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    Summary
    EudraCT Number:2018-000346-19
    Sponsor's Protocol Code Number:HP-CD-CL-2003
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-04-09
    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 ConcernedSweden - MPA
    A.2EudraCT number2018-000346-19
    A.3Full title of the trial
    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.
    En randomiserad, dubbelblind, multi-center, uppföljnings- och safety-studie med CDNF, för patienter med idiopatisk Parkinsons sjukdom (PS) som tidigare deltagit i CDNF/DDS huvudstudien, HP-CD-CL-2002
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An extended clinical study to test the safety of Cerebral Dopamine Neurotrophic Factor (CDNF) by brain infusion via Drug Delivery System (DDS) in patients with Parkinson's disease.
    A.3.2Name or abbreviated title of the trial where available
    Extension Study
    A.4.1Sponsor's protocol code numberHP-CD-CL-2003
    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 SponsorHerantis Pharma Plc
    B.1.3.4CountryFinland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRenishaw Neuro Solutions Ltd.
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEuropean Commission
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportHerantis Pharma Plc
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHerantis Pharma Plc
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street AddressItäinen Pitkäkatu 4B
    B.5.3.2Town/ cityTurku
    B.5.3.3Post code20520
    B.5.3.4CountryFinland
    B.5.4Telephone number+358 40 752 1194
    B.5.6E-mailrebecka.holmnas@herantis.com
    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 nameCerebral Dopamine Neurotrophic Factor
    D.3.2Product code CDNF
    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 INNNot Applicable
    D.3.9.3Other descriptive namerecombinant human Cerebral Dopamine Neurotrophic Factor
    D.3.10 Strength
    D.3.10.1Concentration unit µg/µl microgram(s)/microlitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Idiopathic 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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10013113
    E.1.2Term Disease Parkinson's
    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 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.
    E.2.2Secondary objectives of the trial
    Drug related:
    • Severity of PD motor symptoms as measured by OFF-state UPDRS part III
    • Mobility as measured by OFF-state Timed Up and Go (TUG) test
    • ON-state non-motor and motor function, motor complications, and ON- and OFF-state activities of daily living as measured by UPDRS scores part I-IV
    • Patient’s functional status by home diary
    • Patient’s health and daily activities as measured by PDQ-39 questionnaire
    • Patient’s treatment response on mental status as measured by CGI scale

    Device related:
    • the patency of each individual catheter lines and the whole system
    • the stability of the transcutaneous port

    Exploratory objectives
    Drug related:
    • DAT-PET imaging
    • Serum and cerebrospinal fluid levels of α-synuclein
    • Daily activity measurement by Parkinson’s KinetiGraph
    • Level of distribution of CDNF and proteomic biomarker screen in CSF
    • Genome sequencing testing from saliva

    Device related:
    • the coverage of infusion at the target site
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Completion of the 6 months treatment period in the Main study (HP-CD-CL-2002), including End-of-Study assessment at Visit 17 (Week 24).
    2. Females of childbearing potential must have a negative pregnancy test at study entry and be willing to use a highly effective form of contraception until 30 days after the end of the study (hormonal contraception associated with inhibition of ovulation, IUD, IUS, bilateral tubal occlusion, vasectomised partner or sexual abstinence). Males (non-vasectomised) must be willing to use condom during intercourse and do not donate sperms for three months following each DAT-PET scan. Female partners of childbearing potential should be willing to use a highly effective form of contraception until 30 days after their male partner’s end of the study.
    3. At least one functioning catheter tip in each putamen.
    4. Provision of informed consent. The patient is judged by the investigator to be alert and oriented to person, place, time and situation when giving the informed consent.
    E.4Principal exclusion criteria
    1. Drug-resistant rest tremor, severe dyskinesia or severe head tremor, which could interfere with treatment infusions.
    2. Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, epilepsy, CSF shunt or other implanted central nervous system (CNS) device.
    3. Changes in pathology which give rise to safety concern such as sequelae from catheter implantation, clinically significant intracerebral trauma, oedema, haemorrhage, or infection.
    4. Current psychosis requiring therapy. Brief episodes of hallucinations, disorientation or confusion are not exclusionary.
    5. Presence of clinically significant impulse control disorder by a positive screen on the questionnaire for impulsive-compulsive disorders in Parkinson’s Disease (QUIP-RS) score >20, or, presence of dopamine dysregulation syndrome.
    6. Any unresolved intolerable adverse events or adverse device events in study HP-CD-CL-2002, which are not expected to resolve or cease to an acceptable level of intensity within reasonable time. This includes any Serious Adverse Event (SAE) of at least Grade 3 (severe) in severity, judged to be possibly, probably or definitely related to study treatment.
    7. Any medical condition, which might impair outcome measure assessments or safety measures including ability to undergo MRI or DAT-PET.
    8. Impaired renal function. Estimated Glomerular Filtration rate (eGFR) < 30 mL/min/1.73 m2 .
    9. Concomitant treatment with neuroleptics or antipsychotic medication prescribed for treatment of current psychosis, central dopamine blockers or tricyclic antidepressants. Low dose quetiapine
    and similar medications prescribed for Parkinson’s disease treatment are not exclusionary.
    E.5 End points
    E.5.1Primary end point(s)
    DRUG RELATED
    • Change from extension study start (Week 24) until end of treatment evaluation (Week 49) in adverse events (AEs), Electrocardiogram (ECGs), Beck Depression Inventory (BDI) score, questionnaire for impulsive-compulsive disorder in Parkinson’s disease rating scale (QUIP-RS), Montreal cognitive assessment (MoCA) score, physical examination, vital signs, clinical laboratory variables and CDNF-antibody testing in serum.

    DEVICE RELATED
    • Occurrence of adverse device effects (ADE), for either the whole system or the individual sub systems (guide tubes/catheters, subcutaneous components, port), evaluated separately for the infusion procedures during the study period (Weeks 25, 29, 33, 37, 41 and 45), during the entire study period outside of the infusion procedures (Week 24 to Week 49), with said serious adverse device effect (SADE) including long term effects, neurological deficit (seizures), infection (local to components, in CNS), severe skin breakdown or necrosis requiring component removal, life threatening or major (requiring intervention) intracerebral haemorrhage.
    E.5.1.1Timepoint(s) of evaluation of this end point
    DRUG RELATED
    Change from extension study start (Week 24) until end of treatment evaluation (Week 49).

    DEVICE RELATED
    Occurrence of adverse device effects (ADE) and serious adverse device effect (SADE) at infusion procedures during the study period (Weeks 25, 29, 33, 37, 41 and 45), during the entire study period outside of the infusion procedures (Week 24 to Week 49)
    E.5.2Secondary end point(s)
    DRUG RELATED
    • Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in severity of PD motor symptoms by UPDRS Part III motor scores.
    • Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in mobility by TUG test.
    • Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in severity of PD non-motor and motor symptoms by UPDRS Part I-IV total scores (Parts I, II and IV in ON-state; Part III in OFF-state).
    • Change from baseline (Week -1), at study start (Week 24) until end of treatment evaluation (Week 49) in functional status by home diary score.
    • Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in health and daily activity by PDQ-39 questionnaire score.
    • Change from baseline (Week -1), at study start (Week 24) and end of treatment evaluation (Week 49) in mental status as measured by CGI scale.

    DEVICE RELATED
    • Occurrence of blockage of an individual implanted catheter preventing or limiting infusion (Week 25) until final treatment infusion (Week 45) as measured by pressure rise above 590 mmHg.
    • Cessation of infusions in an individual patient due to:
    o the inability to secure an external system due to looseness of the port,
    o the need for surgical removal of the transcutaneous port or surgical intervention
    to stabilise the port.

    Exploratory Endpoints
    DRUG RELATED
    1) Change in caudate and putamen DAT availability prior to dosing (Week -2) to 12 months of dosing (Week 47) using PET imaging with [ 18 F]FE-PE2I to assess the integrity of the nigrostriatal system.
    2) Change in serum and cerebrospinal fluid levels of total α-synuclein, oligomeric α-synuclein, serine-129 phosphorylated α-synuclein, in the α-synuclein oligomer/total α-synuclein ratio at baseline (Week -1) and, in α-synuclein aggregation propensity in CSF after 12 months of treatment.
    3) Level of distribution and Cmax of CDNF in CSF after the twelfth (Week 20) infusion.
    4) Change in proteomic biomarker screen in CSF at baseline (Week -1) and after the twelfth (Week 45) infusion. A saliva sample for next generation sequencing (NGS) is collected at any timepoint during the study (Week 24 to Week 49), after study discontinuation or after study completion. The analysis together will be correlated to any other study outcome, i.e. secondary endpoints.
    5) Change from first dosing (Week 0) until end of treatment evaluation (Week 49) in daily activity measurement by Parkinson’s KinetiGraph™ (PKG™) Data Logger.

    DEVICE RELATED
    • Coverage of the infusate in target anatomical volume of interest, at final treatment infusion (Week 45) as assessed by MRI.
    E.5.2.1Timepoint(s) of evaluation of this end point
    DRUG RELATED
    • baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in PD non-mortor and motor symptoms, in mpbility, in heath and daily activity.
    • baseline (Week -1), at study start (Week 24) until end of treatment evaluation (Week 49) in functional status and in mental satus

    DEVICE RELATED
    • Week 25 until final treatment infusion (Week 45)

    Exploratory Endpoints
    DRUG RELATED
    1) to dosing (Week -2) to 12 months of dosing (Week 47)
    2) baseline (Week -1) and after the twelfth (Week 45)
    3) first dosing (Week 0) until end of treatment evaluation (Week 49)

    DEVICE RELATED
    • at final treatment infusion (Week 45)
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    This is the extension study for the patients who have completed First-in-Human study HP-CD-CL-2002
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    different doses of the same product
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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 years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 18
    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)
    A long-term (5 years) follow-up study (HP-CD-CL-2004) for patients implanted with the drug delivery system (DDS) who may or may not have received treatment during the main study (HP-CD-CL-2002) and/or during the extension study (HP-CD-CL-2003).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-08-31
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