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

Study Overview
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Brief Summary
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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.

Detailed Description
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A patient's participation in the study will last for six months and will include nine visits: Screening (1 visit, same as HP-CD-CL-2002 End-of-Study visit) Dosing visits: CDNF (6 visits) DAT-PET (1 visit) End-of-study visit (1 visit) Study examinations and assessments Physical examination: pulse rate, blood pressure, temperature, body weight and height, body mass index (BMI), neurological exam ECG (electrocardiography) and blood and urine tests 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 movement recording device 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) For more information: https://treater.eu/clinical-study/

Official Title
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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

Conditions
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Parkinson Disease, Movement Disorders, Neuro-Degenerative Disease, 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: 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 Exclusion Criteria: 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

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, Active Treatment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CDNF mid-dose (400 micrograms)<br>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<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 (1200 micrograms)<br>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<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 |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in UPDRS (Unified Parkinson's Disease Rating Scale) Part III motor score [efficacy] | Changes in severity of PD (Parkinson's disease) motor symptoms assessed by UPDRS Part III motor scores (each scored 0-4; 0=none, 4=severe): Speech; facial expression; tremor a rest; Tremor of hands; rigidity; firger taps; hand movelents; alternating movement of hands; leg agility; rising from chair; posture; gait; postural stability; body bradykinesia and hypokinesia. The total score, the sum of scores received from 27 assessments, is 0 - 108 | Week 40, Week 53 and Week 65 | 
| Change in TUG (Timed Up and Go) test [efficacy] | Changes in mobility assessed by TUG test (in minutes and seconds). | Week 40, Week 53 and Week 65 | 
| Change in UPDRS Total score (Part I-IV) [efficacy] | 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): Part 1 (scored 0-16) Mentation, behaviour and mood. Part 2 (scored 0-52) Activities of daily living. Part 3 (scored 0-108) Motor examination. Part 4 (scored 0-23) Complications of therapy. The total score is 0-199 (0=totally healthy; 199=worst possible). | Week 40, Week 53 and Week 65 | 
| Change in home diary score [efficacy] | Change in functional status of the patient's dyskinesias assessed by home diary score for three-day period. Each half hour is scored: sleep, OFF, ON without dyskinesias, ON with non-troublesome dyskinesias, ON with troublesome dyskinesias. The total time in each state over 3 days is recorded (in hours). The total bad time is defined as OFF time and ON time with troublesome dyskinesia. The total good time is defined as ON time without dyskinesia or ON time with non-troublesome dyskinesia. | Weeks 40, 45, 49, 49, 53, 57, 61 and 65 | 
| Change in PDQ-39 (Parkinson's Disease Questionnaire) score [efficacy] | Changes in health and daily activity assessed by a self-administered PDQ-39 questionnaire comprising of 39 questions related to eight key areas of health in Parkinson's patients: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication and bodily discomfort. Each question is evaluated on a scale of five terms Never, Occasionally, Sometimes, Often or Always or cannot do at all. | Week 40, Week 53 and Week 65 | 
| Change in CGI-I (Clinical Global Impression - Improvement) scale [efficacy] | Change in mental status as measured by CGI-I scale rated by the clinical on a seven-point scale 1-7 (1=very much improved, 4=no change, 7=very much worse). | Weeks 40, 45, 49, 53, 57, 61 and 65 | 
| Occurrence of blockage [performance assessment] | Occurrence of blockage of implanted catheter preventing or limiting infusion assessed by measuring catheter pressure at the infusion pump during infusion (in mmHg). | Week 41, 45, 49, 53, 57 and Week 61 | 
| Stability of transcutaneous port: Inability to start infusion due to connectivity problem in Drug Delivery System | The stability of transcutaneous port is evaluated by recording the cases when the infusion in an individual patient has not been able to start due to connectivity problem between the external infusion set and the transcutaneous port. | Week 41 to Week 61 | 

 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