Safety of CDNF by Brain Infusion in Patients With Parkinson's Disease. Extension to HP-CD-CL-2002 Clinical Study

NCT03775538 | Completed Phase 1 DMC

• 1 other identifier: HP-CD-CL-2003
• Study Type: interventional
• Target: 15
• Locations: 2 countries
• Sites: 3

Brief Summary

This study is an extension to the HP-CD-CL-2002 clinical study. It evaluates the long-term 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). Long-term safety of the DDS is also being evaluated. All patients will receive monthly infusions of either mid- or high-dose of CDNF for a period of 6 months.

Conditions

Parkinson Disease; Movement Disorders; Neuro-Degenerative Disease; Nervous System Diseases; Brain Diseases

Keywords

Parkinson; CDNF; Drug Delivery System; Intracerebral

Outcome Measures

Primary Outcomes (25)

• Incidence of treatment-emergent adverse events (AEs)[safety-tolerability]

  Total number, causality and severity of adverse events at any time during the study period

  Week 40 to Week 65

• Change in Electrocardiogram (ECG): Ventricular rate, PR interval, qRS duration, QT, QTc [safety-tolerability]

  Changes in electrical activity of heartbeat measured by electrocardiogram: Ventricular rate (bpm), PR interval (msec), QRS duration (msec), QT (msec), QTc (msec)

  Week 40, Week 53 and Week 65

• Change in Beck Depression Inventory (BDI) score [safety-tolerability]

  Assessment of change in depression using Beck Depression Inventory (BDI) score: Sadness: Pessimism; Past Failure; Loss of pleasure; Guilty feelings; Punishment Feelings; Self-dislike; Self-criticalness;Suicidal thoughts or wishes; Crying; Agitation; Loss of interest; Indecisiveness;Worthlessness; Loss of energy; Changes in sleeping pattern; Irritability; Changes in appetite; Concentration difficulty; Tiredness or fatique; Loss of interest in sex. Rated on a 4-point scale ranging from 0 to 3 based on severity of each item (0=low intensity; 3=highest intensity). The maximum total score is 63.

  Week 40, Week 53 and Week 65

• Change in Questionnaire for impulsive-compulsive disorder in Parkinson's disease rating scale (QUIP_RS) [safety-tolerability]

  Assessment of changes in impulsive-compulsive disorders using QUIP\_RS. Questions scored 0-4 (0=never; 4=very often) on gambling, sex, buying, eating, performing tasks/hobbies, repeating simple activities, and taking Parkinson's disease medication. Total QUIP-RS Score 0-112

  Week 40, Week 53 and Week 65

• Change in Montreal cognitive assessment (MoCA) [safety-tolerability]

  Assessment of change in cognitive domains using MoCA test: attention and, concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points; a score of 26 or above is considered normal.

  Week 40, Week 53 and Week 65

• Changes in physical examination: anatomic findings [safety-tolerability]

  Changes in anatomic findings found in physical examination of the following body systems: general inspection/upper extremities; head, eyes, ears, nose, throat, and superficial cervial lymph notes; neck, shoulders, back; chest and lungs; cardiovascular; abdomen; lower extremities

  Week 40 and Week 65

• Changes in physical examination: clinical standard neurological examination

  A clinical standard neurological examination by study investigator. Changes in motor function, sensory function, cranial nerve function (visual fields), cortical functions and reflexes are followed in the examination, scored as normal - abnormal without clinical relevance - abnormal with clinical relevance

  Week 40 and Week 65

• Changes in vital signs: blood pressure [safety-tolerability]

  Changes in blood pressure during the study , measured as systolic and diastolic blood pressure (in mmHg)

  Weeks 41, 45, 49, 53, 57, 61, and 63

• Changes in vital signs: pulse rate [safety-tolerability]

  Changes in pulse rate during the study (in beats per minute)

  Weeks 41, 45, 49, 53, 57, 61, and 63

• Changes in vital signs: body temperature [safety-tolerability]

  Changes in body temperature during the study (in degrees celsius)

  Weeks 41, 45, 49, 53, 57, 61, and 63

• Changes in vital signs: body weight [safety-tolerability]

  Changes in body weight during the study (in kilograms)

  Weeks 41, 45, 49, 53, 57, 61, and 63

• Changes in vital signs: body mass index (BMI) [safety-tolerability]

  Changes in body mass index during the study (in kg/m\^2)

  Weeks 41, 45, 49, 53, 57, 61, and 63

• Changes in clinical laboratory safety screen: clinical chemistry [safety-tolerability]

  Changes in laboratory variables for clinical chemistry (Na, K, Urea, creatinine, creatine kinase, Ca, Bilirubin, IgG, Albumin, ALP, ALT, AST)

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: haematology - hemoglobin [safety-tolerability]

  Changes in laboratory variables for haematology: hemoglobin (g/L). Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: haematology - hematocrit [safety-tolerability]

  Changes in laboratory variables for haematology: hematocrit (%, ratio of red blood cell volume to total blood volume). Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: haematology - red blood cell (RBC) count [safety-tolerability]

  Changes in laboratory variables for haematology: RBC count (10E12/L). Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: mean cell volume (MCV) of red blood cells [safety-tolerability]

  Changes in laboratory variables for haematology: MCV of red blood cells (fL). Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: mean cell hemoglobin of RBC (MHC) [safety-tolerability]

  Changes in laboratory variables for haematology: MCH (pg). Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: Platelet count [safety-tolerability]

  Changes in laboratory variables for haematology: Platelet count (10E9/L). Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: white blood cell (WBC) counts [safety-tolerability]

  Changes in laboratory variables for haematology: Cell counts (10E9/L) for total WBC, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: activated partial thromboplastin time (aPTT) [safety-tolerability]

  Changes in laboratory variables for haematology: aPTT (sec) . Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: International Normalized Ratio (INR) [safety-tolerability]

  Changes in laboratory variables for haematology: INR (standardized prothrombin time) to determine the effects of oral anticoagulants on the clotting system. Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Changes in clinical laboratory safety screen: urinanalysis [safety-tolerability]

  Changes in laboratory variables for urinanalysis (blood/erythrocytes, glucose, ketones, leukocytes, nitrites, pH, protein) studied by dipstick and scored 0-3. Result evaluated as "normal", "abnormal without clinical relevance" or "abnormal with clinical relevance".

  Weeks 40, 41, 45, 49, 53, 57, 61, and 65

• Formation of anti-CDNF antibodies [safety-tolerability]

  Formation and change in anti-CDNF antibody concentration (in ng/ml).

  Weeks 40, 45, 49, 53, 57, 61, and 65

• Device related occurrence of adverse device effects [safety-tolerability]

  Occurrence of adverse device effects (ADE) at any time of the study period, 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 40 to Week 65

Secondary Outcomes (8)

• Change in UPDRS (Unified Parkinson's Disease Rating Scale) Part III motor score [efficacy]

  Week 40, Week 53 and Week 65

• Change in TUG (Timed Up and Go) test [efficacy]

  Week 40, Week 53 and Week 65

• Change in UPDRS Total score (Part I-IV) [efficacy]

  Week 40, Week 53 and Week 65

• Change in home diary score [efficacy]

  Weeks 40, 45, 49, 49, 53, 57, 61 and 65

• Change in PDQ-39 (Parkinson's Disease Questionnaire) score [efficacy]

  Week 40, Week 53 and Week 65

Other Outcomes (6)

• Change in DAT (dopamine transporter)-PET imaging [exploratory]

  Week 63

• Change in alpha-synuclein levels [exploratory]

  Week 40, Week Week 61 and Week 65

• Distribution of CDNF: blood serum [exploratory]

  Week 61

Study Arms (2)

CDNF mid-dose (400 micrograms)

EXPERIMENTAL

Patients randomized to this group will receive 6 monthly-intermittent intracerebral doses of Cerebral Dopamine Neurotrophic Factor (CDNF) titrated to mid-dose (400 micrograms) administered via the Renishaw Drug Delivery System (DDS) to the bilateral putamen.

Drug: Cerebral Dopamine Neurotrophic Factor; Device: Renishaw Drug Delivery System

CDNF high-dose (1200 micrograms)

EXPERIMENTAL

Patients randomized to this group will receive 6 monthly-intermittent intracerebral doses of Cerebral Dopamine Neurotrophic Factor (CDNF) titrated to high-dose (1200 micrograms) administered via the Renishaw Drug Delivery System (DDS) to the bilateral putamen.

Drug: Cerebral Dopamine Neurotrophic Factor; Device: Renishaw Drug Delivery System

Interventions

Cerebral Dopamine Neurotrophic Factor DRUG

Repeated intracerebral infusions

Also known as: CDNF

CDNF high-dose (1200 micrograms); CDNF mid-dose (400 micrograms)

Renishaw Drug Delivery System DEVICE

Stereotactically implanted device

Also known as: DDS

CDNF high-dose (1200 micrograms); CDNF mid-dose (400 micrograms)

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Completion of 6 months treatment period in the Main study (HP-CD-CL-2002) including End-of-Study assessment
• Negative pregnancy test at study entry for females of childbearing potential. Willingness of using a highly effective form of contraception until 30 days after end of study. Males: willingness to use condom and not to donate sperm for 3 months following DAT-PET. Willingness of female partners of male study participants to use highly effective form of contraception until 30 days after their male partner's end of the study.
• At least one functioning catheter in each putamen
• Provision of informed consent

You may not qualify if:

• Drug-resistant rest tremor, severe dyskinesia or severe head tremor, which could interfere with treatment infusions
• Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, epilepsy, CSF shunt or other implanted central nervous system device
• Changes in pathology which give rise to safety concern such as sequelae from catheter implantation, clinically significant intracerebral trauma, oedema, haemorrhage, or infection
• Current psychosis requiring therapy
• Presence of clinically significant impulse control disorder by a positive screen on the QUIP-RS questionnaire score \>20, or, presence of dopamine dysregulation syndrome
• An unresolved intolerable adverse event or adverse device event in study HP-CD-CL-2002, which is not expected to resolve or cease to an acceptable level of intensity within reasonable time
• Medical conditions, which might impair outcome measure assessments or safety measures
• Impaired renal function
• Concomitant treatment with neuroleptics or antipsychotic medication prescribed for treatment of current psychosis, central dopamine blockers or tricyclic antidepressants

Sponsors & Collaborators

• Herantis Pharma Plc.: lead
• Renishaw plc.: collaborator

Study Sites (3)

Helsinki University Hospital

Helsinki, 00029, Finland

Location

Skåne University Hospital

Lund, 221 85, Sweden

Location

Karolinska University Hospital

Stockholm, 14186, Sweden

Location

MeSH Terms

Conditions

Parkinson Disease; Movement Disorders; Nervous System Diseases; Brain Diseases

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Central Nervous System Diseases; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Per Svenningsson, MD, Prof.

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-Blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomised, Double-Blind, Active Treatment

Study Record Dates

• First Submitted: October 11, 2018
• First Posted: December 14, 2018
• Study Start: July 5, 2018
• Primary Completion: July 8, 2020
• Study Completion: July 8, 2020
• Last Updated: August 12, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

SE (2); FI (1)