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    Summary
    EudraCT Number:2011-003866-34
    Sponsor's Protocol Code Number:2553
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-05-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2011-003866-34
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessing the Benefit and Safety of Administering Intermittent GDNF Infusions in Parkinson's Disease (PD)
    A.3.2Name or abbreviated title of the trial where available
    Intermittent Bilateral GDNF for Parkinson’s Disease
    A.4.1Sponsor's protocol code number2553
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNorth Bristol NHS Trust (NBT)
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportParkinson's UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportThe Cure Parkinson's Trust
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportMedGenesis Therapeutix Inc.
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNorth Bristol NHS Trust (NBT)
    B.5.2Functional name of contact pointClinical Trials Manager Helen Lewis
    B.5.3 Address:
    B.5.3.1Street AddressResearch & Innovation, Floor 3, Learning & Research Building, Southmead Hospital
    B.5.3.2Town/ cityBristol
    B.5.3.3Post codeBS10 5NB
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441173236468
    B.5.5Fax number+441173236192
    B.5.6E-mailresearch@nbt.nhs.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGlial Cell Line-Derived Neurotrophic Factor (GDNF)
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntracerebral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLiatermin
    D.3.9.3Other descriptive namer-metHuGDNF
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number9.0 to 11.0
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntracerebral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Parkinson's disease
    E.1.1.1Medical condition in easily understood language
    Parkinson's disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10034008
    E.1.2Term Parkinson's syndrome
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the effect of q2 weekly intermittent bilateral intraputamenal GDNF infusions on OFF-state motor function at 9 months.
    E.2.2Secondary objectives of the trial
    To assess the effect of intermittent bilateral intraputamenal GDNF infusions on ON-state motor function, motor complications, and ON- and OFF-state activities of daily living (ADL) at 9 months.
    To assess the safety of intermittent bilateral intraputamenal GDNF infusions in a small pilot cohort of subjects and in the full study population.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    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.
    Internal Reference No: 2797
    Ethics Ref: 13/SW/0181
    EudraCT Number: 2013-001881-40
    E.3Principal inclusion criteria
    Inclusion Criteria
    1. Subjects diagnosed with idopathic PD according to the UK Brain Bank Criteria. Bilateral findings must be present at study entry.
    2. Duration of PD symptoms 5 years, verified by subject’s medical records.
    3. Age 35-75 years.
    4. Presence of motor fluctuations. Subjects must have an average of at least 2.5 hours of Off-time per day on 3-day
    fluctuation diaries completed during screening.
    5. Ability to reliably distinguish motor states (ON without dyskinesias, ON with non-troublesome dyskinesias, ON with
    troublesome dyskinesias and OFF) and accurately complete fluctuation diaries.
    6. UPDRS motor score (part III) in a practically defined OFF-state between 25-45.
    7. Hoehn and Yahr ≤ stage III in the OFF-state.
    8. Responsiveness to levodopa (≥40% improvement in motor UPDRS [part III] following a levodopa challenge)
    9. No change in anti-parkinsonian medication for 6 weeks before screening.
    10. Females of childbearing potential must have a negative pregnancy test at study entry and be willing to use an approved (by the PI or designee) form of contraception until the end of the study.
    11. Provision of informed consent.

    Post-surgery Randomization Criteria
    1. No relevant sequelae from catheter implantation such as clinically significant intracerebral trauma, haemorrhage, or infection.
    2. Total distribution volume providing at least 50% volume coverage of a predefined volume of interest in each putamen (approximately 25% volume coverage of total putamen), as assessed by an independent review of an MRI scan taken within 2 hours post-infusion of diluent at the end of the healing period.
    E.4Principal exclusion criteria
    1. Diagnosed with atypical parkinsonism or any known secondary parkinsonian syndrome including but not limited to
    medication induced, toxic, vascular, post-traumatic or post-infectious parkinsonism, progressive supranuclear palsy,
    multiple systems atrophy, or other neurodegenerative disorder associated with parkinsonism.
    2. Signs or symptoms suggestive of atypical parkinsonian syndrome including supranuclear gaze palsy, early postural
    instability and falls (within 3 years of disease onset), cerebellar signs, myoclonus, disproportionate antecollis,
    extensor plantar responses, cortical sensory loss, emotional incontinence (pseudobulbar affect), severe bulbar
    dysfunction (dysarthria, dysphonia or dysphagia) or respiratory symptoms such as stridor or inspiratory sighs.
    3. Family history of more than 1 first-degree relative with PD.
    4. Severe dyskinesias or severe tremor which could interfere with GDNF infusion.
    5. Prior neurosurgical treatment for PD, including previous treatment with GDNF or deep brain stimulation.
    6. Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease,
    CSF shunt or other implanted CNS device.
    7. Presence of significant depression as defined as a Beck Depression Inventory (BDI) score ≥ 20.
    8. Current or past history of psychosis requiring therapy. The presence of benign hallucinosis is not exclusionary.
    9. Presence or history of clinically significant impulse control disorder or presence or history of dopamine dysregulation syndrome.
    10. MoCA score < 24.
    11. Use within 3 months of planned catheter insertion of concomitant medications known to affect PD symptoms other
    than prescribed PD therapy including but not limited to neuroleptics or other central dopamine receptor blockers.
    12. Any medical condition which might impair outcome measure assessments or safety measures including ability to
    undergo MRI scanning.
    13. Screening MRI demonstrating any abnormality which would suggest an alternative cause for subject’s parkinsonism.
    14. Any medical condition that would put the subject at undue risk from surgical treatment or chronic implants including
    but not limited to bleeding disorders, chronic infections, or immunosuppressive illness.
    15. History within the last 5 years of cancer with the exception of basal cell carcinoma of the skin.
    16. History of drug or alcohol abuse within 2 years of planned catheter insertion.
    17. Use of any investigational drug or device within 90 days of planned catheter insertion.
    18. Active breastfeeding.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the percentage change from baseline in the practically defined OFF-state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III) after 9 months of double-blind treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    As specified above
    E.5.2Secondary end point(s)
    Efficacy
    1. Percentage change from baseline in UPDRS motor score (part III) in the ON-state (following a levodopa challenge) after 9 months of double-blind treatment.
    2. Percentage change from baseline in UPDRS ADL score (part II) in the OFF state and in the ON state after 9 months of double-blind treatment.
    3. Percentage change from baseline in UPDRS total score (sum of motor + ADL scores) in the OFF state and in the ON state after 9 months of double-blind treatment.
    4. Percentage change from baseline in UPDRS mentation, behaviour, and mood score (part I) after 9 months of double-blind treatment.
    5. Percentage change from baseline in UPDRS complications of therapy score (part IV) after 9 months of double-blind treatment.
    6. Change from baseline in PD diary ratings after 9 months of double-blind treatment; i.e., total OFF-time per day, total good quality ON-time per day(ON without dyskinesias or ON with non-troublesome dyskinesias) and ON-time per day with troublesome dyskinesias.

    Safety
    1. Frequency of device-related adverse events (AEs) during the study period
    2. Frequency of treatment-emergent AEs (all treatment-emergent AEs and treatment-emergent AEs related to study drug) during the study period.
    3. Frequency of dyskinesias
    4. Falls, adverse changes in mood, and impulsivity reported as treatment-emergent AEs during the study period (AEs of special interest).
    5. Change from baseline in the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) every 8 weeks.
    6. Change from baseline in the Montreal Cognitive Assessment (MoCA) after 9 months of double-blind treatment.
    7. Change from baseline in the Mattis Dementia Rating Scale (MDRS) after 9 months post of double-blind treatment.
    8. Adverse changes in MRI findings as captured by AE reporting.
    9. Frequency of subjects with anti-GDNF antibodies during the study.
    10. Results of routine laboratory blood tests (haematology, serum chemistry) and urinalysis performed at baseline and at intervals during the trial.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For each as specified above
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state42
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who complete the 9-month treatment period will be offered the opportunity to enroll in an open-label active treatment extension study under a separate protocol, pending approval by the MHRA and the local REC.

    The continuation of GDNF treatment beyond this study or the planned extension study can be in no way guaranteed and may well stop even if the subjects have received great benefit. This is explained in extensive detail in the Patient Information Sheet.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-06-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-09-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-04-28
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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