A Study to Evaluate the Safety, Tolerability, and Blood Levels of ACU193 in Participants With MCI or Mild AD

Study Overview
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Brief Summary
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This Phase 1 study is a single ascending dose (SAD) and multiple ascending dose (MAD), placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous ACU193 when administered to participants diagnosed with Mild Cognitive Impairment (MCI) or Mild Dementia due to Alzheimer's disease (AD).

Official Title
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A Phase 1 Placebo-Controlled, Single- and Multiple-Dose Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous ACU193 in Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: ACU193
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ages 55 to 90 (inclusive). Participant weighs at least 41 kg (90 lbs) and no more than 113 kg (250 lbs) before study drug administration. Female participants must be surgically sterile or be at least two years post-menopausal or at least one year post-menopausal with an elevated follicle stimulating hormone (FSH). Male participants with a female partner of child-bearing potential must use adequate contraception. Individual (or the participant's Legally Authorized Representative [LAR]) is able to give informed consent. Are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Must meet all of the following clinical criteria for MCI due to AD or mild AD at Screening: Participant meets NIA-Alzheimer's Association (NIA-AA) criteria for MCI due to AD or probable AD. A global Clinical Dementia Rating (CDR) of 0.5 or 1.0. A Mini-Mental State Examination (MMSE) score between 18 and 30 (inclusive). A positive amyloid positron emission tomography (PET) scan. Must consent to apolipoprotein E (APOE) genotyping. If using cholinesterase inhibitors or memantine to treat symptoms related to AD, doses must be stable for at least four weeks prior to Baseline and the participant must be willing to keep the doses stable throughout the duration of the study. Must have a reliable informant or caregiver who is willing and able to perform all caregiver roles as specified in the caregiver Informed Consent Form (ICF). Exclusion Criteria: Receipt of any investigational biological drug within less than one year of Baseline or of any investigational small molecule drug within less than six months of Baseline. Receipt of any approved treatments that target amyloid plaques in the brain within less than one year of Baseline. Currently receiving or likely to require the following types of anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, thrombin inhibitors. Has known humanized monoclonal antibody allergy or hypersensitivity. History of significant neurological disease, other than AD, that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson´s disease, or adult epilepsy. Has had magnetic resonance imaging (MRI) or computerized tomography (CT) of brain within previous two years showing pathology that would be inconsistent with a diagnosis of AD. Has MRI with results showing greater than four amyloid-related imaging abnormalities hemorrhage/hemosiderin deposition (ARIA-H), presence of any amyloid-related imaging abnormalities edema/effusions (ARIA-E), or superficial siderosis. Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI. Current serious or unstable clinically important illness that, in the judgment of the Investigator, is likely to affect cognitive assessment including visual and hearing impairment, deteriorate, or affect the participant's safety or ability to complete the study, including psychiatric, hepatic, renal, gastroenterological, respiratory, cardiovascular, endocrinological, immunologic, or hematologic disorders. Has an ongoing or new clinically significant laboratory abnormality, as determined by the Investigator. Has a history or presence of clinically significant abnormal 12-lead electrocardiogram (ECG) or an ECG with QT interval corrected using Fridericia's formula (QTcF) >470 msec for female participants or >450 msec for male participants. As the ECGs are obtained in triplicate and are meant to be interpreted together, if one of the three ECGs in the triplicate has a QTcF above the threshold, eligibility of the participant should be determined based on clinical judgment of the Investigator in consultation with the medical monitor. If two of the three ECGs in the triplicate have a QTcF above the threshold, then the participant would not be eligible. Within one year before Screening, any of the following: myocardial infarction; moderate or severe congestive heart failure, New York Heart Association class III or IV; hospitalization for, or symptom of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy), or hospitalization for arrhythmia. History of seizure, transient ischemic attack (TIA), or stroke within the last 18 months. History of clinically significant carotid or vertebrobasilar stenosis or plaque. History of a malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment within the last five years. Current symptoms meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for major depressive disorder or any current primary psychiatric diagnosis other than AD if, in the judgment of the Investigator, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessments, or affect the participant´s ability to complete the study. Are a suicide risk, as determined by meeting any of the following criteria: Suicide attempt within the six months prior to Baseline. Suicidal ideation as defined by a positive response to Question 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation section. Significant risk of suicide, as judged by the site Investigator. History of multiple concussions, significant head trauma, or objective change in neuropsychological function within the last five years. History of human immunodeficiency virus (HIV). History of alcohol or drug abuse/dependence within the last five years.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study ACU-001 is a placebo-controlled study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple escalating doses of intravenous ACU193. A two-part single-ascending dose (SAD)/multiple-ascending dose (MAD) study design will be conducted in a population of individuals with early AD (MCI or mild dementia due to AD).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACU193 Administration<br>Participants will receive 1 to 3 doses of ACU193 by intravenous (IV) infusion. | Drug: ACU193<br>* Intravenous ACU193<br>|
| Placebo Comparator: Placebo Administration<br>Participants receive 1 to 3 doses of matching ACU193 placebo by intravenous (IV) infusion. 2 participants per cohort will receive placebo. | Drug: Placebo<br>* Intravenous Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Nature of Treatment-Related Adverse Events (AE) or Serious Adverse Events (SAE) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) | Proportion of participants with AE, discontinuations due to AE or SAE, and withdrawals from the study due to AE | Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) | 
| Change in Clinical Laboratory Tests | Incidence and clinically significant abnormal changes in clinical laboratory assessments (hematology, clinical chemistry, urinalysis) | Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) | 
| Changes in 12-Lead ECGs | Clinically significant abnormal changes in 12-Lead ECGs for PR, QRS, QT, QTcF, and QTcB | Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) | 
| Changes in the Columbia-Suicide Severity Rating Scale (C-SSRS) | Presence of suicidal ideation as defined by a positive response to Question 5 on the C-SSRS suicide ideation section | Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) | 
| Changes in Magnetic Resonance Imaging (MRI) | Brain magnetic resonance imaging (MRI) findings to assess amyloid-related imaging abnormalities (ARIA), including incidence of ARIA-E (edema) or ARIA-H (hemosiderosis) | Baseline (predose) up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate Blood Levels of ACU193 | Area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUCt) | Up to 140 days post dose | 
| Estimate Maximum Blood Levels of ACU193 | Maximum observed blood concentration Cmax(obs). | Up to 140 days post dose. | 
| Estimate Time to Reach Maximum Blood Levels of ACU193 | Time to reach Tmax(obs) | Up to 140 days post dose. | 
| Estimate Blood Levels of ACU193 | Area under the plasma concentration-time curve from time 0 to infinity (AUC∞) | Up to 140 days post dose. | 
| Estimate Clearance of ACU193 | Clearance (CL) | Up to 140 days post dose | 
| Estimate Volume of Distribution of ACU193 | Apparent volume of distribution at terminal phase (Vz) | Up to 140 days post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Diseases, Mild Cognitive Impairment, Mild dementia