An extended clinical study to test the safety of Cerebral Dopamine Neurotrophic Factor (CDNF) by brain infusion via Drug Delivery System (DDS) in patients with Parkinson's disease.

• Register: EUCTR
• Last refreshed on: 6 October 2020
• Main ID: EUCTR2018-000346-19-SE
• Date of registration: 09/04/2018
• Prospective Registration: Yes
• Primary sponsor: Herantis Pharma Plc
• Public title: An extended clinical study to test the safety of Cerebral Dopamine Neurotrophic Factor (CDNF) by brain infusion via Drug Delivery System (DDS) in patients with Parkinson's disease.
• Scientific title: A Randomised, Double-Blind, Multi-centre, Active Treatment, Extension and Safety Study for Patients with Idiopathic Parkinson’s Disease (PD) Who Previously Completed the CDNF/DDS Main Study HP-CD-CL-2002. - Extension Study
• Date of first enrolment: 04/06/2018
• Target sample size: 18
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000346-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: different doses of the same product Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Finland, Sweden

Contacts

• Name: Project Manager
• Affiliation: Herantis Pharma Plc

• Name: Project Manager
• Affiliation: Herantis Pharma Plc

Key inclusion & exclusion criteria

Inclusion criteria:
1. Completion of the 6 months treatment period in the Main study (HP-CD-CL-2002), including End-of-Study assessment at Visit 17 (Week 24).
2. 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 30 days after their male partner’s end of the study.
3. At least one functioning catheter tip in each putamen.
4. 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 9
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 9

Exclusion criteria:
1. Drug-resistant rest tremor, severe dyskinesia or severe head tremor, which could interfere with treatment infusions.
2. Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, epilepsy, CSF shunt or other implanted central nervous system (CNS) device.
3. Changes in pathology which give rise to safety concern such as sequelae from catheter implantation, clinically significant intracerebral trauma, oedema, haemorrhage, or infection.
4. Current psychosis requiring therapy. Brief episodes of hallucinations, disorientation or confusion are not exclusionary.
5. 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.
6. Any unresolved intolerable adverse events or adverse device events in study HP-CD-CL-2002, which are not expected to resolve or cease to an acceptable level of intensity within reasonable time. This includes any Serious Adverse Event (SAE) of at least Grade 3 (severe) in severity, judged to be possibly, probably or definitely related to study treatment.
7. Any medical condition, which might impair outcome measure assessments or safety measures including ability to undergo MRI or DAT-PET.
8. Impaired renal function. Estimated Glomerular Filtration rate (eGFR) < 30 mL/min/1.73 m2 .
9. Concomitant treatment with neuroleptics or antipsychotic medication prescribed for treatment of current psychosis, central dopamine blockers or tricyclic antidepressants. Low dose quetiapine
and similar medications prescribed for Parkinson’s disease treatment are not exclusionary.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Idiopathic Parkinson's Disease
MedDRA version: 21.1 Level: LLT Classification code 10013113 Term: Disease Parkinson's System Organ Class: 100000004852

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: Cerebral Dopamine Neurotrophic Factor
Product Code: CDNF
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Not Applicable
Other descriptive name: recombinant human Cerebral Dopamine Neurotrophic Factor
Concentration unit: µg/µl microgram(s)/microlitre
Concentration type: equal
Concentration number: 1.0-

Primary Outcome(s)

Main Objective: To demonstrate the safety and tolerability of
– the IMP administered as long-term monthly intermittent bilateral intraputamenal CDNF infusions, and,
– the investigational medical device for the intended long-term use and within the intended patient population during infusions.

Primary end point(s): DRUG RELATED
• Change from extension study start (Week 24) until end of treatment evaluation (Week 49) 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 infusion procedures during the study period (Weeks 25, 29, 33, 37, 41 and 45), during the entire study period outside of the infusion procedures (Week 24 to Week 49), 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.

Timepoint(s) of evaluation of this end point: DRUG RELATED
Change from extension study start (Week 24) until end of treatment evaluation (Week 49).

DEVICE RELATED
Occurrence of adverse device effects (ADE) and serious adverse device effect (SADE) at infusion procedures during the study period (Weeks 25, 29, 33, 37, 41 and 45), during the entire study period outside of the infusion procedures (Week 24 to Week 49)

Secondary Objective: Drug related:
• Severity of PD motor symptoms as measured by OFF-state UPDRS part III
• Mobility as measured by OFF-state Timed Up and Go (TUG) test
• ON-state non-motor and motor function, motor complications, and ON- and OFF-state activities of daily living as measured by UPDRS scores part I-IV
• Patient’s functional status by home diary
• Patient’s health and daily activities as measured by PDQ-39 questionnaire
• Patient’s treatment response on mental status as measured by CGI scale

Device related:
• the patency of each individual catheter lines and the whole system
• the stability of the transcutaneous port

Exploratory objectives
Drug related:
• DAT-PET imaging
• Serum and cerebrospinal fluid levels of a-synuclein
• Daily activity measurement by Parkinson’s KinetiGraph
• Level of distribution of CDNF and proteomic biomarker screen in CSF
• Genome sequencing testing from saliva

Device related:
• the coverage of infusion at the target site

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: DRUG RELATED
• baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in PD non-mortor and motor symptoms, in mpbility, in heath and daily activity.
• baseline (Week -1), at study start (Week 24) until end of treatment evaluation (Week 49) in functional status and in mental satus

DEVICE RELATED
• Week 25 until final treatment infusion (Week 45)

Exploratory Endpoints
DRUG RELATED
1) to dosing (Week -2) to 12 months of dosing (Week 47)
2) baseline (Week -1) and after the twelfth (Week 45)
3) first dosing (Week 0) until end of treatment evaluation (Week 49)

DEVICE RELATED
• at final treatment infusion (Week 45)

Secondary end point(s): DRUG RELATED
• Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in severity of PD motor symptoms by UPDRS Part III motor scores.
• Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in mobility by TUG test.
• Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) 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 baseline (Week -1), at study start (Week 24) until end of treatment evaluation (Week 49) in functional status by home diary score.
• Change from baseline (Week -1), at study start (Week 24), after three months (Week 37), and end of treatment evaluation (Week 49) in health and daily activity by PDQ-39 questionnaire score.
• Change from baseline (Week -1), at study start (Week 24) and end of treatment evaluation (Week 49) in mental status as measured by CGI scale.

DEVICE RELATED
• Occurrence of blockage of an individual implanted catheter preventing or limiting infusion (Week 25) until final treatment infusion (Week 45) as measured by pressure rise above 590 mmHg.
• Cessation of infusions in an individual patient due to:
o the inability to secure an external system due to looseness of the port,
o the need for surgical removal of the transcutaneous port or surgical intervention
to stabilise the port.

Exploratory Endpoints
DRUG RELATED
1) Change in caudate and putamen DAT availability prior to dosing (Week -2) to 12 months of dosing (Week 47) using PET imaging with [ 18 F]FE-PE2I to assess the integrity of the nigrostriatal system.
2) Change in serum and cerebrospinal fluid levels of total a-synuclein, oligomeric a-synuclein, serine-129 phosphorylated a-synuclein, in the a-synuclein oligomer/total a-synuclein ratio at baseline (Week -1) and, in a-synuclein aggregation propensity in CSF after 12 months of treatment.
3) Level of distribution and Cmax of CDNF in CSF after the twelfth (Week 20) infusion.
4) Change in proteomic biomarker screen in CSF at baseline (Week -1) and after the twelfth (Week 45) infusion. A saliva sample for next generation sequencing (NGS) is collected at any timepoint during the study (Week 24 to Week 49), after study discontinuation or after study completion. The analysis together will be correlated to any other study outcome, i.e. secondary endpoints.
5) Change from first dosing (Week 0) until end of treatment evaluation (Week 49) in daily activity measurement by Parkinson’s KinetiGraph™ (PKG™) Data Logger.

DEVICE RELATED
• Coverage of the infusate in target anatomical volume of interest, at final treatment infusion (Week 45) as assessed by MRI.

Secondary ID(s)

HP-CD-CL-2003

Source(s) of Monetary Support

European Commission

Herantis Pharma Plc

Renishaw Neuro Solutions Ltd.

Ethics review

Status: Approved
Approval date: 16/05/2018
Contact: