Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson's Disease

Study Overview
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Brief Summary
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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
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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/

Official Title
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Phase 1-2, Randomised, Double-Blind, Placebo Controlled, Safety and Tolerability Study of Intraputamenal Cerebral Dopamine Neurotrophic Factor (CDNF) Infusions Via an Investigational Drug Delivery System to Patients With Parkinson's Disease

Conditions
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Parkinson Disease, Movement Disorders, Neurodegenerative Diseases, Nervous System Diseases, Brain Diseases

Intervention / Treatment
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* Drug: Cerebral Dopamine Neurotrophic Factor
* Device: Renishaw Drug Delivery System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic Parkinson's disease based on UK brain bank criteria Duration of PD motor symptoms 5-15 years (inclusive) Age 35-75 years (inclusive) Presence of motor fluctuations. At least 5 daily doses of levodopa Ability to reliably distinguish motor states and accurately complete fluctuation diaries UPDRS motor score (part III) in a practically defined OFF-state between 25-50 (inclusive) Hoehn and Yahr ≤ stage III in the OFF-state Responsiveness to levodopa No change in anti-parkinsonian medication for 6 weeks before screening Provision of Informed Consent Exclusion Criteria: Diagnosed with atypical parkinsonism or any known secondary parkinsonian syndrome. Signs or symptoms suggestive of atypical parkinsonian syndrome. Drug-resistant rest tremor. Prior neurosurgical treatment for PD, including lesioning or deep brain stimulation Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, epilepsia, CSF shunt or other implanted CNS device Presence of significant depression as defined as a BDI score ≥ 20 Current psychosis requiring therapy. Presence of clinically significant impulse control disorder ((QUIP-RS) score > 20), or, presence of dopamine dysregulation syndrome. MoCA score < 24. Use within 3 months of planned catheter insertion of concomitant medications known to affect PD symptoms other than prescribed PD therapy. Any medical condition, which might impair outcome measure assessments or safety measures including ability to undergo MRI or DAT-PET. Hypersensitivity or allergy to gadolinium or to any of excipients of macrocyclic GBCA used for the surgical planning MRI. Screening and/or planning MRI demonstrating any abnormality, which would suggest an alternative cause for patient's parkinsonism or preclude neurosurgery. 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 History within the last 5 years of cancer with the exception of basal cell carcinoma of the skin History of drug or alcohol abuse within 2 years of screening Use of any investigational drug or device within 90 days of screening Active breastfeeding

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, Double-Blind, Placebo Controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients randomized to this group will receive 6 monthly infusions of placebo/vehicle | Drug: Cerebral Dopamine Neurotrophic Factor<br>* Repeated intracerebral infusions<br>* Other names: CDNF;Device: Renishaw Drug Delivery System<br>* Stereotactically implanted device<br>* Other names: DDS;|
| Experimental: CDNF mid-dose<br>Patients randomized to this group will receive 6 doses of CDNF titrated to mid-dose | Drug: Cerebral Dopamine Neurotrophic Factor<br>* Repeated intracerebral infusions<br>* Other names: CDNF;Device: Renishaw Drug Delivery System<br>* Stereotactically implanted device<br>* Other names: DDS;|
| Experimental: CDNF high-dose<br>Patients randomized to this group will receive 6 doses of CDNF titrated to high-dose | Drug: Cerebral Dopamine Neurotrophic Factor<br>* Repeated intracerebral infusions<br>* Other names: CDNF;Device: Renishaw Drug Delivery System<br>* Stereotactically implanted device<br>* Other names: DDS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) | Number and severity of adverse events | Week 15 to Week 40 | 
| Electrocardiogram (ECG) | Changes in electrical activity of heartbeat measured by electrocardiogram | Week 15 to Week 40 | 
| Beck Depression Inventory (BDI) score | Assessment of change in depression using Beck Depression Inventory (BDI) score | Week 15 to Week 40 | 
| Questionnaire for impulsive-compulsive disorder in Parkinson's disease rating scale (QUIP_RS) | Assessment of changes in impulsive-compulsive disorders using QUIP_RS | Week 15 to Week 40 | 
| Montreal cognitive assessment (MoCA) | Assessment of change in cognitive domains using MoCA test | Week 15 to Week 40 | 
| Physical examination | Changes in anatomic findings found in physical examination | Week 15 to Week 40 | 
| Vital signs | Changes in vital signs | Week 15 to Week 40 | 
| Clinical laboratory safety screen | Changes in clinical laboratory variables (chemistry, haematology, urinanalysis) | Week 15 to Week 40 | 
| Formation of anti-CDNF antibodies | Change in anti-CDNF antibody concentration | Week 15 to Week 40 | 
| Device related changes in safety measures | 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. | Week 8 to Week 40 | 
| Device related accuracy of implantation | 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. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UPDRS (Unified Parkinson's Disease Rating Scale) Part III motor score | Changes in severity of PD (Parkinson's disease) motor symptoms assessed by UPDRS Part III motor scores | Week 15 to Week 40 | 
| TUG (Timed Up and Go) test | Changes in mobility assessed by TUG test | Week 15 to Week 40 | 
| UPDRS Total score (Part I-IV) | 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). | Week 15 to Week 40 | 
| Home diary score | Change in functional status assessed by home diary score | Week 16 to Week 24 | 
| PDQ-39 (Parkinson's Disease Questionnaire) score | Changes in health and daily activity assessed by PDQ-39 questionnaire score | Week 15 to Week 40 | 
| change in CGI (Clinical Global Impressions) scale | • Change from baseline until end of treatment evaluation in mental status as measured by CGI scale. | Week 16 to Week 40 | 
| Occurrence of blockage | Occurrence of blockage of implanted catheter preventing or limiting infusion assessed by measuring catheter pressure | Week 11 to Week 36 | 
| Cessation of infusions | Cessation of infusions in an individual patient | Week 11 to Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson, CDNF, Drug Delivery System, Intracerebral