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

Phase 1

Completed

• Conditions: Parkinson Disease; Neurodegenerative Diseases; Movement Disorders; Nervous System Diseases; Brain Diseases
• Interventions: Drug: Cerebral Dopamine Neurotrophic Factor; Device: Renishaw Drug Delivery System

• Registration Number: NCT03295786
• Lead Sponsor: Herantis Pharma Plc.

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/

Study Timeline

• Study First Submitted: 2017-09-14
• Study First Submitted QC: 2017-09-25
• Study Start: 2017-09-26
• Study First Posted: 2017-09-28
• Primary Completion: 2019-12-19
• Study Completion: 2019-12-19
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-10
• Last Update Posted: 2020-01-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 17

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Renishaw Drug Delivery System	Patients randomized to this group will receive 6 monthly infusions of placebo/vehicle
CDNF mid-dose	Renishaw Drug Delivery System	Patients randomized to this group will receive 6 doses of CDNF titrated to mid-dose
CDNF high-dose	Renishaw Drug Delivery System	Patients randomized to this group will receive 6 doses of CDNF titrated to high-dose
CDNF mid-dose	Cerebral Dopamine Neurotrophic Factor	Patients randomized to this group will receive 6 doses of CDNF titrated to mid-dose
Placebo	Cerebral Dopamine Neurotrophic Factor	Patients randomized to this group will receive 6 monthly infusions of placebo/vehicle
CDNF high-dose	Cerebral Dopamine Neurotrophic Factor	Patients randomized to this group will receive 6 doses of CDNF titrated to high-dose

Primary Outcome Measures

Name	Time	Method
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
Physical examination	Week 15 to Week 40	Changes in anatomic findings found in physical examination
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.
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
Clinical laboratory safety screen	Week 15 to Week 40	Changes in clinical laboratory variables (chemistry, haematology, urinanalysis)
Vital signs	Week 15 to Week 40	Changes in vital signs
Formation of anti-CDNF antibodies	Week 15 to Week 40	Change in anti-CDNF antibody concentration
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.

Secondary Outcome Measures

Name	Time	Method
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
Occurrence of blockage	Week 11 to Week 36	Occurrence of blockage of implanted catheter preventing or limiting infusion assessed by measuring catheter pressure
TUG (Timed Up and Go) test	Week 15 to Week 40	Changes in mobility assessed by TUG test
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
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).
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.
Cessation of infusions	Week 11 to Week 36	Cessation of infusions in an individual patient

Trial Locations

Locations (3)

Helsinki University Hospital; 🇫🇮 Helsinki, Finland

Skåne University Hospital; 🇸🇪 Lund, Sweden

Karolinska University Hospital, Huddinge; 🇸🇪 Stockholm, Sweden