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    Clinical Trial Results:
    A Placebo-Controlled, Randomised, Double-Blind Trial to Assess the Safety and Efficacy of Intermittent Bilateral Intraputamenal Glial Cell Line-Derived Neurotrophic Factor (GDNF) Infusions Administered via Convection Enhanced Delivery (CED) in Subjects with Parkinson’s Disease

    Summary
    EudraCT number
    2011-003866-34
    Trial protocol
    GB  
    Global end of trial date
    29 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Dec 2020
    First version publication date
    04 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2553
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03652363
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    North Bristol NHS Trust
    Sponsor organisation address
    Level 3, Learning & Research building, Bristol, United Kingdom, BS10 5NB
    Public contact
    Clinical Trials Manager Helen Lewis, North Bristol NHS Trust (NBT) , +44 1173236468, research@nbt.nhs.uk
    Scientific contact
    Clinical Trials Manager Helen Lewis, North Bristol NHS Trust (NBT) , +44 1173236468, research@nbt.nhs.uk
    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
    06 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assessing the benefit and safety of administering intermittent glial cell line derived neurotrophic factor (GDNF) infusions in PD. At present only drugs which improve the symptoms of Parkinson’s disease (PD) are available. What is needed is a treatment which slows or reverses disease progression. The aim of this research is to test such a treatment. We have now developed an in-house device which animal model studies suggest will allow GDNF to be given much more reliably to the putamen area of the brain. We feel that this now allows for definitive testing of GDNFs effects in humans. We propose conducting a placebo controlled trial of intermittent GDNF infusions in 42 patients at our centre. We anticipate that the information gained from this study, if successful, will rapidly lead to a large multinational trial with the prospect of a new disease slowing therapy being available to PD patients within 5 years.
    Protection of trial subjects
    Ahead of enrolling "Primary Study Participants (n=36)", six "Pilot Study Participants" will be enrolled (4 active GDNF; 2 placebo). The pilot study cohort safety data was submitted for the MHRA evaluation after the last of the pilot patients had received three months of infusions. Only after the MHRA reported their evaluation satisfactory were we permitted to begin enrolling Primary Study Stage patients, during this evaluation period, however, the pilot patients continued to receive infusions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Oct 2012
    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
    United Kingdom: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    35
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between October 2012 and April 2015, 196 subjects from throughout the UK were pre-screened, of whom 64 patients underwent full study screening , 43 were enrolled and implanted with the device, and 41 were randomized and treated with study medication (6 in the Pilot Stage, 35 in the Primary Stage).

    Pre-assignment
    Screening details
    Eligibility criteria and informed consent followed by a series of questions relating to having Parkinson's disease, their health and medications. Participants underwent a physical examination, measuring; blood pressure, memory, ECG and submitting a blood sample. If eligible participants completed a 3 day motor diary, and additional screening visits

    Period 1
    Period 1 title
    Primary (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    GDNF
    Arm description
    Intermittent Bilateral intraputamenal convection enhanced delivery of GDNF for Parkinson's Disease
    Arm type
    Experimental

    Investigational medicinal product name
    Glial Cell Line-Derived Neurotrophic Factor (GDNF)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intracerebral use
    Dosage and administration details
    Post-randomization the n=35 patients that made up the primary stage population, from which the primary and secondary outcome measures were determined, received a total of 10 study treatments at 4-week intervals (Weeks 0 to 36). At each treatment, 400 ml of infusate (300 ml GDNF or placebo, followed by 100 ml artificial CSF) were delivered per catheter. The infusate GDNF concentration was 0.2 mg/ml, and the total GDNF dose given every 4 weeks was 240 mg (120 mg/putamen). The pilot stage patients received infusions every 2 weeks at 0.1 μg/μL.

    Arm title
    Placebo
    Arm description
    Intermittent Bilateral intraputamenal convection enhanced delivery of artificial CSF, aCSF
    Arm type
    Placebo

    Investigational medicinal product name
    Artificial Cerebral Spinal Fluid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intracerebral use
    Dosage and administration details
    Initially received every 2 weeks, this was adjusted during the Pilot phase to every 4 weeks

    Number of subjects in period 1
    GDNF Placebo
    Started
    21
    20
    Completed
    21
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GDNF
    Reporting group description
    Intermittent Bilateral intraputamenal convection enhanced delivery of GDNF for Parkinson's Disease

    Reporting group title
    Placebo
    Reporting group description
    Intermittent Bilateral intraputamenal convection enhanced delivery of artificial CSF, aCSF

    Reporting group values
    GDNF Placebo Total
    Number of subjects
    21 20 41
    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)
    17 18 35
        From 65-84 years
    4 2 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.9 ± 8.75 54.3 ± 7.6 -
    Gender categorical
    Units: Subjects
        Female
    12 7 19
        Male
    9 13 22
    Race
    Units: Subjects
        White
    21 19 40
        Asian
    0 1 1
    Hoehn and Yahr stage in OFF state
    Hoehn and Yahr stage in OFF state (n %)
    Units: Subjects
        Stage 0
    0 0 0
        Stage 1
    0 0 0
        Stage 1.5
    0 0 0
        Stage 2
    11 5 16
        Stage 2.5
    4 9 13
        Stage 3
    6 6 12
    Weight
    Weight at Baseline (kg)
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    76.15 ± 14.201 79.34 ± 21.216 -
    Height
    Height at baseline (m)
    Units: meter
        arithmetic mean (standard deviation)
    1.707 ± 0.08 1.714 ± 0.099 -
    BMI
    BMI at baseline (kg/m^2)
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    26.096 ± 4.22 26.758 ± 5.55 -
    NARTerror score
    National Adult Reading Test (NART) error score is the number of words pronounced incorrectly out of 50 total words.
    Units: Points
        arithmetic mean (standard deviation)
    11.8 ± 5.36 13.3 ± 6.91 -
    Duration since first PD symptoms
    Units: Years
        arithmetic mean (standard deviation)
    10.6 ± 5.01 10.6 ± 5.54 -
    Duration since PD diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    8.6 ± 4.39 7.9 ± 3.5 -
    Responsiveness to levodopa
    Units: percent
        arithmetic mean (standard deviation)
    56.86 ± 11.303 54.17 ± 9.977 -

    End points

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    End points reporting groups
    Reporting group title
    GDNF
    Reporting group description
    Intermittent Bilateral intraputamenal convection enhanced delivery of GDNF for Parkinson's Disease

    Reporting group title
    Placebo
    Reporting group description
    Intermittent Bilateral intraputamenal convection enhanced delivery of artificial CSF, aCSF

    Primary: Percentage change in the practically defined OFF state UPDRS motor score

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    End point title
    Percentage change in the practically defined OFF state UPDRS motor score
    End point description
    End point type
    Primary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    17
    18
    Units: Percentage
        arithmetic mean (standard deviation)
    -17.3 ± 17.6
    -11.8 ± 15.76
    Statistical analysis title
    Treatment Comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4123
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.9
         upper limit
    7.1
    Variability estimate
    Standard deviation

    Secondary: Percentage change in UPDRS motor score (part III) in the ON state

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    End point title
    Percentage change in UPDRS motor score (part III) in the ON state
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    21
    20
    Units: Percentage
        arithmetic mean (standard deviation)
    -8.2 ± 32.36
    6.1 ± 22.26
    Statistical analysis title
    Treatment Comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1108
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.1
         upper limit
    3.4

    Secondary: Percentage change in UPDRS mentation, behavior, and mood score (part I)

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    End point title
    Percentage change in UPDRS mentation, behavior, and mood score (part I)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    17
    18
    Units: Percentage
        arithmetic mean (standard deviation)
    48.3 ± 164.51
    -18.6 ± 58.03
    Statistical analysis title
    Treatment Comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.1331
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23
         upper limit
    163.4

    Secondary: Percentage change in UPDRS complications of therapy score (part IV)

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    End point title
    Percentage change in UPDRS complications of therapy score (part IV)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    17
    18
    Units: Percentage
        arithmetic mean (standard deviation)
    6.9 ± 34.32
    15 ± 43.37
    Statistical analysis title
    Treatment Comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.4197
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Percentage change in UPDRS ADL score (part II) in the OFF and in the ON state

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    End point title
    Percentage change in UPDRS ADL score (part II) in the OFF and in the ON state
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    21
    20
    Units: percent
    arithmetic mean (standard deviation)
        OFF
    -14.6 ± 25.94
    -2.9 ± 26
        ON
    13.1 ± 109.56
    -9.8 ± 53.14
    Statistical analysis title
    OFF state treatment comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2329
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.6
         upper limit
    6.7
    Statistical analysis title
    ON state treatment comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4371
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.4
         upper limit
    78

    Secondary: Percentage change in UPDRS total score (sum of motor + ADL scores) in the OFF and the ON state

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    End point title
    Percentage change in UPDRS total score (sum of motor + ADL scores) in the OFF and the ON state
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    21
    20
    Units: percent
    arithmetic mean (standard deviation)
        OFF
    -18.4 ± 17.19
    -10.3 ± 10.42
        ON
    -6.1 ± 40.16
    2.4 ± 21.25
    Statistical analysis title
    OFF state treatment comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0696
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.7
         upper limit
    0.7
    Statistical analysis title
    ON state treatment comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.4084
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.2
         upper limit
    12.1

    Secondary: Change in PD diary ratings

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    End point title
    Change in PD diary ratings
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline assessment at Week 0 (post surgical implantation and test infusion but prior to first treatment infusion) to Week 40
    End point values
    GDNF Placebo
    Number of subjects analysed
    17
    18
    Units: hour
    arithmetic mean (standard deviation)
        Total OFF time per day
    -1.01 ± 1.902
    0.42 ± 2.052
        Total good-quality ON time per day
    1.3 ± 1.886
    -0.43 ± 1.858
        ON time per day with troublesome dyskinesias
    -0.12 ± 1.190
    -0.11 ± 0.549
    Statistical analysis title
    Total OFF time per day treatment comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.165
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.41
         upper limit
    0.429
    Statistical analysis title
    Good-Quality ON Time treatment comparison
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.125
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.339
         upper limit
    2.651
    Statistical analysis title
    ON time per day (with troublesome dyskinesias)
    Statistical analysis description
    LS mean difference vs placebo
    Comparison groups
    GDNF v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9174
    Method
    Mixed models analysis
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    0.698

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported from the point of consent to end of treatment
    Adverse event reporting additional description
    AEs marked as 'Occurrences causally related to treatment number' could be related to the trial treatment or the trial device.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    GDNF
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    GDNF Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 21 (47.62%)
    7 / 20 (35.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Pelvic pain / Muscular weakness / Deep vein thrombosis / Spinal
    Additional description: Car accident
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oral disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Paranoia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Complication associated with device
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Application site scar
    Additional description: Skin overgrowth.
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Application site reaction
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 20 (15.00%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Application site erythema
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Application site infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin exfoliation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Site inflammation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: Port site infection, antibiotics required.
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
    Additional description: Diagnosed with E.coli pyelonephritis.
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         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
    GDNF Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    20 / 20 (100.00%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 21 (19.05%)
    6 / 20 (30.00%)
         occurrences all number
    8
    16
    Joint injury
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 20 (20.00%)
         occurrences all number
    2
    5
    Head injury
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 20 (20.00%)
         occurrences all number
    5
    7
    Nervous system disorders
    Lhermitte's sign
         subjects affected / exposed
    8 / 21 (38.10%)
    0 / 20 (0.00%)
         occurrences all number
    9
    0
    Paraesthesia
         subjects affected / exposed
    8 / 21 (38.10%)
    2 / 20 (10.00%)
         occurrences all number
    17
    2
    Freezing phenomenon
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 20 (15.00%)
         occurrences all number
    5
    3
    Eye disorders
    Diplopia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    6 / 21 (28.57%)
    7 / 20 (35.00%)
         occurrences all number
    10
    14
    Cough
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 20 (20.00%)
         occurrences all number
    5
    4
    Dizziness
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 20 (5.00%)
         occurrences all number
    5
    1
    Pain in extremity
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 20 (5.00%)
         occurrences all number
    5
    1
    Drug effect decreased
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 20 (20.00%)
         occurrences all number
    2
    4
    Application site pain
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 20 (20.00%)
         occurrences all number
    1
    5
    Nausea
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Arthralgia
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    Depressed mood
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    Fatigue
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 20 (10.00%)
         occurrences all number
    5
    4
    Burning sensation
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    Confusion
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    Lethargy
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Insomnia
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 20 (15.00%)
         occurrences all number
    1
    3
    Psychiatric disorders
    Impulsive behaviour
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Anxiety
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 20 (20.00%)
         occurrences all number
    0
    0
    Paranoia
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Diarrhoea
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    8
    0
    Skin and subcutaneous tissue disorders
    Application site erythema
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 20 (15.00%)
         occurrences all number
    3
    5
    Application site reaction
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 20 (15.00%)
         occurrences all number
    3
    3
    Application site swelling
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 20 (20.00%)
         occurrences all number
    1
    4
    Musculoskeletal and connective tissue disorders
    Dyskinesia
         subjects affected / exposed
    9 / 21 (42.86%)
    5 / 20 (25.00%)
         occurrences all number
    12
    5
    Muscle spasms
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 20 (15.00%)
         occurrences all number
    5
    4
    On and off phenomenon
         subjects affected / exposed
    7 / 21 (33.33%)
    2 / 20 (10.00%)
         occurrences all number
    12
    2
    Back pain
         subjects affected / exposed
    2 / 21 (9.52%)
    5 / 20 (25.00%)
         occurrences all number
    3
    5
    Dystonia
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 21 (28.57%)
    8 / 20 (40.00%)
         occurrences all number
    8
    10
    Application site infection
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 20 (10.00%)
         occurrences all number
    6
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 20 (10.00%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2012
    To allow intraputamenal GDNF and placebo infusions to be delivered using a linear ramping regime, rather than a stepped infusion profile.
    17 Oct 2012
    Switching to a fully programmable linear ramping scheme is thought to minimize the risk of infusion errors, while providing for a desirable distribution profile in tissue.
    25 Apr 2013
    This amendment covers a switch from 2 weekly infusion intervals to 4 weekly infusion intervals, along with a compensatory increase in the concentration of GDNF to maintain the original total dose delivered per 4 week period (240 micrograms).
    26 Jun 2013
    Minor alterations in screening assessments and outcome data collected.
    02 Jun 2014
    Part 1: To change the protocol to include that Gadolinium contrast will be infused into the putamen at the time of the first test infusion and this is explained in the amendment and Participant Information Sheet. Part 2: To agree to repeat certain screening tests or baseline efficacy measures if they fall beyond certain substantial time intervals.
    01 Aug 2014
    The study has been suspended by the sponsor following monitoring which revealed a number of minor breaches of GCP, collectively constituting a major breach of GCP. As this is what we submitted to the MHRA, and they check things like this.
    24 Sep 2014
    To restart the trial.
    02 Dec 2014
    Amendment to Patient Information Sheet and to Patient Consent form.
    26 Mar 2015
    This amendment to simplify the magnetic resonance imaging (MRI) schedule and delete the previously planned functional MRI sub-study.
    02 Jul 2015
    Change to the patient consent form to allow access to blinded trial subject data by monitoring and auditing groups such as Pfizer, external contract research organizations, and UBC.
    05 Nov 2015
    To further revise the study protocol, the alterations are of a minor nature to address or clarify areas of potential misinterpretation or administrative type alterations to the protocol.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Aug 2014
    The study was halted by the sponsor following monitoring which revealed a number of minor breaches of GCP, collectively constituting a major breach of GCP. Recruitment was stopped but treatment was not stopped, 14 patients were still receiving treatment at this time.
    24 Sep 2014

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30808022
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