Single Ascending Dose Study of MEDI1341 in Healthy Volunteers

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: MEDI1341
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Participants are randomized to one of two groups within a cohort of 8 participants (N=6 MEDI1341; N=2 placebo)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive a single intravenous (IV) infusion of placebo matched to MEDI1341 and will be followed up for 13 weeks. | Drug: Placebo<br>* Participants will receive IV infusion of placebo matched to MEDI1341.<br>|
| Experimental: Cohort 1: MEDI1341 Dose 1<br>Participants will receive a single IV infusion of MEDI1341 Dose 1 and will be followed up for 13 weeks. | Drug: MEDI1341<br>* Participants will receive IV infusion of MEDI1341 doses as stated in the arms' description.<br>* Other names: TAK-341;|
| Experimental: Cohort 2: MEDI1341 Dose 2<br>Participants will receive a single IV infusion of MEDI1341 Dose 2 and will be followed up for 13 weeks. | Drug: MEDI1341<br>* Participants will receive IV infusion of MEDI1341 doses as stated in the arms' description.<br>* Other names: TAK-341;|
| Experimental: Cohort 3: MEDI1341 Dose 3<br>Participants will receive a single IV infusion of MEDI1341 Dose 3 and will be followed up for 13 weeks. | Drug: MEDI1341<br>* Participants will receive IV infusion of MEDI1341 doses as stated in the arms' description.<br>* Other names: TAK-341;|
| Experimental: Cohort 4: MEDI1341 Dose 4<br>Participants will receive a single IV infusion of MEDI1341 Dose 4 and will be followed up for 13 weeks. | Drug: MEDI1341<br>* Participants will receive IV infusion of MEDI1341 doses as stated in the arms' description.<br>* Other names: TAK-341;|
| Experimental: Cohort 5: MEDI1341 Dose 5<br>Participants will receive a single IV infusion of MEDI1341 Dose 5 and will be followed up for 13 weeks. | Drug: MEDI1341<br>* Participants will receive IV infusion of MEDI1341 doses as stated in the arms' description.<br>* Other names: TAK-341;|
| Experimental: Cohort 6: MEDI1341 Dose 6<br>Participants will receive a single IV infusion of MEDI1341 Dose 6 and will be followed up for 13 weeks. | Drug: MEDI1341<br>* Participants will receive IV infusion of MEDI1341 doses as stated in the arms' description.<br>* Other names: TAK-341;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | 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. | Day 1 through 92 days after a single dose of study drug | 
| Number of Participants With Abnormal Vital Signs, Physical and Neurological Examinations, and Body Weight Measurements Reported as TEAEs | 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. | Day 1 through 92 days after a single dose of study drug | 
| 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) | 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. | 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 | Change from baseline in heart rate by 12-Lead ECG in paper and digital recordings are reported. | 12-lead paper ECG: Baseline (Day -49) to Day 92; Digital ECG: Baseline (Day 1) to Day 92 | 
| Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs | Laboratory assessment included hematology, clinical chemistry, and urinalysis. Participants with abnormal laboratory parameters reported as TEAEs are reported. | Day 1 through 92 days after a single dose of study drug | 
| Number of Abnormal Findings for Ophthalmic Assessment (Ophthalmic Examination and Slit-lamp Examination) for Placebo and Cohorts 4 to 6 at Follow-up Visit | Number of abnormal findings for ophthalmic assessment (ophthalmic examination and slit-lamp examination) at follow-up visit (Day 57) are reported. | Follow-up Visit (Day 57) | 
| Intraocular Pressure at Screening for Placebo and Cohorts 4 to 6 | Intraocular pressure at Screening (Day -49) is reported. | Screening (Day -49) | 
| Intraocular Pressure at Day 29 for Placebo and Cohorts 4 to 6 | Intraocular pressure at Day 29 is reported. | Day 29 | 
| Intraocular Pressure at Day 92 for Placebo and Cohorts 4 to 6 | Intraocular pressure at Day 92 is reported. | Day 92 | 
| Number of Participants With Injection Site Reactions | Participants who had injection site reactions (bleeding, bruising, erythema, swelling, or induration) on Day 1 are reported. | Day 1 | 
| Visual Analogue Scale (VAS) Pain Score for Site Reaction Pain | 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. | Day 1 (within 24 hours after end of infusion) | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior Assessed by Columbia Suicide Severity Rating Scale (C-SSRS) | 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. | Screening (Day -49) through 92 days after a single dose of study drug | 
| Number of Participants With Montreal Cognitive Assessment (MoCA) Total Score at 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. | Screening (Day -1) | 
| Number of Participants With MoCA Total Score at 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. | Day 92 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of MEDI1341 | The Cmax of MEDI1341 is reported. | 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 | The tmax of MEDI1341 is reported. | 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 | The AUC0-t of MEDI1341 is reported. | 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 | The AUC0-∞ of MEDI1341 is reported. | 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 | The t1/2λz of MEDI1341 is reported. | 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 | The CL of MEDI1341 is reported. | 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 | The Vss of MEDI1341 is reported. | 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 | The MRT of MEDI1341 is reported. | 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 | Maximum change from baseline through Day 92 and change from baseline at Day 92 in plasma concentrations of total α-synuclein are reported. | Baseline (Day 1 predose) through Day 92 | 
| Percentage Change From Baseline in Cerebrospinal Fluid Concentrations of Free α-synuclein | Change from baseline in cerebrospinal fluid concentrations of free α-synuclein is reported. | Baseline (Day 1 predose) and Day 29 | 
| Percentage of Participants With Positive Antidrug Antibodies (ADAs) to MEDI1341 by Titer Levels at Day 92 | Percentage of participants with positive ADAs to MEDI1341 by titer levels are reported. | Day 92 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Healthy Volunteers, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity