Long-Term Follow-up Safety After DDS Implantation With/Without CDNF Infusions

Study Overview
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Brief Summary
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This study is a follow up to the HP-CD-CL-2002 clinical study. It evaluates the long-term safety in patients with Parkinson's disease after implantation of an investigational drug delivery system (DDS) with or without infusions of CDNF. All patients will have at least the port explanted.

Detailed Description
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A patients participation in the study will last for up to 4 years and will include up to nine visits: Screening (1 visit, same as HP-CD-CL-2003 End-of-Study visit) Pre-surgery / explantation surgery / post-surgery (3 visits) Safety (4 visits) DAT-PET (Dopamine Transporter - Positron Emission Tomography) examination (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. Magnetic resonance imaging (MRI) Positron emission tomography scans (PET) Skin condition over any remaining implanted subcutaneous portion of the device. Skin healing after port / device removal. For more information: https://treater.eu/clinical-study/

Official Title
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A Long-Term Follow-up Safety Study for Patients With Idiopathic Parkinson's Disease (PD) Implanted With the DDS and/or Who Received Treatment in the Main Study and/or Extension Study

Conditions
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Parkinson Disease, Movement Disorders, Neuro-Degenerative Disease, Nervous System Diseases, Brain Diseases

Intervention / Treatment
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* Device: Renishaw Drug Delivery System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completion of visit 4 (implantation of DDS) within main study HP-CD-CL-2002. Patients who: Discontinued main study after visit 4 of main study or discontinued extension study. Received 6 doses in main study but didn't participate in extension study. Received 12 doses including extension study. Provision of informed consent. Exclusion Criteria: None

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
Intervention Model: Single Group Assignment
Interventional Model Description: Open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: No Arm<br>As this is the follow up study, there are no arms | Device: Renishaw Drug Delivery System<br>* Device that allows pharmaceuticals to be delivered into the brain is to be assessed over a period of time to inform of the long term safety of the implanted device.<br>|

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 | Until study completion, up to month 58 | 
| Change in Electrocardiogram (ECG): Ventricular rate (bpm), [safety-tolerability] | Changes in electrical activity of heartbeat measured by electrocardiogram: Ventricular rate (bpm), | Week 71 and Month 25 | 
| Change in Electrocardiogram (ECG): PR (pulse rate) interval, qRS duration, QT, QTc (msec) [safety-tolerability] | Changes in electrical activity of heartbeat measured by electrocardiogram: PR interval (msec), QRS duration (msec), QT (msec), QTc (msec) | Week 71 and Month 25 | 
| 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 71 and Month 25 | 
| 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 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 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 71 and Month 25 | 
| 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 71 and Month 25 | 
| 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 71, and Months 25, 34, 58 | 
| 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 71, and Months 25, 34, 58 | 
| 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 55, 57, 58, 75 | 
| Changes in vital signs: pulse rate [safety-tolerability] | Changes in pulse rate during the study (in beats per minute) | Weeks 55, 57, 58, 75 | 
| Changes in vital signs: body temperature [safety-tolerability] | Changes in body temperature during the study (in degrees celcius) | Weeks 55, 57, 58, 75 | 
| Changes in vital signs: body weight [safety-tolerability] | Changes in body weight during the study (in kilograms) | Weeks 55, 57, 58, 75 | 
| Changes in vital signs: body mass index (BMI) [safety-tolerability] | Changes in body mass index during the study (in kg/m^2) | Weeks 55, 57, 58, 75 | 
| 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 (Immunoglobulin G), Albumin, ALP(Alkaline phosphatase), ALT (Alanine transaminase), AST (Aspartate transaminase)) | Weeks 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| Changes in clinical laboratory safety screen: haematology - haemoglobin [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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| Changes in clinical laboratory safety screen: haematology - haematocrit [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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| 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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| 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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| Changes in clinical laboratory safety screen: mean cell haemoglobin of RBC (MHC) [safety-tolerability] | Changes in laboratory variables for haematology: MCH (Mean cell hemoglobin) (pg). Result evaluated as normal, abnormal without clinical relevance or abnormal with clinical relevance. | Weeks 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| 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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| Changes in clinical laboratory safety screen: white blood call (WBC) count [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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| 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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| Changes in clinical laboratory safety screen: International Normalised 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 53, 55, 57, 58, 71 and Months 25, 34, 58 | 
| 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 53, 55, 57, 58, 71 and Month 25 | 
| Formation of anti-CDNF antibodies [safety-tolerability] | Formation and change in anti-CDNF antibody concentration (in ng/ml). | Weeks 58, 78 and Month 25 | 
| 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 49 and Month 58 | 

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 71 and Month 25 | 
| Change in TUG (Timed Up and Go) test [efficacy] | Changes in mobility assessed by TUG test (in minutes and seconds). | Week 71 and Month 25 | 
| 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 71 and Month 25 | 
| 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, 53, 57, 58, 61, 65, 71, and Month 25 | 
| 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 71 and Month 25 | 
| 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, 58, 61, 65, 71, and Month 25 | 
| Healing of patient skin after port removal | Any Adverse Events (AEs) or Serious Adverse Events (SAEs) related to the skin condition once the port has been removed | Month 25, 34 and 58 | 

 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, Parkinson Disease, Nervous System Disease, Movement Disorders, Brain Diseases, Neurodegenerative Diseases, Parkinsonian Disorders, Basal Ganglia Diseases, Central Nervous System Diseases, Dopamine, Cardiotonic Agents, Sympathomimetrics, Autonomic Agents, Peripheral Nervous System Agents, Physiological Effects of Drugs, Dopamine Agents, Neurotransmitter Agents, Molecular Mechanisms of Pharmacological Action, Protective Agents