Brain Diseases, Movement Disorders, Nervous System Diseases, Neurodegenerative Diseases, Parkinson Disease
Conditions
Keywords
Parkinson, CDNF, Drug Delivery System, Intracerebral
Brief summary
This study evaluates the safety and tolerability of CDNF in patients with Parkinson's disease, when dosed directly into the brain using an implanted investigational drug delivery system (DDS). Safety and accuracy of the DDS is also being evaluated. One-third of the patients will receive monthly infusions with placebo and two-third of the patients will receive monthly infusions with either mid- or high-doses of CDNF for a period of 6 months.
Detailed description
A patient's participation in the study will last for ten months and will include sixteen to seventeen visits: * Screening (2 visits) * Planning of surgery - Surgery: implantation of drug delivery system - Post-surgery follow-up (3 visits) * Test infusions with vehicle (1-2 visits) * Positron emission tomography (PET) examinations before the first and after the last dose (2 visits) * Baseline and randomisation to CDNF or placebo group (1 visit) * Dosing visits: CDNF or placebo (6 visits) * End-of-study visit (1 visit) Study examinations and assessments \- Physical examination: pulse rate, blood pressure, temperature, body weight and height * ECG (electrocardiography) and blood and urine tests * HIV, hepatitis B and C blood tests (on first visit) * Pregnancy tests for women of childbearing age * Completion of a patient diary to record mobility and time asleep * Parkinson's Kinetigraph (PKGTM) Data Logger: a watch-type device worn on the wrist for certain periods during the study to record movements * Questionnaires, rating scales and forms: quality of life, mood, memory, impulse control, mental health * Assessment of the port and the skin around the port * Cerebrospinal fluid sampling by lumbar puncture * Magnetic resonance imaging (MRI) * Positron emission tomography scans (PET) * Computed tomography (CT) For more information: https://treater.eu/clinical-study/
Interventions
Repeated intracerebral infusions
Stereotactically implanted device
Sponsors
Renishaw plc.
Herantis Pharma Plc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-Blind
Intervention model description
Randomised, Double-Blind, Placebo Controlled
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Idiopathic Parkinson's disease based on UK brain bank criteria 2. Duration of PD motor symptoms 5-15 years (inclusive) 3. Age 35-75 years (inclusive) 4. Presence of motor fluctuations. 5. At least 5 daily doses of levodopa 6. Ability to reliably distinguish motor states 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 10. No change in anti-parkinsonian medication for 6 weeks before screening 11. Provision of Informed Consent
Exclusion criteria
1. Diagnosed with atypical parkinsonism or any known secondary parkinsonian syndrome. 2. Signs or symptoms suggestive of atypical parkinsonian syndrome. 3. Drug-resistant rest tremor. 4. Prior neurosurgical treatment for PD, including 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 BDI score ≥ 20 7. Current psychosis requiring therapy. 8. Presence of clinically significant impulse control disorder ((QUIP-RS) score \> 20), or, presence of dopamine dysregulation syndrome. 9. 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. 11. Any medical condition, which might impair outcome measure assessments or safety measures including ability to undergo MRI or DAT-PET. 12. Hypersensitivity or allergy to gadolinium or to any of excipients of 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. 14. Any medical condition that would put the patient 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Formation of anti-CDNF antibodies | Week 15 to Week 40 | Change in anti-CDNF antibody concentration |
| Vital signs | Week 15 to Week 40 | Changes in vital signs |
| Adverse events (AEs) | Week 15 to Week 40 | Number and severity of adverse events |
| Electrocardiogram (ECG) | Week 15 to Week 40 | Changes in electrical activity of heartbeat measured by electrocardiogram |
| Beck Depression Inventory (BDI) score | Week 15 to Week 40 | Assessment of change in depression using Beck Depression Inventory (BDI) score |
| Questionnaire for impulsive-compulsive disorder in Parkinson's disease rating scale (QUIP_RS) | Week 15 to Week 40 | Assessment of changes in impulsive-compulsive disorders using QUIP\_RS |
| Montreal cognitive assessment (MoCA) | Week 15 to Week 40 | Assessment of change in cognitive domains using MoCA test |
| Physical examination | Week 15 to Week 40 | Changes in anatomic findings found in physical examination |
| Clinical laboratory safety screen | Week 15 to Week 40 | Changes in clinical laboratory variables (chemistry, haematology, urinanalysis) |
| Device related accuracy of implantation | Week 8 | The accuracy of implantation of the Drug Delivery System (DDS) 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. |
| Device related changes in safety measures | Week 8 to Week 40 | Occurrence of adverse device effects (ADE), for either the whole system or the individual sub systems (guide tubes/catheters, subcutaneous components, port), 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cessation of infusions | Week 11 to Week 36 | Cessation of infusions in an individual patient |
| UPDRS (Unified Parkinson's Disease Rating Scale) Part III motor score | Week 15 to Week 40 | Changes in severity of PD (Parkinson's disease) motor symptoms assessed by UPDRS Part III motor scores |
| TUG (Timed Up and Go) test | Week 15 to Week 40 | Changes in mobility assessed by TUG test |
| UPDRS Total score (Part I-IV) | Week 15 to Week 40 | Change in severity of PD non-motor and motor symptoms assessed by UPDRS Part I-IV total scores (Parts I, II and IV in ON-state; Part III in OFF-state). |
| Home diary score | Week 16 to Week 24 | Change in functional status assessed by home diary score |
| PDQ-39 (Parkinson's Disease Questionnaire) score | Week 15 to Week 40 | Changes in health and daily activity assessed by PDQ-39 questionnaire score |
| change in CGI (Clinical Global Impressions) scale | Week 16 to Week 40 | • Change from baseline until end of treatment evaluation in mental status as measured by CGI scale. |
| Occurrence of blockage | Week 11 to Week 36 | Occurrence of blockage of implanted catheter preventing or limiting infusion assessed by measuring catheter pressure |
Other
| Measure | Time frame | Description |
|---|---|---|
| DAT (dopamine transporter)-PET imaging | Week 14 to Week 38 | Change in caudate and putamen DAT availability using PET imaging. |
| Coverage of infusate | Week 11 to Week 36 | Coverage of the infusate in target anatomy assessed by MRI (Magnetic resonance imaging) |
| Daily activity measurement | Week 16 to Week 40 | Change in daily activity measured by Parkinson's KinetiGraph™ (PKG™) Data Logger |
| Distribution of CDNF | Week 24 and Week 36 | Level of distribution of CDNF in serum and Cmax of CDNF in CSF |
| alpha-synuclein levels | Week 15 to Week 40 | Changes in serum and CSF (cerebrospinal fluid) concentrations of various α-synuclein species |
Countries
Finland, Sweden
Outcome results
None listed