NCT04449484已完成1 期
A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of MEDI1341 in Subjects With Parkinson's Disease
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Suicidal Ideation
研究概览
简要总结
This is a multicenter, randomized, double-blind, placebo-controlled study of multiple ascending iv doses of MEDI341 in male and female subjects with Parkinson's Disease.
详细描述
The study will include up to 3 cohorts, with 12 subjects in each, for a total of up to 36 randomised subjects.
The study comprises a screening period of up to 49 days, an 8-week double-blind treatment period, and a 13-week follow-up period. Each subject will receive three 60 minute iv infusions of MEDI1341 or placebo during the 8-week treatment period, with 4 weeks between infusions. The overall study duration (enrolment, treatment, and follow-up periods) will be up to 28 weeks per subject.
A Dose Escalation Committee will review data from each cohort to allow progression to the next higher dose cohort in the study.
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)
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •In the opinion of the investigator, a recent clinically significant illness (other than PD), infection, medical/surgical procedure, or significant trauma within 30 days prior to screening, or between screening and randomization, that is likely to deteriorate, compromise the subject's safety or ability to complete the study, or compromise the interpretation of the study results (Note: a history of coronavirus disease 2019 [COVID 19] infection with unresolved medical sequelae would be considered exclusionary.)
- •Presence of a serious or unstable clinically significant illness, including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic or autoimmune disease (eg, multiple sclerosis), hematologic or other major disease, which, in the judgment of the investigator, is poorly controlled or otherwise likely to deteriorate, compromise the subject's safety or ability to complete the study, or compromise the interpretation of the study results
- •Significant neurological disease affecting the CNS (other than PD) that, in the opinion of the investigator, may affect motor function or the ability to complete the study, including but not limited to progressive supranuclear palsy, multiple system atrophy (MSA; including MSA-P and MSA-C or other MSA terminology: striatonigral degeneration, olivopontocerebellar atrophy or autonomic failure), postencephalitic parkinsonism, metabolic diseases with parkinsonian signs and symptoms (eg, Wilson disease, manganese exposure) or other secondary forms of Parkinsonism, and ischemic or traumatic brain injury (including multiple episodes of head trauma, or head trauma resulting in protracted loss of consciousness within the 5 years prior to screening or between screening and randomization)
- •Brain MRI scan that shows clinically significant evidence of malignant, ischemic, demyelinating, structural, or degenerative brain disease or has findings that compromise the safety of LP
- •Has undergone surgery for the treatment of PD (eg, pallidotomy, deep brain stimulation, fetal tissue transplantation) or has undergone any other brain surgery at any time, even for non-PD conditions
- •History of epilepsy or seizures, except febrile childhood seizures
- •History of transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to screening or between screening and randomization
- •Presence of any psychiatric disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V; APA 2013) or symptom if, in the judgment of the investigator, the psychiatric disorder or symptom is likely to confound interpretation of the study results, affect motor function assessment, or affect the subject's ability to complete the study
- •A diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation, or significant inherited cognitive impairment
- •Suicidality, represented by answering "yes" to Question 4 or Question 5 on the C SSRS, indicating active suicidal ideation with any intent to act, during the subject's lifetime, as assessed at screening, or between screening and randomization
- •Suicidal behavior such that a determination of "yes" is made on the Suicidal Behavior section of the C SSRS for "Actual Attempt," "Interrupted Attempt," "Aborted Attempt," or "Preparatory Acts or Behavior," during the subject's lifetime, as assessed at screening, or between screening and randomization
- •History of alcohol or drug abuse or dependence (except nicotine dependence), as defined by the DSM-V, within 2 years prior to screening or between screening and randomization
- •Within 1 year prior to screening, any of the following: myocardial infarction; hospitalization for congestive heart failure; hospitalization for, or symptoms of unstable angina; unexplained syncope
- •Moderate or severe congestive heart failure, or known ejection fraction < 40%
- •Known significant structural heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy) that is considered likely to lead to a deterioration of cardiac function over the course of the study
- •History of cancer within 5 years prior to screening or between screening and randomization, with the exception of non-metastatic basal and/or squamous cell carcinoma of the skin
- •History of allergy/hypersensitivity to immunizations or immunoglobulins
- •Any condition that, in the opinion of the investigator or medical monitor, makes the subject unsuitable for the study
- •Requires treatment with another monoclonal antibody
- •Use of any investigational medicine, device, or biologic within 3 months or 5 half-lives of that intervention (whichever is longer) prior to screening
- •Previous allogeneic bone marrow or stem cell transplant
- •Use of typical or atypical antipsychotic medication, or other medication with dopamine antagonist properties (eg, metoclopramide, domperidone), within 6 months prior to randomization
- •Use of immunosuppressive medication within 6 months prior to randomization. (Note: Inhaled and topical corticosteroids are permitted. Low-dose systemic corticosteroids [< 10 mg per day prednisone or equivalent], for autoimmune disease that is considered to be quiescent, in remission, or otherwise well controlled are permitted). Other immunosuppressive drugs and biologics are contraindicated.
- •Received non-leukocyte depleted whole blood transfusion within 6 months prior to screening
- •Received any commercially available vaccine within 30 days prior to randomization. (Note: for COVID-19 vaccines authorized by the FDA for emergency use, this time frame applies from last vaccination or booster dose, whichever is required to consider vaccination complete in line with applicable guidance.)
- •Participation in another study investigating:
- •Active or passive immunization against α synuclein for PD, at any time prior to screening, or
- •Immunoglobulin G therapy within 6 months before screening
- •Any clinically significant abnormality as determined by investigator at screening or between screening and randomization in physical examination, vital signs, ECG, or clinical laboratory test results that may compromise the subject's safety or ability to complete the study or compromise the interpretation of the study results
- •Presence of any of the following MRI contraindications: pacemaker; cardiac defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; recent (within one year) coronary or carotid stent; ear implant; CSF shunt; other implanted medical device (eg, insulin pump); metal fragments or foreign objects in the eyes, skin, or body; claustrophobia that would contraindicate a brain MRI scan
- •Brain MRI findings (or historical radiologic reports, if available) that show evidence of clinically significant structural brain disease which, in the opinion of the investigator, contraindicates performance of LP
- •Any spinal abnormality or other aspects (eg, tattoos) or other clinical findings (papilledema seen with ophthalmoscopy) that may complicate or contraindicate LP, as judged by the investigator
- •Ophthalmic abnormalities. The following are considered exclusionary:
- •Congenital or acquired ophthalmic conditions (primary or secondary) that are considered poorly controlled within the last 12 months prior to screening, with or without treatment, or otherwise expected to lead to significant deterioration in visual acuity in the next 6 months after randomization
- •Specific ophthalmic conditions:
- •i. Current or past history of inflammation affecting the uveal tract or sclera ii. Diabetic retinopathy iii. Neovascular or exudative (wet) form of age-related macular degeneration iv. Active central serous retinopathy (central serous chorioretinopathy) v. Subjects with active autoimmune disease vi. Subjects taking immunosuppressive drugs (other than low doses of systemic steroids [< 10 mg per day of prednisone equivalent], for autoimmune disease that is considered to be inactive, in remission, or otherwise well-controlled). Other immunosuppressive drugs are contraindicated.
- •vii. Mature cataracts (Grade ≥ 4 per the Lens Opacities Classification System III) or lower grade cataracts that are otherwise considered by the examining ophthalmologist to prevent adequate examination of the uveal tract or posterior ocular segment. (Note: Previous cataract surgery or an age-related cataract with age-appropriate lens opacification and no other important identified secondary causes [eg, diabetes, corticosteroids, vitamin deficiencies, trauma, radiation, or systemic fluid and electrolyte disturbances] is not necessarily exclusionary.)
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) concentrations >1.5 × the upper limit of normal (ULN) at screening, or between screening and baseline
- •Estimated creatinine clearance < 50 mL/min or creatinine > 1.5 × ULN at screening
- •Clinically significant vital sign abnormalities at screening or on Day 1, defined as (a) systolic blood pressure ≥ 160 mmHg, (b) diastolic blood pressure ≥ 90 mmHg (blood pressure assessed at rest; may be repeated up to 3 times), or (c) pulse rate < 45 or > 100 beats per minute (at rest)
- •Clinically significant abnormality in ECG rhythm, conduction or morphology at screening or between screening and randomization, including but not limited to:
- •Clinically significant PR (PQ) interval prolongation (PR > 220 msec)
- •Intermittent second or third degree atrioventricular (AV) block (AV block II Mobitz Type I, Wenckebach, while asleep or in deep rest is not exclusionary)
- •Bundle branch block or intraventricular conduction delay with QRS interval duration ≥ 120 msec
- •A Fridericia's corrected QT (QTcF) interval measurement > 470 msec, or a shortened QTcF < 340 msec, at screening or between screening and randomization; or a family history of long or short QT syndrome
- •Positive serologic findings for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen, or hepatitis C virus antibodies, with relevant confirmatory testing conducted, where applicable, in accordance with Centers for Disease Control and Prevention guidance for HIV and viral hepatitis
- •Current blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory tests of coagulation
- •Poor venous access, such that IV drug delivery or PK/safety blood sampling would be difficult
- •Donation of blood or plasma within 2 months prior to screening and until 2 months after the final follow-up visit
- •A positive serum pregnancy test result at screening or prior to randomization
- 另有 2 项未显示
研究组 & 干预措施
MEDI1341
Experimental
3 doses given at 4 week intervals
干预措施: MEDI1341 (Drug)
Placebo
Placebo Comparator
3 doses given at 4 week intervals
干预措施: Placebo (Other)
结局指标
主要结局
Suicidal Ideation
时间窗: 21 weeks
Evaluation of presence or absence of suicidal ideation as measured by the Columbia Suicide Severity Rating Scale (C-SSRS)
Adverse Events
时间窗: 28 weeks
Incidence, Nature, Severity and Seriousness of adverse events from screening
Ophthalmic assessments
时间窗: 21 weeks
Incidence from baseline in abnormal ocular findings
Vital Signs
时间窗: 21 weeks
Change from baseline in Blood Pressure measured in millimetres of Mercury
Body Weight
时间窗: 21 weeks
Change from baseline measured in Kilograms
Safety Laboratory Tests
时间窗: 21 weeks
Incidence from baseline in abnormal laboratory test results
Electrocardiograms
时间窗: 21 weeks
Change from baseline in ECG QTcF interval
Oral Body Temperature
时间窗: 21 weeks
Change from baseline in body temperature measured in degrees Celcius
Cognitive impairment
时间窗: 21 weeks
Change from baseline in the total score of the Montreal Cognitive assessment; a 30-point test (the higher the score, the better the cognition)
Suicidal Behaviour
时间窗: 21 weeks
Evaluation of presence or absence of suicidal behaviour as measured by the Columbia Suicide Severity Rating Scale (C-SSRS)
次要结局
未报告次要终点
研究者
研究点 (1)
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