| 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 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. |
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| E.2.2 | Secondary 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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
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| E.4 | Principal 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. |
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| E.5 End points |
| E.5.1 | Primary 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. |
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| E.5.1.1 | Timepoint(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 |
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| E.5.2 | Secondary 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.
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| E.5.2.1 | Timepoint(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) |
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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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other 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. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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