E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic Parkinson's Disease |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013113 |
E.1.2 | Term | Disease Parkinson's |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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) |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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-motor and motor symptoms, in mobility, in health and daily activity. • baseline (Week -1), at study start (Week 24) until end of treatment evaluation (Week 49) in functional status and in mental status
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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
This is the extension study for the patients who have completed First-in-Human study HP-CD-CL-2002 |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
different doses of the same product |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |