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    Clinical Trial Results:
    An Extension Study 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
    		 2013-001881-40
    Trial protocol
    		 GB  
    Global end of trial date
    15 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2022
    First version publication date
    09 Apr 2022
    Other versions
    Summary report(s)
    		 tudy 2797 CSR_171018_FINAL_REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    2797
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    North Bristol NHS Trust
    Sponsor organisation address
    Level 3, Learning and Research building , Bristol, United Kingdom, BS10 5NB
    Public contact
    Clinical Trials Manager Helen Lewis, North Bristol NHS Trust (NBT) , +44 1173238602, research@nbt.nhs.uk
    Scientific contact
    Clinical Trials Manager Helen Lewis, North Bristol NHS Trust (NBT) , +44 1173238602, 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
    25 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of intermittent bilateral intraputamenal GDNF infusions on OFF-state motor function after 18 months of treatment with the effects after 9 months of treatment in subjects who completed in Study 2553.
    Protection of trial subjects
    Local institutional approval was obtained including protocol approval, the study was executed in accord with the Helsinki Declaration of 1975 and all patients provided written informed consent. The Trial Steering Committee and an independent Data Monitoring Committee provided clinical oversight.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 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
    		 All 41 patients randomised and treated in the parent study were enrolled and completed the extension study.

    Pre-assignment
    Screening details
    		 All parent study completers had the option to enrol in the extension investigation. Exclusion criteria were early discontinuation of treatment or significant protocol deviation in the parent study, presence of clinically significant depression, cognitive decline or any new medical condition that might impair outcome measure assessments or safety.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GDNF - GDNF
    Arm description
    		 Patients randomised to receive GDNF in the Parent study and continuing these GDNF infusions in this extension study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glial Cell Line-Derived Neutrophic Factor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intracerebral use
    Dosage and administration details
    GDNF concentration was 0.2 mg/ml every 4 weeks

    Arm title
    		 Placebo - GDNF
    Arm description
    		 Participants randomised to placebo in Parent study and then received GDNF infusions for this extension study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glial Cell Line-Derived Neutrophic Factor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intracerebral use
    Dosage and administration details
    GDNF concentration was 0.2 mg/ml every 4 weeks

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

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GDNF - GDNF
    Reporting group description
    		 Patients randomised to receive GDNF in the Parent study and continuing these GDNF infusions in this extension study

    Reporting group title
    Placebo - GDNF
    Reporting group description
    		 Participants randomised to placebo in Parent study and then received GDNF infusions for this extension study

    Reporting group values
    		 GDNF - GDNF Placebo - GDNF 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
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.9 ( 8.8 ) 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 week 0 of parent study
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 76.15 ( 14.201 ) 79.34 ( 21.216 ) -
    Height
    Height at baseline (week 0 of parent study)
    Units: meter
        arithmetic mean (standard deviation)
    		 1.707 ( 0.08 ) 1.714 ( 0.099 ) -
    BMI
    BMI at baseline (week 0 of parent study)
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 26.096 ( 4.22 ) 26.758 ( 5.55 ) -
    NART error score
    National Adult Reading Test (NART) error score is the number of words pronounced incorrectly out of 50 total words. Score from week 0 of parent study.
    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: Years
        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 - GDNF
    Reporting group description
    		 Patients randomised to receive GDNF in the Parent study and continuing these GDNF infusions in this extension study

    Reporting group title
    Placebo - GDNF
    Reporting group description
    		 Participants randomised to placebo in Parent study and then received GDNF infusions for this extension study

    Primary: Percentage change in defined OFF state UPDRS motor score (part III)

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    End point title
    		 Percentage change in defined OFF state UPDRS motor score (part III)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline (1 week post parent study) to week 80/e40.
    End point values
    		 GDNF - GDNF Placebo - GDNF
    Number of subjects analysed
    21
    20
    Units: percent
        arithmetic mean (standard deviation)
    -26.7 ( 20.7 )
    27.6 ( 23.6 )
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Least Squares Mean Difference vs Placebo
    Comparison groups
    GDNF - GDNF v Placebo - GDNF
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.9
         upper limit
    		 14.6

    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 (1 week post Parent study) to end of treatment (week 80/e40).
    End point values
    		 GDNF - GDNF Placebo - GDNF
    Number of subjects analysed
    21
    20
    Units: Percentage change
        arithmetic mean (standard deviation)
    -7 ( 32.3 )
    5.1 ( 22.7 )
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Least Squares Mean Difference vs Placebo
    Comparison groups
    GDNF - GDNF v Placebo - GDNF
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.7
         upper limit
    		 14.2

    Secondary: Percentage change in UPDRS ADL (part II)

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    End point title
    		 Percentage change in UPDRS ADL (part II)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline (I week post parent study) to end of treatment (week 40)
    End point values
    		 GDNF - GDNF Placebo - GDNF
    Number of subjects analysed
    21
    20
    Units: Percentage change
    arithmetic mean (standard deviation)
        OFF
    -34.3 ( 22.3 )
    28.2 ( 26.2 )
        ON
    -33.9 ( 62.6 )
    32.3 ( 52 )
    Statistical analysis title
    		 Treatment Comparison in the OFF state
    Statistical analysis description
    Least Squares Mean Difference vs. Placebo in the OFF state
    Comparison groups
    GDNF - GDNF v Placebo - GDNF
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.2
         upper limit
    		 11.4
    Statistical analysis title
    		 Treatment Comparison in the ON state
    Statistical analysis description
    Least Squares Mean Difference vs. Placebo
    Comparison groups
    GDNF - GDNF v Placebo - GDNF
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.1
         upper limit
    		 33.5

    Secondary: Percentage change in UPDRS total score (sum of motor and ADL)

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    End point title
    		 Percentage change in UPDRS total score (sum of motor and ADL)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 80/e40
    End point values
    		 GDNF - GDNF Placebo - GDNF
    Number of subjects analysed
    21
    20
    Units: percent
    arithmetic mean (standard deviation)
        ON
    -17.5 ( 31.9 )
    -11.3 ( 23.1 )
        OFF
    -31.3 ( 14.8 )
    -28.3 ( 19.8 )
    Statistical analysis title
    		 Treatment Comparison in the OFF state
    Statistical analysis description
    Least Squares Mean Difference vs Placebo
    Comparison groups
    Placebo - GDNF v GDNF - GDNF
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.6
         upper limit
    		 8
    Statistical analysis title
    		 Treatment Comparison in the ON state
    Statistical analysis description
    Least Squares Mean Difference vs Placebo
    Comparison groups
    GDNF - GDNF v Placebo - GDNF
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.7
         upper limit
    		 9.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported for all patients between week 40 (start of extension) and until 28 days after the last dose of study medication.
    Adverse event reporting additional description
    AEs were reported when experienced by at least 5 patients overall
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    GDNF - GDNF
    Reporting group description
    		 Patients randomised to receive GDNF in the Primary study and continuing these infusions in this extension study

    Reporting group title
    Placebo - GDNF
    Reporting group description
    		 Participants randomised to placebo in primary study and now receiving GDNF infusions for this extension study

    Serious adverse events
    		 GDNF - GDNF Placebo - GDNF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 21 (85.71%)
    10 / 20 (50.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Traumatic muscle rupture
         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
    Surgical and medical procedures
    menorrhagia requiring hysterectomy
    Additional description: menorrhagia requiring hysterectomy and post- operative infection
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    multifactorial confusion and fluctuating cognition
         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
    depression and paranoia
    Additional description: recurrence of pre-study depression and 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
    Device related events
         subjects affected / exposed
    9 / 21 (42.86%)
    10 / 20 (50.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GDNF - GDNF Placebo - GDNF
    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
    5 / 21 (23.81%)
    7 / 20 (35.00%)
         occurrences all number
    5
    7
    Contusion
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 20 (15.00%)
         occurrences all number
    4
    3
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    10 / 21 (47.62%)
    9 / 20 (45.00%)
         occurrences all number
    8
    9
    Lhermitte's sign
         subjects affected / exposed
    9 / 21 (42.86%)
    4 / 20 (20.00%)
         occurrences all number
    9
    4
    Paresthesia
         subjects affected / exposed
    6 / 21 (28.57%)
    7 / 20 (35.00%)
         occurrences all number
    6
    7
    On and off phenomenon
         subjects affected / exposed
    4 / 21 (19.05%)
    7 / 20 (35.00%)
         occurrences all number
    4
    7
    Freezing phenomenon
         subjects affected / exposed
    7 / 21 (33.33%)
    3 / 20 (15.00%)
         occurrences all number
    7
    3
    Dystonia
         subjects affected / exposed
    5 / 21 (23.81%)
    4 / 20 (20.00%)
         occurrences all number
    5
    4
    Dizziness
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 20 (15.00%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 20 (20.00%)
         occurrences all number
    2
    4
    Drug effect decreased
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 20 (15.00%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 20 (15.00%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Nasopharyngitis
         subjects affected / exposed
    7 / 21 (33.33%)
    6 / 20 (30.00%)
         occurrences all number
    7
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 21 (14.29%)
    5 / 20 (25.00%)
         occurrences all number
    3
    5
    Pain in extremity
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 20 (10.00%)
         occurrences all number
    5
    2
    Joint injury
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 20 (10.00%)
         occurrences all number
    4
    2
    Infections and infestations
    Application site infection
         subjects affected / exposed
    5 / 21 (23.81%)
    4 / 20 (20.00%)
         occurrences all number
    5
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 20 (20.00%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2014
    Amendment to protocol, PIS and Patient consent form.
    19 Sep 2014
    Modification of the magnetic resonance imaging (MRI) schedule.
    16 Dec 2015
    Amendment to protocol, informed consent form and patient information sheet.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30829619
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