A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of MEDI1341 in Healthy Male and Female Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
This is a study of single ascending intravenous doses of MEDI1341 or placebo in up to 48 healthy volunteers, aged 18 to 65 years. The study will include up to 6 planned cohorts; each cohort will comprise 8 participants.
Each participant will receive a single 60 minute intravenous infusion of MEDI1341 or placebo and will undergo scheduled assessments over a period of 13 weeks.
The main aim of the study is to assess the safety and tolerability of single doses of MEDI1341 in healthy volunteers.
详细描述
This is a randomized, double-blind, placebo-controlled study of single ascending intravenous doses of MEDI1341 in male and nonfertile female healthy volunteers, aged 18 to 65 years.
The study will include up to 6 planned cohorts; each cohort will comprise 8 participants. Within each cohort, 6 participants will be randomized to receive MEDI1341 and 2 will be randomized to receive placebo. A Safety Review Committee will review data from each cohort before progression to the next higher dose cohort occurs. On Day 1, each randomized participant will receive a single 60 minute intravenous infusion of MEDI1341 or placebo and will undergo scheduled safety, pharmacokinetic, pharmacodynamic, and immunogenicity assessments. Additional study assessments will occur on Days 2, 4, 8, 15, 22, 29, 43, 57, and 92.
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
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants must be healthy, with no clinically significant abnormality identified on the medical or laboratory evaluation at screening
- •Participants must weigh ≥50 kg and must have a body mass index between 18 and 32 kg/m^2, inclusive
- •Participants must have a 12-lead electrocardiogram recorded at screening that is normal for the appropriate age group and shows no abnormalities that will compromise safety in this study
- •Participants must have no clinically significant findings on the clinical neurological examinations at screening and at baseline or on the ophthalmic examination at screening.
排除标准
- •Nicotine use within 6 months before screening
- •Considered to be at a high risk of developing a stroke
- •Significant medical history of dizziness, blackouts, fainting, or vaso-vagal attacks
- •History of any significant ophthalmic disorder, including congenital, genetic or acquired conditions affecting the retina or choroid
- •History of severe allergy or history of hypersensitivity to immunizations or immunoglobulins
- •History of any significant psychiatric disorder
- •History of alcohol abuse
- •History of cancer within 5 years of screening
- •History of drug abuse
- •Any contraindication to Lumbar Puncture
- •Any clinically significant abnormality in ECG rhythm, conduction or morphology
- •Positive serologic findings at screening for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen, or hepatitis C virus antibodies
- •Use of prescription or non-prescription drugs
- •For female participants, a positive serum or urine pregnancy test result at screening
研究组 & 干预措施
Placebo
Participants will receive a single intravenous (IV) infusion of placebo matched to MEDI1341 and will be followed up for 13 weeks.
干预措施: Placebo (Drug)
Cohort 1: MEDI1341 Dose 1
Participants will receive a single IV infusion of MEDI1341 Dose 1 and will be followed up for 13 weeks.
干预措施: MEDI1341 (Drug)
Cohort 2: MEDI1341 Dose 2
Participants will receive a single IV infusion of MEDI1341 Dose 2 and will be followed up for 13 weeks.
干预措施: MEDI1341 (Drug)
Cohort 3: MEDI1341 Dose 3
Participants will receive a single IV infusion of MEDI1341 Dose 3 and will be followed up for 13 weeks.
干预措施: MEDI1341 (Drug)
Cohort 4: MEDI1341 Dose 4
Participants will receive a single IV infusion of MEDI1341 Dose 4 and will be followed up for 13 weeks.
干预措施: MEDI1341 (Drug)
Cohort 5: MEDI1341 Dose 5
Participants will receive a single IV infusion of MEDI1341 Dose 5 and will be followed up for 13 weeks.
干预措施: MEDI1341 (Drug)
Cohort 6: MEDI1341 Dose 6
Participants will receive a single IV infusion of MEDI1341 Dose 6 and will be followed up for 13 weeks.
干预措施: MEDI1341 (Drug)
结局指标
主要结局
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
时间窗: Day 1 through 92 days after a single dose of study drug
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Intraocular Pressure at Screening for Placebo and Cohorts 4 to 6
时间窗: Screening (Day -49)
Intraocular pressure at Screening (Day -49) is reported.
Number of Participants With Abnormal Vital Signs, Physical and Neurological Examinations, and Body Weight Measurements Reported as TEAEs
时间窗: Day 1 through 92 days after a single dose of study drug
Vital signs assessment included body temperature, respiration rate, pulse rate, and blood pressure. Participants with abnormal vital signs, physical and neurological examinations, and body weight measurements reported as TEAEs are reported.
Change from Baseline in 12-Lead Electrocardiogram (ECG) Data in Paper and Digital Recordings (PR Interval, QRS Duration, QT Interval, QTcF Interval, and RR Interval)
时间窗: 12-lead paper ECG: Baseline (Day -49) to Day 92; Digital ECG: Baseline (Day 1) to Day 92
Changes from baseline in 12-Lead ECG data in paper recordings (PR interval, QRS duration, QT interval, and QTcF interval) and digital recordings (PR interval, QRS duration, QT interval, QTcF interval, and RR interval) are reported.
Change from Baseline in Heart Rate by 12-Lead ECG in Paper and Digital Recordings
时间窗: 12-lead paper ECG: Baseline (Day -49) to Day 92; Digital ECG: Baseline (Day 1) to Day 92
Change from baseline in heart rate by 12-Lead ECG in paper and digital recordings are reported.
Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs
时间窗: Day 1 through 92 days after a single dose of study drug
Laboratory assessment included hematology, clinical chemistry, and urinalysis. Participants with abnormal laboratory parameters reported as TEAEs are reported.
Number of Abnormal Findings for Ophthalmic Assessment (Ophthalmic Examination and Slit-lamp Examination) for Placebo and Cohorts 4 to 6 at Follow-up Visit
时间窗: Follow-up Visit (Day 57)
Number of abnormal findings for ophthalmic assessment (ophthalmic examination and slit-lamp examination) at follow-up visit (Day 57) are reported.
Intraocular Pressure at Day 92 for Placebo and Cohorts 4 to 6
时间窗: Day 92
Intraocular pressure at Day 92 is reported.
Intraocular Pressure at Day 29 for Placebo and Cohorts 4 to 6
时间窗: Day 29
Intraocular pressure at Day 29 is reported.
Number of Participants With Injection Site Reactions
时间窗: Day 1
Participants who had injection site reactions (bleeding, bruising, erythema, swelling, or induration) on Day 1 are reported.
Visual Analogue Scale (VAS) Pain Score for Site Reaction Pain
时间窗: Day 1 (within 24 hours after end of infusion)
The VAS (0 to 10 cm) was used to describe reaction site pain. The score 0 means 'no pain at all' and 10 score means 'worst pain imaginable'. The higher the VAS score, the greater the reaction site pain experienced.
Number of Participants With Suicidal Ideation and Suicidal Behavior Assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
时间窗: Screening (Day -49) through 92 days after a single dose of study drug
The C-SSRS is a scale capturing occurrence, severity, and frequency of suicide-related thoughts and behaviours, and has a binary response (yes/no). * Suicidal Ideation: a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intent to act, active suicidal ideation with some intent to act without specific plan, active suicidal ideation with specific plan and intent. * Suicidal Behaviour: a "yes" answer to any of 5 suicidal behaviour questions: preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt (non-fatal), completed suicide.
Number of Participants With Montreal Cognitive Assessment (MoCA) Total Score at Screening (Day -1)
时间窗: Screening (Day -1)
The MoCA is s standardized cognitive screening tool for mild cognitive impairment and dementia. The total score was used as outcome measure and this score ranges from 0-31, with higher scores representing better cognitive ability and scores below 26 were considered as cognitive dysfunction.
Number of Participants With MoCA Total Score at Day 92
时间窗: Day 92
The MoCA is s standardized cognitive screening tool for mild cognitive impairment and dementia. The total score was used as outcome measure and this score ranges from 0-31, with higher scores representing better cognitive ability and scores below 26 were considered as cognitive dysfunction.
次要结局
- Maximum Observed Serum Concentration (Cmax) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Time to Maximum Serum Concentration (tmax) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Area Under the Serum Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC0-t) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Terminal Half-life (t1/2λz) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Serum Clearance (CL) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Volume of Distribution at Steady State (Vss) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Mean Residence Time (MRT) of MEDI1341(Day 1 (predose; 0 minute and 8 and 24 hours at the end of infusion), and Days 4, 8, 15, 22, 29, 43, 57, and 92)
- Percentage Change From Baseline in Plasma Concentrations of Total α-synuclein(Baseline (Day 1 predose) through Day 92)
- Percentage Change From Baseline in Cerebrospinal Fluid Concentrations of Free α-synuclein(Baseline (Day 1 predose) and Day 29)
- Percentage of Participants With Positive Antidrug Antibodies (ADAs) to MEDI1341 by Titer Levels at Day 92(Day 92)