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    Clinical Trial Results:
    A Randomised, Double-Blind, Multi-centre, Active Treatment, Extension and Safety Study for Patients with Idiopathic Parkinson’s Disease (PD) Who Previously Completed the CDNF/DDS Main Study HP-CD-CL-2002.

    Summary
    EudraCT number
    		 2018-000346-19
    Trial protocol
    		 SE   FI  
    Global end of trial date
    31 Aug 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HP-CD-CL-2003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herantis Pharma Plc
    Sponsor organisation address
    Bertel Jungin Aukio 1, FI-02600 , Espoo, Finland,
    Public contact
    Project Manager, Herantis Pharma Plc, dpo@herantis.com
    Scientific contact
    Project Manager, Herantis Pharma Plc, dpo@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
    31 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the safety and tolerability of – the IMP administered as long-term monthly intermittent bilateral intraputamenal CDNF infusions, and, – the investigational medical device for the intended long-term use and within the intended patient population during infusions.
    Protection of trial subjects
    All subjects received written and verbal information regarding the study. The given information emphasised that participation in the study was voluntary and that the subject could withdraw from the study at any time and for any reason. All subjects were given the opportunity to ask questions about the study and were given sufficient time to decide whether to participate in the study. Before any study-related procedures, the informed consent form was signed and personally dated by the subject (no patient needed a legally acceptable representative or witness) and by the person who conducted the informed consent discussion. The consent included information that data was recorded, collected, processed and could be transferred to European Economic Area (EEA) or non-EEA countries. In accordance with the European Union Data Protection Directive (95/46/EC), the data did not identify any persons taking part in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jul 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 10 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Finland: 7
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    10
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients who underwent surgery in the Main Protocol Phase study (CDNF/DDS Main Study HP-CD-CL-2002) for implantation of the four catheters of the Drug Delivery System (DDS) into each putamen (i.e., 2 catheters in each putamen).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 400 µg (mid dose, 200 µg/putamen)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cerebral Dopamine Neurotrophic Factor (CDNF)
    Investigational medicinal product code
    Other name
    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 infused via an implanted drug delivery system. The IMP was flushed out by infusing 4x 80 microlitres of artificial cerebrospinal fluid at the end of each infusion

    Arm title
    		 1200 µg (high dose, 600 µg/putamen)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cerebral Dopamine Neurotrophic Factor (CDNF)
    Investigational medicinal product code
    Other name
    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 infused via an implanted drug delivery system. The IMP was flushed out by infusing 4x 80 microlitres of artificial cerebrospinal fluid at the end of each infusion.

    Number of subjects in period 1
    		400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Started
    8
    7
    Completed
    8
    6
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    400 µg (mid dose, 200 µg/putamen)
    Reporting group description
    		 -

    Reporting group title
    1200 µg (high dose, 600 µg/putamen)
    Reporting group description
    		 -

    Reporting group values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen) Total
    Number of subjects
    		 8 7 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 5 10
        From 65-84 years
    		 3 2 5
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.6 ± 7.8 61.9 ± 8.4 -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 4 6 10
    Duration of disease (PD motor symptoms)
    Units: Subjects
        6 years
    		 1 0 1
        8 years
    		 0 1 1
        9 years
    		 1 1 2
        10 years
    		 2 2 4
        11 years
    		 1 0 1
        12 years
    		 0 1 1
        13 years
    		 1 1 2
        14 years
    		 2 1 3
    Hoehn and Yahr staging
    Units: Subjects
        staging 2
    		 4 3 7
        staging 2.5
    		 2 2 4
        staging 3
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    400 µg (mid dose, 200 µg/putamen)
    Reporting group description
    		 -

    Reporting group title
    1200 µg (high dose, 600 µg/putamen)
    Reporting group description
    		 -

    Primary: ECG

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    End point title
    		 ECG [1]
    End point description
    End point type
    Primary
    End point timeframe
    ECGs were recorded at Screening (Visit 18, Week 24; i.e., Visit 17 in the Main Protocol Phase), at interim visit (Visit 22, Week 37), and at End of Extension Phase (Visit 26, Week 49), for screening of coronary heart disease.
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: unit(s)
    arithmetic mean (standard deviation)
        PR interval (msec) - Visit 17 (Week 24) Baseline
    175.25 ± 31.33
    156.29 ± 14.30
        PR interval (msec) - Visit 26 (Week 49)
    170.00 ± 35.89
    150.80 ± 13.46
        QRS duration (msec) - Visit 17 (Week 24) Baseline
    96.50 ± 24.79
    90.57 ± 9.36
        QRS duration (msec) - Visit 26 (Week 49)
    96.25 ± 25.24
    86.80 ± 11.19
        QT (msec) - Visit 17 (Week 24) Baseline
    384.75 ± 48.01
    407.14 ± 16.85
        QT (msec) - Visit 26 (Week 49)
    390.00 ± 42.24
    394.80 ± 17.12
        QTc (msec) - Visit 17 (Week 24) Baseline
    419.75 ± 24.82
    419.00 ± 21.31
        QTc (msec) - Visit 26 (Week 49)
    416.63 ± 34.18
    426.60 ± 20.22
        Ventricular rate (bpm) - Visit 17 (Week 24)
    73.00 ± 11.92
    64.29 ± 9.34
        Ventricular rate (bpm) - Visit 26 (Week 49)
    69.63 ± 12.47
    70.80 ± 10.64
    No statistical analyses for this end point

    Primary: Beck Depression Inventory II (BDI-II)

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    End point title
    		 Beck Depression Inventory II (BDI-II) [2]
    End point description
    End point type
    Primary
    End point timeframe
    The self-administered questionnaire BDI was completed by the patients at screening (Visit 17, Week 24), at interim visit (Visit 22, Week 37), and at the End of Extension Phase (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: unit(s)
    arithmetic mean (standard deviation)
        Visit 17 (Week 24) - baseline
    8.63 ± 3.93
    9.00 ± 7.66
        Visit 26 (Week 49)
    9.13 ± 4.76
    8.17 ± 6.31
    No statistical analyses for this end point

    Primary: Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS)

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    End point title
    		 Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS) [3]
    End point description
    End point type
    Primary
    End point timeframe
    The self-administered questionnaire QUIP-RS was completed by the patients at screening (Visit 17, Week 24), at interim visit (Visit 22, Week 37), and at the End of Extension Phase (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: unit(s)
    arithmetic mean (standard deviation)
        Total ICD Score (A-D) - Visit 17 (Week 24)
    1.88 ± 2.47
    3.00 ± 5.92
        Total ICD Score (A-D) - Visit 26 (Week 49)
    1.88 ± 3.72
    1.50 ± 2.07
        Total QUIP-RS Score (A-G) - Visit 17 (Week 24)
    3.88 ± 4.64
    3.71 ± 6.95
        Total QUIP-RS Score (A-G) - Visit 26 (Week 49)
    3.75 ± 7.03
    3.00 ± 4.00
    No statistical analyses for this end point

    Primary: Montreal Cognitive Assessment (MoCA)

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    End point title
    		 Montreal Cognitive Assessment (MoCA) [4]
    End point description
    End point type
    Primary
    End point timeframe
    The MoCA was completed by the patients at screening (Visit 17, Week 24), at interim visit (Visit 22, Week 37), and at the End of Extension Phase (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: unit(s)
    arithmetic mean (standard deviation)
        Visit 17 (Week 24) - baseline
    28.88 ± 0.64
    28.00 ± 2.83
        Visit 26 (Week 49)
    29.25 ± 0.89
    26.80 ± 5.54
    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 [5]
    End point description
    Physical examination is the process of evaluating objective anatomic findings through the use of observation, palpation, percussion, and auscultation. The following body systems were examined: General Inspection/Upper extremities; head, eyes, ears, nose, throat, and superficial cervical lymph nodes; neck, shoulders, back; chest and lungs; cardiovascular; abdomen; lower extremities Baseline is defined as the Visit 17 (Week 24) assessment from the HP-CD-CL-2002 Study
    End point type
    Primary
    End point timeframe
    A physical examination was performed at Screening (Visit 18, Week 24; i.e., Visit 17 in the Main Protocol Phase), and at End of Extension Phase (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: unit(s)
    number (not applicable)
        Abdomen- baseline
    0
    0
        Abdomen - Visit 26 (Week 49)
    0
    0
        Cardiovascular - baseline
    0
    0
        Cardiovascular - Visit 26 (Week 49)
    0
    0
        Chest and lungs - baseline
    0
    0
        Chest and lungs - Visit 26 (Week 49)
    0
    0
        General inspection / Upper extremities - baseline
    1
    1
        General inspection / Upper extremities - Visit 26
    0
    1
        Head,eyes,ears,nose,throat,lymph nodes - baseline
    0
    0
        Head,eyes,ears,nose,throat,lymph nodes - Visit 26
    1
    0
        Lower extremities - baseline
    0
    1
        Lower extremities - Visit 26 (Week 49)
    0
    0
        Neck, shoulders and back - baseline
    1
    1
        Neck, shoulders and back - Visit 26 (Week 49)
    1
    1
        Motor function - baseline
    4
    5
        Motor function - Visit 26 (Week 49)
    7
    5
        Sensory function - baseline
    1
    0
        Sensory function - Visit 26 (Week 49)
    1
    1
        Cranial nerve function - baseline
    0
    1
        Cranial nerve function - Visit 26 (Week 49)
    0
    0
        Cortical functions - baseline
    0
    0
        Cortical functions - Visit 26 (Week 49)
    0
    1
    No statistical analyses for this end point

    Primary: Vital signs

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    End point title
    		 Vital signs [6]
    End point description
    End point type
    Primary
    End point timeframe
    Vital signs were assessed at Screening (Visit 18, Week 24; i.e., Visit 17 in the Main Protocol Phase), and at End of Extension Phase (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: unit(s)
    arithmetic mean (standard deviation)
        BMI (kg/m2)- Visit 17 (Week 24) baseline
    24.23 ± 3.86
    24.29 ± 3.77
        BMI (kg/m2) - Visit 26 (Week 49)
    24.22 ± 3.64
    23.86 ± 4.05
        Diastolic blood pressure (mmHg) - Visit 17
    80.13 ± 7.75
    76.00 ± 8.23
        Diastolic blood pressure (mmHg) - Visit 26
    81.50 ± 7.50
    70.20 ± 13.46
        Height (cm) - Visit 17 (Week 24) baseline
    168.38 ± 8.11
    179.57 ± 7.18
        Height (cm) - Visit 26 (Week 49)
    168.13 ± 8.31
    181.20 ± 7.85
        Pulse rate (bpm) - Visit 19 (Week 25)
    70.13 ± 14.72
    64.29 ± 5.94
        Pulse rate (bpm) - Visit 26 (Week 49)
    73.00 ± 10.80
    76.00 ± 8.57
        Systolic blood pressure (mmHg) - Visit 17
    129.75 ± 16.54
    137.86 ± 27.87
        Systolic blood pressure (mmHg) - Visit 26
    126.25 ± 12.15
    127.80 ± 21.81
        Temperature (C) - Visit 17 (Week 24) baseline
    36.56 ± 0.44
    36.54 ± 0.37
        Temperature (C) - Visit 26 (Week 49)
    36.75 ± 0.23
    36.64 ± 0.55
        Weight (kg) - Visit 17 (Week 24) baseline
    68.39 ± 9.11
    77.94 ± 10.28
        Weight (kg) - Visit 26 (Week 49)
    68.14 ± 8.55
    77.98 ± 11.73
    No statistical analyses for this end point

    Primary: Laboratory Variables - Abnormal with clinical relevance

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    End point title
    		 Laboratory Variables - Abnormal with clinical relevance [7]
    End point description
    There were no abnormal with clinical relevance laboratory values at baseline (i.e., at start of the Extension Phase at Week 24) nor at Visit 26 (Week 49, End of study). Clinical laboratory variables included: - Clinical chemistry (Alanine transaminase, Alkaline phosphatase, Aspartate transaminase, Bilirubin, Calcium, Creatine kinase, Creatinine and eGFR, Potassium, Sodium, IgG, Albumin, Urea) - Hematology analysis (Activated partial thromboplastin time (aPTT), International Normalized Ratio (INR), Hematocrit, Hemoglobin Leukocyte differential count, Mean cell hemoglobin of RBC (MCH), Mean cell volume of RBC (MCV), Platelet count, Red blood cell count (RBC), White blood cell count (WBC) - Urinalysis (Blood (alternative: erythrocytes), Glucose, Ketones, Leukocytes, Nitrites, pH, Protein)
    End point type
    Primary
    End point timeframe
    Laboratory variables were evaluated from the Extension Phase start (Visit 18, Week 24) to the end of treatment evaluation (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: number
        Laboratory Variable - Visit 17 (Week 24) baseline
    0
    0
        Laboratory Variable - Visit 26 (Week 49)
    0
    0
    No statistical analyses for this end point

    Primary: Anti-CDNF Antibodies - Abnormal

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    End point title
    		 Anti-CDNF Antibodies - Abnormal [8]
    End point description
    The samples from Visit 26 (Week 49) were analysed for anti-CDNF antibody titre and CDNF levels in serum, unless Visit 26 samples were not collected and further samples were analysed in case of a positive finding.
    End point type
    Primary
    End point timeframe
    Serum samples for CDNF were collected at Screening, prior to infusion of the 8th through to the 12th treatment dosing and at End of Extension Phase (Visit 26, Week 49).
    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: The primary endpoints were assessments of safety and no statistical testing was performed.
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: number
        Visit 21 (Week 33) - negative
    0
    1
        Visit 21 (Week 33) - positive
    0
    0
        Visit 22 (Week 37) - negative
    1
    0
        Visit 22 (Week 37) - positive
    0
    0
        Visit 23 (Week 41) - negative
    1
    0
        Visit 23 (Week 41) - positive
    0
    0
        Visit 24 (Week 45) - negative
    1
    1
        Visit 24 (Week 45) - positive
    0
    0
        Visit 26 (Week 49) - negative
    7
    5
        Visit 26 (Week 49) - positive
    1
    0
    No statistical analyses for this end point

    Secondary: Parkinson disease motor and non-motor symptoms by UPDRS part I-IV total scores and overall total scores

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    End point title
    		 Parkinson disease motor and non-motor symptoms by UPDRS part I-IV total scores and overall total scores
    End point description
    Placebo patients included at visit 9 (Week -1) were re-randomized for active treatment after the end of the main study.
    End point type
    Secondary
    End point timeframe
    From baseline in the Main Protocol Phase (Week -1), at Extension Phase start (Week 24), after three months (Week 37), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: score
    arithmetic mean (standard deviation)
        part I - Visit 9 (Week 1)
    1.00 ± 1.41
    2.00 ± 2.08
        part I - Visit 17 (Week 24)
    0.88 ± 0.99
    1.86 ± 1.77
        part I - Visit 26 (Week 49)
    0.75 ± 0.71
    2.67 ± 1.97
        part II - Visit 9 (Week 1)
    8.13 ± 6.31
    10.00 ± 4.16
        part II - Visit 17 (Week 24)
    8.38 ± 3.74
    12.14 ± 4.45
        part II - Visit 26 (Week 49)
    8.63 ± 5.66
    10.50 ± 5.68
        part III - Visit 9 (Week 1)
    28.75 ± 9.50
    32.43 ± 6.53
        part III - Visit 17 (Week 24)
    26.50 ± 5.76
    31.00 ± 10.23
        part III - Visit 26 (Week 49)
    26.00 ± 12.85
    31.00 ± 13.06
        part IV - Visit 9 (Week 1)
    6.25 ± 3.15
    5.86 ± 2.34
        part IV - Visit 17 (Week 24)
    6.88 ± 2.90
    5.14 ± 1.95
        part IV - Visit 26 (Week 49)
    6.63 ± 2.33
    5.50 ± 1.38
        UPDRS Total - Visit 9 (Week 1)
    44.13 ± 15.57
    50.29 ± 11.10
        UPDRS Total - Visit 17 (Week 24)
    42.63 ± 9.02
    50.14 ± 14.35
        UPDRS Total - Visit 26 (Week 49)
    42.00 ± 18.17
    47.40 ± 15.36
    No statistical analyses for this end point

    Secondary: Timed Up and Go (TUG) values

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    End point title
    		 Timed Up and Go (TUG) values
    End point description
    Placebo patients included at visit 9 (Week -1) were re-randomized for active treatment after the end of the main study.
    End point type
    Secondary
    End point timeframe
    From baseline in the Main Protocol Phase (Week -1), at Extension Phase start (Week 24), after three months (Week 37), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: seconds
    arithmetic mean (standard deviation)
        Visit 9 (Week -1) Baseline
    12.96 ± 5.73
    9.74 ± 2.87
        Visit 17 (Week 24)
    16.72 ± 19.63
    10.95 ± 5.20
        Visit 26 (Week 49)
    19.03 ± 27.16
    9.15 ± 2.96
    No statistical analyses for this end point

    Secondary: Functional status by home diary score - OFF time

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    End point title
    		 Functional status by home diary score - OFF time
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing (Week 0), at Extension Phase start (Week 24), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: hours
    arithmetic mean (standard deviation)
        Visit 10 (Week 0) First Dosing
    5.58 ± 2.48
    4.20 ± 2.47
        Visit 17 (Week 24)
    5.23 ± 2.03
    4.54 ± 1.38
        Visit 26 (Week 49)
    4.24 ± 3.30
    3.54 ± 2.42
    No statistical analyses for this end point

    Secondary: Functional status by home diary score - ON without dyskinesias

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    End point title
    		 Functional status by home diary score - ON without dyskinesias
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing (Week 0), at Extension Phase start (Week 24/Visit 18), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: hours
    arithmetic mean (standard deviation)
        Visit 10 (Week 0) First Dosing
    9.11 ± 4.68
    9.20 ± 1.93
        Visit 17 (Week 24)
    8.48 ± 1.93
    9.89 ± 2.51
        Visit 26 (Week 49)
    9.35 ± 1.59
    11.53 ± 3.25
    No statistical analyses for this end point

    Secondary: Functional status by home diary score - ON with non-troublesome dyskinesias

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    End point title
    		 Functional status by home diary score - ON with non-troublesome dyskinesias
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing (Week 0), at Extension Phase start (Week 24), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: hours
    arithmetic mean (standard deviation)
        Visit 10 (Week 0) First Dosing
    2.82 ± 3.60
    1.60 ± 2.15
        Visit 17 (Week 24)
    3.36 ± 3.05
    0.74 ± 1.12
        Visit 26 (Week 49)
    2.91 ± 2.28
    0.00 ± 0.00
    No statistical analyses for this end point

    Secondary: Functional status by home diary score - ON with troublesome dyskinesias

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    End point title
    		 Functional status by home diary score - ON with troublesome dyskinesias
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing (Week 0), at Extension Phase start (Week 24), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: hours
    arithmetic mean (standard deviation)
        Visit 10 (Week 0) First Dosing
    0.31 ± 0.58
    0.52 ± 0.97
        Visit 17 (Week 24)
    0.25 ± 0.42
    0.07 ± 0.19
        Visit 26 (Week 49)
    0.44 ± 0.62
    0.00 ± 0.00
    No statistical analyses for this end point

    Secondary: Functional status by home diary score - Bad time

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    End point title
    		 Functional status by home diary score - Bad time
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing (Week 0), at Extension Phase start (Week 24), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: hours
    arithmetic mean (standard deviation)
        Visit 10 (Week 0) First Dosing
    5.90 ± 2.15
    4.72 ± 2.20
        Visit 17 (Week 24)
    5.48 ± 1.90
    4.61 ± 1.35
        Visit 26 (Week 49)
    4.68 ± 3.20
    3.54 ± 2.42
    No statistical analyses for this end point

    Secondary: Functional status by home diary score - Good time

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    End point title
    		 Functional status by home diary score - Good time
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing (Week 0), at Extension Phase start (Week 24), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: hours
    arithmetic mean (standard deviation)
        Visit 10 (Week 0) First Dosing
    11.93 ± 2.92
    10.80 ± 1.63
        Visit 17 (Week 24)
    11.83 ± 1.95
    10.63 ± 2.27
        Visit 26 (Week 49)
    12.26 ± 2.32
    11.53 ± 3.25
    No statistical analyses for this end point

    Secondary: Parkinson disease questionnaire - PDQ-39 total score

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    End point title
    		 Parkinson disease questionnaire - PDQ-39 total score
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline in the Main Protocol Phase (Week -1), at Extension Phase start (Week 24), after three months (Week 37), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: score
    arithmetic mean (standard deviation)
        Visit 9 (Week -1) Baseline
    25.05 ± 12.30
    19.82 ± 9.80
        Visit 17 (Week 24)
    24.25 ± 12.41
    27.68 ± 9.92
        Visit 22 (Week 37)
    23.44 ± 13.18
    20.92 ± 14.86
        Visit 26 (Week 49)
    23.26 ± 13.42
    22.97 ± 12.99
    No statistical analyses for this end point

    Secondary: Clinical Global Impression

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    End point title
    		 Clinical Global Impression
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline in the Main Protocol Phase (Week -1), at Extension Phase start (Week 24), and at end of treatment evaluation (Week 49).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: score
    arithmetic mean (standard deviation)
        Visit 9 (Week -1) Baseline
    1.00 ± 0.00
    2.00 ± 1.73
        Visit 17 (Week 24)
    3.50 ± 0.76
    4.57 ± 0.53
        Visit 26 (Week 49)
    3.50 ± 0.93
    4.33 ± 0.82
    No statistical analyses for this end point

    Secondary: Patency of drug delivery system

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    End point title
    		 Patency of drug delivery system
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing in the Extension Phase (Week 25) until final treatment infusion (Week 45).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: number of lines
        All infusions constantly <590 mmHg
    192
    156
    No statistical analyses for this end point

    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
    Assessed at every treatment dosing visit during the Extension Phase of the study, i.e., Visit 19 (Week 25) through Visit 24 (Week 45).
    End point values
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Number of subjects analysed
    8
    7
    Units: number of events
        Looseness of port
    0
    0
        Surgical intervention to stabilise port
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire observation period (i.e., from Week 24 to Week 49) and on the days of infusion on Weeks 25, 29, 33, 37, 41, and 45, and during the entire study period outside of infusion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    400 µg (mid dose, 200 µg/putamen)
    Reporting group description
    		 -

    Reporting group title
    1200 µg (high dose, 600 µg/putamen)
    Reporting group description
    		 -

    Serious adverse events
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Infection
    Additional description: Infection without known location, unspecified
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 400 µg (mid dose, 200 µg/putamen) 1200 µg (high dose, 600 µg/putamen)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Elastofibroma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Implant site pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Implant site reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 7 (42.86%)
         occurrences all number
    1
    5
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hyperthermia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    1
    2
    Hallucination
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Nitrite urine present
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Weight decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nervous system disorders
    Cerebral gas embolism
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    3
    3
    Cerebral microhaemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 7 (71.43%)
         occurrences all number
    4
    9
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Parkinson's disease
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Pleurothotonus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Sensory disturbance
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Photokeratitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Skin reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blister
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Livedo reticularis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Pain in jaw
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Genital herpes
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Implant site infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Folate deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2019
    Protocol Amendment #1: - Additional exploratory analyses were added for already collected CSF samples in order to analyse changes in the aggregation propensity of α-synuclein in CSF, measure level of distribution of CDNF, and screen for proteomic biomarker. A saliva sample was collected for genome sequence testing for correlations with other endpoints; - Study period: The study period was prolonged to approximately 9 months;- PD medication prior to DAT-PET scanning: recommendation not to be off levodopa medication for 10 hours, and not off dopamine agonist or MAO-B inhibitors for 24 hours. - Deletion of procedures at Visit 19 (Week 25): At Visit 19, the following assessments to be originally performed prior to the seventh (7th) treatment infusion, were deleted: serum sample for anti-CDNF antibody, patient PD diary and PKG data collection. - Change in time window for MRI scan after infusion: The original MRI post-infusion protocol was updated to commence the MRI post-infusion within 60 minutes after the end of treatment infusion. - Silicon cap wearing regime: The new regimen instructed patients to wear the port cap immediately after surgery and, after dressings are removed, on a 12-hours on 12-hours off basis, wearing it overnight. - Explantation procedures after study discontinuation; - Change of forbidden concomitant medications; - Clarification of the explantation options; - Update of risk mitigation section; -Port assessment: Infusion should be postponed if there is purulent exudate when pressure is applied to the area around the port or the application set does not easily attach to the port; - Reporting of device deficiencies; - UPDRS off-score rating: The CSP was modified to clarify that the UPDRS OFF-score (part III motor part) rating for each individual patient should be performed by the same Investigator to reduce the effects of interrater variability.
    07 Apr 2020
    Protocol Amendment #2: - Visit window widened: Due to the COVID-19 outbreak, the hospital or the national authorities could lay upon restriction for patients travelling to or visiting the clinical sites (both the neurology clinics and PET centres). To allow some flexibility in scheduling the visits according to the protocol, the visit window for the last three infusion visits (Visits 22, 23, and 24) was widened from originally ±5 days to ±14 days. Based on the duration of the pharmacological effect observed in preclinical studies, the change in the visit window was deemed to not affect the outcome of the treatment. For the safety of the patient and to allow flexibility in the protocol, the DAT-PET visit (Visit 25) could be postponed until it was safe for the patient to visit the PET centre. Regardless of when the visit could be performed, the End of Study visit in the Extension Phase (Visit 26) was to be scheduled after Visit 25. Under these special circumstances, additional unscheduled visits could be arranged as remote (phone) visits if the postponement of Visit 25 and Visit 26 would take more than two months. - Cross-contamination safety precautions: During the COVID-19 outbreak, special precautions to reduce the risk of cross-contamination were to be considered. For that reason, and as the PKG devices and wrist bands could be used by several patients, the wristbands had to be sanitized at the clinical study site every time the device was collected and before it was sent out to the next patient.

    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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