulse rate
    66.20 ± 11.50
    75.20 ± 9.78
    73.00 ± 11.68
        Body Temperature
    36.26 ± 0.24
    36.78 ± 0.41
    36.62 ± 0.38
        Body Weight
    70.08 ± 7.45
    70.16 ± 11.15
    78.30 ± 12.39
    No statistical analyses for this end point

    Primary: Clinical Laboratory Variables - Clinical Chemistry

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    End point title
    Clinical Laboratory Variables - Clinical Chemistry [8]
    End point description
    Clinical Chemistry; as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    at End-of-Study (Week 24)
    Notes
    [8] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: ukat/L,umol/L,ml/min/1.73,mmol/ml,g/L
    number (not applicable)
        ALP
    1.34
    1.36
    1.42
        ALT
    0.14
    0.21
    0.19
        AST
    0.36
    0.37
    0.33
        Albumin
    40.60
    42.00
    39.40
        Bilirubin
    8.00
    8.80
    9.60
        Calcium
    2.31
    2.34
    2.37
        Creatinine kinase
    1.69
    1.70
    1.27
        Creatinine
    63.20
    68.60
    64.80
        IgG
    9.30
    11.12
    9.99
        Potassium
    3.78
    3.90
    4.06
        Sodium
    139.20
    139.80
    140.80
        Urea
    5.56
    7.22
    7.06
        eGFR
    73.50
    86.67
    111.00
    No statistical analyses for this end point

    Primary: Clinical Laboratory Variables - Hematology

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    End point title
    Clinical Laboratory Variables - Hematology [9]
    End point description
    as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    at End-of-Study (Week 24)
    Notes
    [9] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: 10E9/L, g/L, pg, fL, 10E12/L, s
    number (not applicable)
        Basophils
    0.09
    0.08
    0.07
        Eosinophils
    0.17
    0.15
    0.11
        Hematocrit
    16.45
    16.05
    24.58
        Hemoglobin
    137.40
    135.40
    142.60
        INR
    1.06
    1.00
    1.03
        Lymphocytes
    1.72
    1.91
    1.27
        MCH
    30.80
    30.00
    30.00
        MCV
    92.00
    89.60
    88.80
        Monocytes
    0.45
    0.40
    0.51
        Neutrophils
    3.67
    3.23
    5.04
        Platelet count
    267.40
    247.20
    281.40
        RBC
    4.46
    4.52
    4.76
        WBC
    6.04
    5.76
    6.98
        aPTT
    26.20
    27.40
    30.50
    No statistical analyses for this end point

    Primary: Clinical Laboratory Variables - Urinalysis (dipstick)

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    End point title
    Clinical Laboratory Variables - Urinalysis (dipstick) [10]
    End point description
    as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    at End-of-Study (Week 24)
    Notes
    [10] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: present/absent
    number (not applicable)
        Blood
    3.00
    2.00
    1.00
        Glucose
    0.00
    0.00
    0.00
        Ketones
    1.00
    1.00
    1.00
        Leukocytes
    1.50
    1.00
    0.00
        Protein
    1.00
    1.00
    0.00
        pH
    6.74
    5.10
    5.20
    No statistical analyses for this end point

    Primary: ECG

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    End point title
    ECG [11]
    End point description
    Difference in mean value from baseline; as part of the overall safety assessment
    End point type
    Primary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    Notes
    [11] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: msec, bpm
    least squares mean (standard deviation)
        PR Interval
    12.80 ± 13.46
    3.60 ± 9.53
    -154.60 ± 302.83
        QRS duration
    -3.20 ± 6.42
    0.40 ± 4.10
    -1.20 ± 3.03
        QT
    -2.80 ± 18.14
    -10.80 ± 18.36
    4.40 ± 7.92
        QTc
    -5.20 ± 16.32
    -11.20 ± 10.71
    -5.00 ± 13.69
        Ventricular rate
    0.20 ± 8.64
    0.40 ± 9.02
    -3.60 ± 6.11
    No statistical analyses for this end point

    Primary: Adverse Events

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    End point title
    Adverse Events [12]
    End point description
    Two periods are reported, to distinguish between the Adverse Events related to the surgery, procedures, and device, and, the Adverse Events reported after IMP treatment start.
    End point type
    Primary
    End point timeframe
    From Surgery (Week -8) to Treatment Start (Week 0), and, from Treatment Start (Week 0) to End-of-Study (Week 24)
    Notes
    [12] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    6
    6
    5
    Units: 200
        Surgery until Treatment Start
    34
    28
    30
        Treatment Start until End-of-Study
    34
    36
    38
    No statistical analyses for this end point

    Primary: Anti-CDNF Antibody (ADA)

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    End point title
    Anti-CDNF Antibody (ADA) [13]
    End point description
    As part of the overall safety analysis.
    End point type
    Primary
    End point timeframe
    At Baseline (Week -1) and prior to the last dosing (Week 20).
    Notes
    [13] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: positive/negative units
        positive
    0
    0
    0
        negative
    5
    5
    5
    No statistical analyses for this end point

    Primary: Positional accuracy of Implantation

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    End point title
    Positional accuracy of Implantation [14]
    End point description
    The positional accuracy measured by comparing the tip of each individual catheter defined in the plan of the surgical procedure (target) with the position of each catheter measured by the post-operative CT scan (actual) given as the resultant of the X, Y and Z axes error between the target and actual tip position.
    End point type
    Primary
    End point timeframe
    Surgery - Visit 4 (Week -8)
    Notes
    [14] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    6
    6
    5
    Units: mm
        arithmetic mean (standard deviation)
    1.93 ± 0.83
    0.97 ± 0.77
    1.62 ± 0.98
    No statistical analyses for this end point

    Primary: Anatomical accuracy of implantation

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    End point title
    Anatomical accuracy of implantation [15]
    End point description
    Number of patients with both catheter tips within each putamen and the number of patients the surgeon answered 'yes' to the question “Satisfied with the location of the catheter position from a safety perspective?” (with one answer for all catheters altogether).
    End point type
    Primary
    End point timeframe
    Surgery - Visit 4 (Week -8)
    Notes
    [15] - 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: safety endpoint, descriptive statistics.
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    6
    6
    5
    Units: Number of patients
        Both catheters left putamen
    6
    6
    5
        Both catheters right putamen
    6
    6
    5
        Surgeon satisfied with location
    6
    6
    5
    No statistical analyses for this end point

    Secondary: Unified Parkinson's Disease Rating Scale - Part III (UPDRS III)

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    End point title
    Unified Parkinson's Disease Rating Scale - Part III (UPDRS III)
    End point description
    Estimated difference vs. placebo
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    -1.1 (-10.6 to 8.3)
    -2.0 (-11.6 to 7.5)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose
    Statistical analysis description
    Analysis of change from Baseline to Week 24 in UPDRS Part III, OFF stage (Full Analysis Set)
    Comparison groups
    CDNF mid-dose v Vehicle
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose
    Statistical analysis description
    Analysis of change from Baseline to Week 24 in UPDRS Part III, OFF stage (Full Analysis Set)
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.65
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - all CDNF
    Statistical analysis description
    Analysis of change from Baseline to Week 24 in UPDRS Part III, OFF stage (Full Analysis Set)
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.68
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Unified Parkinson's Disease Rating Scale - Parts I-IV (UPDRS Total)

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    End point title
    Unified Parkinson's Disease Rating Scale - Parts I-IV (UPDRS Total)
    End point description
    Estimated difference vs. placebo
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
    least squares mean (confidence interval 95%)
        UPDRS Part I
    0 (0 to 0)
    0.2 (-1.9 to 2.2)
    1.3 (-0.7 to 3.2)
        UPDRS Part II
    0 (0 to 0)
    -0.4 (-5.3 to 4.5)
    -0.1 (-5.0 to 4.7)
        UPDRS Part III
    0 (0 to 0)
    -1.1 (-10.6 to 8.3)
    -2.0 (-11.6 to 7.5)
        UPDRS Part IV
    0 (0 to 0)
    2.7 (1.0 to 4.4)
    0.7 (-1.0 to 2.3)
        UPDRS Total
    0 (0 to 0)
    1.9 (-10.3 to 14.1)
    -0.3 (-12.5 to 11.9)
    Statistical analysis title
    ANCOVA for Total UPDRS Score - mid-dose
    Statistical analysis description
    Analysis of change from Baseline to Week 24 in Total UPDRS Score (Full Analysis Set) vs. Vehicle
    Comparison groups
    CDNF mid-dose v Vehicle
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.74
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA for Total UPDRS Score - high-dose
    Statistical analysis description
    Analysis of change from Baseline to Week 24 in Total UPDRS Score (Full Analysis Set) vs. Vehicle
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.96
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA for Total UPDRS Score - all CDNF
    Statistical analysis description
    Analysis of change from Baseline to Week 24 in Total UPDRS Score (Full Analysis Set) vs. Vehicle
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.87
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Timed Up-and-Go test (TUG)

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    End point title
    Timed Up-and-Go test (TUG)
    End point description
    Change from Baseline until End-of-Study vs. Vehicle
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: seconds
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    -3.6 (-17.0 to 9.8)
    3.9 (-8.6 to 16.4)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose
    Comparison groups
    Vehicle v CDNF mid-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.56
    Method
    ANCOVA
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.51
    Method
    ANCOVA
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - all CDNF
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.92
    Method
    ANCOVA
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Unified Parkinson's Disease Rating Scale Part I (UPDRS I)

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    End point title
    Unified Parkinson's Disease Rating Scale Part I (UPDRS I)
    End point description
    Mean change from baseline to end-of-study vs. Vehicle
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    0.2 (-1.9 to 2.2)
    1.3 (-0.7 to 3.2)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose
    Comparison groups
    Vehicle v CDNF mid-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.87
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - all CDNF
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.35
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Unified Parkinson's Disease Rating Scale Part II (UPDRS II)

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    End point title
    Unified Parkinson's Disease Rating Scale Part II (UPDRS II)
    End point description
    Change from baseline until end-of-study vs. Vehicle
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    -0.4 (-5.3 to 4.5)
    -0.1 (-5.0 to 4.7)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose
    Comparison groups
    Vehicle v CDNF mid-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.95
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - all CDNF
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.88
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Unified Parkinson's Disease Rating Scale Part IV (UPDRS IV)

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    End point title
    Unified Parkinson's Disease Rating Scale Part IV (UPDRS IV)
    End point description
    Change from baseline until end-of-study vs. Vehicle
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    2.7 (1.0 to 4.4)
    0.7 (-1.0 to 2.3)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose
    Comparison groups
    Vehicle v CDNF mid-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0042
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - all CDNF
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.059
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Parkinson's Home Diary

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    End point title
    Parkinson's Home Diary
    End point description
    Mean change from baseline to end-of-study vs. Vehicle in OFF, ON with troublesome dyskinesias, ON with non-troublesome dyskinesias, ON. In addition the derived average Bad time (OFF + ON with troublesome dyskinesias) and derived average Good time (ON without troublesome dyskinesias + ON) are assessed in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: hours
    least squares mean (confidence interval 95%)
        Derived average Bad time
    0 (0 to 0)
    2.6 (0.9 to 4.3)
    0.8 (-0.9 to 2.5)
        Derived average Good time
    0 (0 to 0)
    -0.7 (-3.7 to 2.3)
    0.3 (-2.6 to 3.2)
        OFF
    0 (0 to 0)
    2.4 (0.5 to 4.3)
    0.7 (-1.1 to 2.6)
        ON with troublesome dyskinesias
    0 (0 to 0)
    0.1 (-0.5 to 0.7)
    0.0 (-0.6 to 0.5)
        ON without troublesome dyskinesias
    0 (0 to 0)
    0.4 (-4.0 to 4.9)
    -1.3 (-5.7 to 3.2)
        ON
    0 (0 to 0)
    -0.5 (-4.4 to 3.4)
    1.6 (-2.0 to 5.1)
    Statistical analysis title
    ANCOVA (FAS) - Bad time all CDNF vs. Vehicle
    Comparison groups
    Vehicle v CDNF mid-dose v CDNF high-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.039
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - Good time all CDNF vs. Ve...
    Comparison groups
    Vehicle v CDNF mid-dose v CDNF high-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.89
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - OFF time all CDNF vs. V...
    Comparison groups
    Vehicle v CDNF mid-dose v CDNF high-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - ON with dyskinesias, all CDNF
    Comparison groups
    Vehicle v CDNF mid-dose v CDNF high-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.89
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - ON without dyskinesias, all...
    Comparison groups
    Vehicle v CDNF mid-dose v CDNF high-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.83
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - ON time all CDNF
    Comparison groups
    Vehicle v CDNF mid-dose v CDNF high-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.62
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Parkinson's Disease Questionnaire - 39 point (PDQ-39)

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    End point title
    Parkinson's Disease Questionnaire - 39 point (PDQ-39)
    End point description
    Mean change in score from baseline until end-of-study vs. Vehicle
    End point type
    Secondary
    End point timeframe
    from Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    1.8 (-13.2 to 16.9)
    5.1 (-9.9 to 20.2)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose vs. vehicle
    Comparison groups
    Vehicle v CDNF mid-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.79
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose vs. vehicle
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.47
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    Copy of ANCOVA (FAS) - all CDNF vs. vehicle
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Clinical Global Impression (CGI)

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    End point title
    Clinical Global Impression (CGI)
    End point description
    Mean change in scale from baseline to end-of-study vs. Vehicle. 7 point scale to indicate if in the opinion of the investigator is doing better or worse than the previous assessment (1=very much better, 4=no change, 7= very much worse).
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1) until End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: scale
        least squares mean (confidence interval 95%)
    0 (0 to 0)
    0.1 (-1.1 to 1.4)
    0.6 (-0.6 to 1.8)
    Statistical analysis title
    ANCOVA (FAS) - mid-dose vs. Vehicle
    Comparison groups
    Vehicle v CDNF mid-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - high-dose vs. Vehicle
    Comparison groups
    Vehicle v CDNF high-dose
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.27
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    Copy of ANCOVA (FAS) - all CDNF vs. Vehicle
    Comparison groups
    Vehicle v CDNF high-dose v CDNF mid-dose
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.41
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Port Stability

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    End point title
    Port Stability
    End point description
    Number of cessation of infusions the inability to secure an external system due to looseness of port (Looseness of port) and the need for surgical removal of the transcutaneous port or surgical intervention to stabilise the port (Surgical intervention to stabilise the port).
    End point type
    Secondary
    End point timeframe
    Visit 6 vehicle infusion (Week -5) to Visit 15 (Week 20)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    6
    6
    5
    Units: Number of events
        Looseness of port
    0
    0
    0
        Surgical intervention to stabilise port
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Patency

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    End point title
    Patency
    End point description
    The patency of the drug delivery system measured as occurrence of blockage of an individual implanted catheter preventing or limiting infusion as measured by pressure rise above 590 mmHg.
    End point type
    Secondary
    End point timeframe
    Post-implantation (Week -5) until end of treatment evaluation (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    6
    6
    5
    Units: Pressure rises above 590 mmHg
        Catheters >590 mmHg at individual infusion
    0
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Dopamine Transporter Positron Emission Tomography (DAT-PET)

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    End point title
    Dopamine Transporter Positron Emission Tomography (DAT-PET)
    End point description
    Mean change analysed for six predefined brain areas.
    End point type
    Other pre-specified
    End point timeframe
    From pre-treatment (Week -2) until post-treatment (Week 22)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: BPnd
    least squares mean (standard deviation)
        Total Nucleus caudate
    -0.28 ± 0.13
    -0.05 ± 0.25
    -0.28 ± 0.30
        Total Putamen
    -0.10 ± 0.09
    0.08 ± 0.19
    -0.13 ± 0.12
        Total Striatum
    -0.17 ± 0.07
    0.03 ± 0.18
    -0.19 ± 0.19
        Total Substantia nigra
    -0.04 ± 0.08
    0.07 ± 0.26
    -0.10 ± 0.08
        Total Ventral striatum
    -0.26 ± 0.15
    0.09 ± 0.33
    -0.37 ± 0.36
        Total infused putamen
    -0.09 ± 0.09
    0.10 ± 0.21
    -0.15 ± 0.13
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetics - CDNF concentration

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    End point title
    Pharmacokinetics - CDNF concentration
    End point description
    CDNF concentration in blood serum and cerebrospinal fluid (CSF) before and after the sixth dosing
    End point type
    Other pre-specified
    End point timeframe
    at Baseline (Week -1; CSF only) and after the sixth dosing (Week 20)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: ng/mL
    arithmetic mean (standard deviation)
        CSF prior to infusion
    5.0 ± 0
    5.0 ± 0
    5.0 ± 0
        CSF 2h post end of infusion
    5.0 ± 0
    82.2 ± 65.4
    131.8 ± 129.5
        Serum prior to infusion
    1.0 ± 1.2
    0.8 ± 0.4
    1.9 ± 1.9
        Serum 2h post end of infusion
    1.0 ± 1.2
    1.0 ± 0.7
    4.6 ± 2.1
        Serum 4h post end of infusion
    0.9 ± 1.0
    1.2 ± 0.9
    4.2 ± 1.8
    No statistical analyses for this end point

    Other pre-specified: Parkinson's Kinetigraph (PKG)

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    End point title
    Parkinson's Kinetigraph (PKG)
    End point description
    Mean change estimated different of the two treatment groups vs. vehicle.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0) End-of-Study (Week 24)
    End point values
    Vehicle CDNF mid-dose CDNF high-dose
    Number of subjects analysed
    5
    5
    5
    Units: score
    least squares mean (confidence interval 95%)
        Mean Daily BK>=III
    0 (0 to 0)
    -12.5 (-33.8 to 8.7)
    -5.6 (-26.9 to 15.7)
        Mean Daily DK>=III
    0 (0 to 0)
    3.4 (-13.6 to 20.3)
    5.0 (-11.7 to 21.8)
        Median BKS
    0 (0 to 0)
    -5.2 (-13.5 to 3.1)
    -3.1 (-11.5 to 5.2)
        Median BKS (LED corrected)
    0 (0 to 0)
    -8.5 (-23.1 to 6.2)
    -3.2 (-18.9 to 12.4)
        Median DKS
    0 (0 to 0)
    0.9 (-7.4 to 9.3)
    2.9 (-5.4 to 11.2)
        Median DKS (LED corrected)
    0 (0 to 0)
    1.1 (-8.0 to 10.2)
    3.1 (-6.4 to 12.7)
    Statistical analysis title
    ANCOVA (FAS) - BK>=III all CDNF vs. Vehicle
    Statistical analysis description
    Full Analysis Set
    Comparison groups
    CDNF mid-dose v CDNF high-dose v Vehicle
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - DK>=III all CDNF vs. Veh...
    Statistical analysis description
    Full Analysis Set
    Comparison groups
    CDNF mid-dose v CDNF high-dose v Vehicle
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.52
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) - BKS all CDNF vs. Vehicle
    Statistical analysis description
    Full Analysis Set
    Comparison groups
    CDNF mid-dose v CDNF high-dose v Vehicle
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.22
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) -BKS LED adjusted all CDNF vs Vehicle
    Comparison groups
    CDNF mid-dose v CDNF high-dose v Vehicle
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) -DKS all CDNF vs. Vehicle
    Comparison groups
    CDNF mid-dose v CDNF high-dose v Vehicle
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.56
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    ANCOVA (FAS) -DKS LED adjusted all CDNF vs Vehicle
    Comparison groups
    CDNF mid-dose v CDNF high-dose v Vehicle
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.58
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Other pre-specified: Coverage of the infusate in target anatomy

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    End point title
    Coverage of the infusate in target anatomy [16]
    End point description
    Coverage of the infusate in putamen, as assessed by MRI, as a percentage of infusate volume over putamen volume.
    End point type
    Other pre-specified
    End point timeframe
    first vehicle infusion (Week -5)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics.
    End point values
    Vehicle CDNF mid-dose
    Number of subjects analysed
    1 [17]
    1 [18]
    Units: percent volume/volume
    number (not applicable)
        Percentage coverage left putamen
    67.00
    65.45
        Percentage coverage right putamen
    60.64
    74.68
    Notes
    [17] - Gadolinium removed from the market during trial, only first two patients analysed (first infusion)
    [18] - Gadolinium removed from the market during trial, only first two patients analysed (first infusion)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From surgery (Week -8) to end of study (Week 24). In addition, a separate analysis was done from surgery (Week -8) to first dosing (Week 0), and from first dosing (Week 0) to end of study (Week 24).
    Adverse event reporting additional description
    All adverse events occurring during the study were reported and collected in the eCRF, starting from obtained Informed Consent and until End of Study visit in the study. AEs/ADEs were collected with non-leading questions at each clinic visit, by direct observation of the patient, or by spontaneous reports by the patient.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Vehicle
    Reporting group description
    all patients who underwent surgery and were later randomised to the vehicle treatment group.

    Reporting group title
    CDNF mid-dose
    Reporting group description
    all patients who underwent surgery and were later randomised to the mid-dose CDNF treatment group.

    Reporting group title
    CDNF high-dose
    Reporting group description
    all patients who underwent surgery and were later randomised to the high-dose CDNF treatment group.

    Serious adverse events
    Vehicle CDNF mid-dose CDNF high-dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Radius fracture
    Additional description: A month after surgery, prior to treatment start, the patient fell and fractured their radius. The patient underwent surgery to set the fracture. The patient recovered.
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (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
    Implant site necrosis
    Additional description: Necrosis of the skin around the port site four weeks after surgery, prior to treatment start. The patient underwent skin graft plastic surgery and fully recovered.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State / disorientation
    Additional description: Post-surgery, prior to treatment start, the patients were hospitalised due to disorientation or confusional state. The patients recovered.
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Implant site infection
    Additional description: Two weeks after surgery, prior to treatment start, the patient was hospitalised due to suspected infection of the skin around the port site. The patient was treated with antibiotics and fully recovered.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
    Additional description: The patient was diagnosed with a brain abscess by MRI after receiving several treatment infusions. The infection likely happened during an infusion.
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Vehicle CDNF mid-dose CDNF high-dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Aortic dilatation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Surgical and medical procedures
    Carpal tunnel decompression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Dental operation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Impaired healing
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    2
    Implant site necrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    3
    1
    Implant site reaction
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    4 / 5 (80.00%)
         occurrences all number
    3
    4
    11
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Confusional state
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    2
    Delusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    0
    3
    Hallucination
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    1
    Impulse-control disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    3
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Irritability
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    Foot fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Head injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    2
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
         occurrences all number
    2
    1
    2
    Procedural pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Radius fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Tendon rupture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood pressure systolic increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram T wave inversion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic enzyme increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Nitrite urine present
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Cerebral microhaemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Dyskinesia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    0
    Headache
         subjects affected / exposed
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    1 / 5 (20.00%)
         occurrences all number
    3
    5
    2
    Neuralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Pleurothotonus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Sensory disturbance
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Balance disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Cranial nerve disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Motor dysfunction
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    2
    1
    0
    Parkinson's disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    1
    Tremor
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Cerebral gas embolism
    Additional description: Non-symptomatic, based on imaging findings showing air or fluid pockets.
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    4 / 5 (80.00%)
         occurrences all number
    7
    5
    9
    Visual field defect
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Corneal erosion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Strabismus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    3
    Renal and urinary disorders
    Leukocyturia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Micturition urgency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Product issues
    Device leakage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Skin dystrophy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle rigidity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Spinal column stenosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Hyponatraemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Brain abscess
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Implant site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    3
    2
    Infected bite
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Infusion site infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Skin infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2017
    Eligibility criteria modified to more clearly define inclusion and discontinuation criteria. Plans for treatment after completion of the study - extension study. Recording of infusion pump pressures. Clarification of the timeframe to conduct the post-infusion MRI. Review timepoints of safety lab and imaging scans for safety clarified.
    16 Feb 2018
    Deletion of gadolinium test-infusions. Introduction of an optional CT(A) scan.
    16 Feb 2018
    Timepoint correction for PET. Neurological examination. Discontinuation criterion clarifying missing of an infusion. Clarification of follow-up data for the DSMB. Clarification of medication recording during surgery. Instructions for LED calculation. Deletion of thrombin time testing.
    18 Apr 2019
    Update of risk mitigation section. Port assessment and instructions when an infusion should be postponed. Silicon cap wearing regime changed. Allowance of anti-Parkinson medication prior to PET scanning.
    28 Aug 2019
    Additional exploratory analysis - proteomics biomarkers and alpha-synuclein. Study period was extended by 9 months. MRI scans before and after an infusion. Concomitant medication and use of selegiline. UPDRS off-score rating by same rater. Safety laboratory variables. Reporting of device deficiencies.

    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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