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    Summary
    EudraCT Number:2015-004175-73
    Sponsor's Protocol Code Number:HP-CD-CL-2002
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-07-07
    Trial 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 ConcernedFinland - Fimea
    A.2EudraCT number2015-004175-73
    A.3Full title of the trial
    A Phase I-II, Randomised, Double-Blind, Placebo Controlled, Safety and Tolerability Study of Intermittent Bilateral Intraputamenal Cerebral Dopamine Neurotrophic Factor (CDNF) Infusions Administered via an Investigational Drug Delivery System to Patients with Idiopathic Parkinson’s Disease (PD) of Moderate Severity.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to test the safety of CDNF by brain infusion in patients with Parkinson's disease.
    A.4.1Sponsor's protocol code numberHP-CD-CL-2002
    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 Plc
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEuropean Commission
    B.4.2CountryBelgium
    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 Director
    B.5.3 Address:
    B.5.3.1Street AddressBertel Jungin aukio 1
    B.5.3.2Town/ cityEspoo
    B.5.3.3Post code02600
    B.5.3.4CountryFinland
    B.5.4Telephone number358401585669
    B.5.6E-mailsigrid.booms@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 nameCDNF
    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 mg/ml milligram(s)/millilitre
    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
    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
    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 investigational medicinal product administered as monthly intermittent bilateral intraputamenal CDNF infusions, and,
    - the investigational medical device for the intended use and within the intended patient population during device implantation and follow-up, including the test infusion procedure.

    To demonstrate the accuracy of investigational device as implantation accuracy to the target site during implantation surgery.
    E.2.2Secondary objectives of the trial
    To evaluate the drug related effects on:
    -The severity of PD motor symptoms, measured by OFF-state UPDRS part III motor scores after 6 months' treatment
    -Mobility, measured by OFF-state Timed Up and Go test after 6 months' treatment
    -ON-state non-motor and motor function, motor complications, and ON- and OFF-state activities of daily living, measured by UPDRS part I-IV scores after 6 months' treatment
    -The patient’s functional status by home diary after 6 months' treatment
    -The patient’s health and daily activities, measured by PDQ-39 questionnaire
    -The patient’s treatment response on mental status, measured by CGI scale

    To evaluate the device by:
    -The patency of each individual catheter lines, and the whole system, after implantation and during the trial
    -The stability of the transcutaneous port in respect of enabling attachment of external system for infusions during the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible patients must fulfill all of the following criteria (at screening):

    1.Subjects diagnosed with idiopathic PD according to the UK Brain Bank Criteria. Bilateral findings must be present at study entry.

    2. Duration of PD motor symptoms 5-15 years (inclusive), verified by subject’s medical records.

    3. Age 35-75 years (inclusive).

    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. At least 5 daily doses of Levodopa
    6. Ability to reliably distinguish motor states (ON without dyskinesia, ON with non-troublesome dyskinesia, ON with troublesome dyskinesia and OFF) and accurately complete fluctuation diaries.

    7. UPDRS motor score (part III) in a practically defined OFF-state between 25-50 (inclusive).

    8. Hoehn and Yahr ≤ stage III in the OFF-state.

    9. Responsiveness to levodopa (≥30% improvement in motor UPDRS [part III] following a levodopa challenge)

    10. No change in anti-parkinsonian medication for 6 weeks before screening.

    11. 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 three months after their male partner's DAT-PET scan.

    12.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.

    Post-surgery Randomization Criteria

    13. No relevant sequelae from catheter implantation such as clinically significant intracerebral trauma, haemorrhage, or infection.

    14. At least one functioning catheter tip in each putamen.

    15. Implanted catheter trajectories are satisfactory from a safety perspective and there have been no changes in pathology after implantation surgery(s), which give rise to safety concerns.
    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. Drug-resistant rest tremor, severe dyskinesia or severe head tremor, which could interfere with treatment and test infusions.

    4. Prior neurosurgical treatment for PD, including previous treatment with platelet-derived growth factor (PDGF-BB), glial cell-line derived neurotrophic factor (GDNF), lesioning or deep brain stimulation.

    5. Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, epilepsia, CSF shunt or other implanted CNS device.

    6. Presence of significant depression as defined as a Beck Depression Inventory (BDI) score ≥ 20.

    7. Current psychosis requiring therapy. The presence of benign hallucinosis is not exclusionary.

    8. 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.

    9. Montreal Cognitive Assessment (MoCA) score < 24.

    10. 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 antipsychotic medication prescribed for the treatment of psychosis, central dopamine receptor blockers, or other tricyclic antidepressants.

    11. Any medical condition, which might impair outcome measure assessments or safety measures including ability to undergo MRI or DAT-PET. Estimated Glomerular Filtration
    rate (eGFR) < 30 mL/min/1.73 m2.

    12.Hypersensitivity or allergy to gadolinium or to any of the excipients of the macrocyclic GBCA used for the surgical planning MRI.

    13. Screening and/or planning MRI demonstrating any abnormality, which would suggest an alternative cause for patient’s parkinsonism or preclude neurosurgery, including but not limited to brain atrophy, anatomical abnormalities within the catheter target area and inability to plan safe trajectories for 4 catheters (2 per putamen) to the target area of the putamen.

    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 screening.

    17. Use of any investigational drug or device within 90 days of screening.

    18. Active breastfeeding.
    E.5 End points
    E.5.1Primary end point(s)
    DRUG RELATED
    Change from baseline (Week -1) until end of treatment evaluation (Week 24) 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 implantation procedure (Week -8), the healing period (Weeks -8 to -5), the first vehicle infusion for the first two patients (Week -4), the infusion procedures during the study period (Weeks -5, 0, 4, 8, 10, 12, 16, 20 and 22), during the entire study period outside of the implantation and infusion procedures (Week -8 to Week 24), 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.

    The accuracy of implantation of the drug delivery system will be measured comparing the tip of each individual catheters defined in the plan of the surgical procedure with the position of those measured by the post-operative CT scan (Week -8). Given the size of the putamen this translates into the tip being within 3mm of the theoretical target measures as the sum of the X, Y and Z axis difference between the target and actual tip position.
    E.5.1.1Timepoint(s) of evaluation of this end point
    DRUG RELATED
    AEs: week -1 (Baseline) + at every visit until study end/week 24.
    BDI score: w -1, 12, 24
    Questionnaire (QUIP_RS): w -1, 12, 24
    MoCA score: w -1, 12, 24
    ECG: w -1 (baseline), w 12, w 24
    Physical examination: w -8, w -1 (baseline), w 24
    Vital signs: w -1 (baseline), w 0, 4, 8, 10, 12, 16, 20, 22, 23, 24
    Clinical laboratory variables: w -1 (baseline), 0, 4, 8, 12, 16, 20, 24
    Serum CDNF-antibody: w -1 (baseline), 4, 8, 12, 16, 20, 24

    DEVICE RELATED
    Occurrence of ADE at:
    Implantation (week -8); The healing period (w -8 to -5);
    The first vehicle infusion (w -4) for the first 2 patients and/or patients that require a repeat test infusion;
    The infusions (w -5, 0, 4, 8, 10, 12, 16, 20, 22);
    W -4 to 24;
    Accuracy of implantation: w -8
    E.5.2Secondary end point(s)
    DRUG RELATED
    Change from baseline (Week -1), after three months (Week 12), and end of treatment evaluation (Week 24) in severity of PD motor symptoms by UPDRS Part III motor scores.

    Change from baseline (Week -1), after three months (Week 12), and end of treatment evaluation (Week 24) in mobility by TUG test.

    Change from baseline (Week -1), after three months (Week 12), and end of treatment evaluation (Week 24) 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 first dosing (Week 0) until end of treatment evaluation (Week 24) in functional status by home diary score.

    Change from baseline (Week -1), after three months (Week 12), and end of treatment evaluation (Week 24) in health and daily activity by PDQ-39 questionnaire score.

    Change from baseline (Week -1) until end of treatment evaluation (Week 24) in mental status as measured by CGI scale.

    DEVICE RELATED
    Occurrence of blockage of an individual implanted catheter preventing or limiting infusion post-implantation (week -5) until final primary study test infusion (week 22) as measured by pressure rise above 590 mmHg.

    Cessation of infusions in an individual patient due to:
    - the inability to secure an external system due to looseness of the port,
    - the need for surgical removal of the transcutaneous port or surgical intervention to stabilize the port.
    E.5.2.1Timepoint(s) of evaluation of this end point
    DRUG RELATED

    PD motor symptoms (UPDRS part III): week -1 (baseline), 12, 24

    Mobility (TUG test) : week -1 (baseline), 12, 24

    PD motor symptoms (total scores UPDRS part I, II, IV in ON-state; Part III in OFF-state): week -1 (baseline), 12, 24

    Home diary scores: week 0, 4, 8, 12, 16, 20, 24

    Health and daily activity (PDQ-39): week-1 (baseline), 12, 24

    Mental status (CGI): week-1 (baseline), 4, 8, 12, 16, 20, 24

    DEVICE RELATED

    At infusion visit post-surgery (week -5, -4 (first 2 patients) -5, 0, 4, 8, 10, 12, 16, 20, 22)

    Coverage of infusate in target anatomy (test infusion): week-5, 10, 22

    Occurrence of blockage of implanted catheter and cessation of infusions: At infusion visit post-surgery (week -5, -4 (first 2 patients) -5, 0, 4, 8, 10, 12, 16, 20, 22)
    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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    The IMP is delivered via a device, including an implanted system and a transcutaneous port; guide catheters; external administration lines; a pump; and a robot (hardware and software) for surgical implantation of the system.
    The objectives include demonstrating the performance of the device with regard to implantation accuracy and patency after implantation; stability of the transcutaneous port; coverage of the infusion of the target; and the impact of re-positioning a guide tube and catheter.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 trial3
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial 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: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 17
    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)
    All subjects who complete the 6-month treatment period will be offered the opportunity to enroll in an active treatment extension study for a further 6 doses of CDNF. The extension study will be subject to approval by the regulatory authority and ethics committee.

    Except for the transcutaneous port, the implanted drug delivery device is planned to remain in the brain after the end of the study, unless surgical removal of the implanted device is medically indicated or requested by the patient.
    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 Decision2017-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-12-19
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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