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

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

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.

Study Overview

• Status: Completed
• Conditions: Brain Diseases; Nervous System Diseases; Parkinson Disease; Movement Disorders; Neurodegenerative Diseases
• Intervention / Treatment: Drug: Cerebral Dopamine Neurotrophic Factor; Device: Renishaw Drug Delivery System

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 Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Hospital
• Sweden
  • Lund, Sweden, 221 85
    • Skåne University Hospital
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital, Huddinge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DAT (dopamine transporter)-PET imaging	Change in caudate and putamen DAT availability using PET imaging.	Week 14 to Week 38
alpha-synuclein levels	Changes in serum and CSF (cerebrospinal fluid) concentrations of various α-synuclein species	Week 15 to Week 40
Distribution of CDNF	Level of distribution of CDNF in serum and Cmax of CDNF in CSF	Week 24 and Week 36
Daily activity measurement	Change in daily activity measured by Parkinson's KinetiGraph™ (PKG™) Data Logger	Week 16 to Week 40
Coverage of infusate	Coverage of the infusate in target anatomy assessed by MRI (Magnetic resonance imaging)	Week 11 to Week 36

Collaborators and Investigators

• Sponsor: Herantis Pharma Plc.
• Collaborators: Renishaw plc.
• Investigators: Principal Investigator: Per Svenningsson, MD, Karolinska University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 26, 2017
• Primary Completion (ACTUAL): December 19, 2019
• Study Completion (ACTUAL): December 19, 2019

Study Registration Dates

• First Submitted: September 14, 2017
• First Submitted That Met QC Criteria: September 25, 2017
• First Posted (ACTUAL): September 28, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 10, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Parkinson; Drug Delivery System; CDNF; Intracerebral
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Synucleinopathies; Parkinson Disease; Nervous System Diseases; Brain Diseases; Neurodegenerative Diseases; Movement Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Cardiotonic Agents; Dopamine Agents; Sympathomimetics; Dopamine
• Other Study ID Numbers: HP-CD-CL-2002; 2015-004175-73 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No