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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 17
- 试验地点
- 3
- 主要终点
- Adverse events (AEs)
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-Blind
入排标准
- 年龄范围
- 35 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Idiopathic Parkinson's disease based on UK brain bank criteria
- •Duration of PD motor symptoms 5-15 years (inclusive)
- •Age 35-75 years (inclusive)
- •Presence of motor fluctuations.
- •At least 5 daily doses of levodopa
- •Ability to reliably distinguish motor states and accurately complete fluctuation diaries
- •UPDRS motor score (part III) in a practically defined OFF-state between 25-50 (inclusive)
- •Hoehn and Yahr ≤ stage III in the OFF-state
- •Responsiveness to levodopa
- •No change in anti-parkinsonian medication for 6 weeks before screening
- •Provision of Informed Consent
排除标准
- •Diagnosed with atypical parkinsonism or any known secondary parkinsonian syndrome.
- •Signs or symptoms suggestive of atypical parkinsonian syndrome.
- •Drug-resistant rest tremor.
- •Prior neurosurgical treatment for PD, including lesioning or deep brain stimulation
- •Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, epilepsia, CSF shunt or other implanted CNS device
- •Presence of significant depression as defined as a BDI score ≥ 20
- •Current psychosis requiring therapy.
- •Presence of clinically significant impulse control disorder ((QUIP-RS) score > 20), or, presence of dopamine dysregulation syndrome.
- •MoCA score <
- •Use within 3 months of planned catheter insertion of concomitant medications known to affect PD symptoms other than prescribed PD therapy.
- •Any medical condition, which might impair outcome measure assessments or safety measures including ability to undergo MRI or DAT-PET.
- •Hypersensitivity or allergy to gadolinium or to any of excipients of macrocyclic GBCA used for the surgical planning MRI.
- •Screening and/or planning MRI demonstrating any abnormality, which would suggest an alternative cause for patient's parkinsonism or preclude neurosurgery.
- •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
- •History within the last 5 years of cancer with the exception of basal cell carcinoma of the skin
- •History of drug or alcohol abuse within 2 years of screening
- •Use of any investigational drug or device within 90 days of screening
- •Active breastfeeding
研究组 & 干预措施
Placebo
Patients randomized to this group will receive 6 monthly infusions of placebo/vehicle
干预措施: Cerebral Dopamine Neurotrophic Factor (Drug)
Placebo
Patients randomized to this group will receive 6 monthly infusions of placebo/vehicle
干预措施: Renishaw Drug Delivery System (Device)
CDNF mid-dose
Patients randomized to this group will receive 6 doses of CDNF titrated to mid-dose
干预措施: Cerebral Dopamine Neurotrophic Factor (Drug)
CDNF mid-dose
Patients randomized to this group will receive 6 doses of CDNF titrated to mid-dose
干预措施: Renishaw Drug Delivery System (Device)
CDNF high-dose
Patients randomized to this group will receive 6 doses of CDNF titrated to high-dose
干预措施: Cerebral Dopamine Neurotrophic Factor (Drug)
CDNF high-dose
Patients randomized to this group will receive 6 doses of CDNF titrated to high-dose
干预措施: Renishaw Drug Delivery System (Device)
结局指标
主要结局
Adverse events (AEs)
时间窗: Week 15 to Week 40
Number and severity of adverse events
Electrocardiogram (ECG)
时间窗: Week 15 to Week 40
Changes in electrical activity of heartbeat measured by electrocardiogram
Physical examination
时间窗: Week 15 to Week 40
Changes in anatomic findings found in physical examination
Device related changes in safety measures
时间窗: Week 8 to Week 40
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.
Beck Depression Inventory (BDI) score
时间窗: Week 15 to Week 40
Assessment of change in depression using Beck Depression Inventory (BDI) score
Questionnaire for impulsive-compulsive disorder in Parkinson's disease rating scale (QUIP_RS)
时间窗: Week 15 to Week 40
Assessment of changes in impulsive-compulsive disorders using QUIP_RS
Montreal cognitive assessment (MoCA)
时间窗: Week 15 to Week 40
Assessment of change in cognitive domains using MoCA test
Clinical laboratory safety screen
时间窗: Week 15 to Week 40
Changes in clinical laboratory variables (chemistry, haematology, urinanalysis)
Vital signs
时间窗: Week 15 to Week 40
Changes in vital signs
Formation of anti-CDNF antibodies
时间窗: Week 15 to Week 40
Change in anti-CDNF antibody concentration
Device related accuracy of implantation
时间窗: Week 8
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.
次要结局
- UPDRS (Unified Parkinson's Disease Rating Scale) Part III motor score(Week 15 to Week 40)
- Occurrence of blockage(Week 11 to Week 36)
- TUG (Timed Up and Go) test(Week 15 to Week 40)
- Home diary score(Week 16 to Week 24)
- PDQ-39 (Parkinson's Disease Questionnaire) score(Week 15 to Week 40)
- UPDRS Total score (Part I-IV)(Week 15 to Week 40)
- change in CGI (Clinical Global Impressions) scale(Week 16 to Week 40)
- Cessation of infusions(Week 11 to Week 36)