Clinical trial NCT04931459: A Study to Evaluate the Safety, Tolerability, and Blood Levels of ACU193 in Participants With MCI or Mild AD
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer Disease
Keywords: Alzheimer's Diseases
Mild Cognitive Impairment
Mild dementia
Lead sponsor: Acumen Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: National Institute on Aging (NIA)
First posted: 2021-06-18
Enrollment: 65
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: Inclusion Criteria:

1. Males or females ages 55 to 90 (inclusive).
2. Participant weighs at least 41 kg (90 lbs) and no more than 113 kg (250 lbs) before study drug administration.
3. 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.
4. Individual (or the participant's Legally Authorized Representative \[LAR\]) is able to give informed consent.
5. Are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
6. Must meet all of the following clinical criteria for MCI due to AD or mild AD at Screening:

   1. Participant meets NIA-Alzheimer's Association (NIA-AA) criteria for MCI due to AD or probable AD.
   2. A global Clinical Dementia Rating (CDR) of 0.5 or 1.0.
   3. A Mini-Mental State Examination (MMSE) score between 18 and 30 (inclusive).
   4. A positive amyloid positron emission tomography (PET) scan.
7. Must consent to apolipoprotein E (APOE) genotyping.
8. 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.
9. 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:

1. 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.
2. Currently receiving or likely to require the following types of anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, thrombin inhibitors.
3. Has known humanized monoclonal antibody allergy or hypersensitivity.
4. 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.
5. 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.
6. 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.
7. Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI.
8. 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.
9. Has an ongoing or new clinically significant laboratory abnormality, as determined by the Investigator.
10. 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.
11. 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.
12. History of seizure, transient ischemic attack (TIA), or stroke within the last 18 months.
13. History of clinically significant carotid or vertebrobasilar stenosis or plaque.
14. 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.
15. 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.
16. Are a suicide risk, as determined by meeting any of the following criteria:

    1. Suicide attempt within the six months prior to Baseline.
    2. Suicidal ideation as defined by a positive response to Question 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation section.
    3. Significant risk of suicide, as judged by the site Investigator.
17. History of multiple concussions, significant head trauma, or objective change in neuropsychological function within the last five years.
18. History of human immunodeficiency virus (HIV).
19. History of alcohol or drug abuse/dependence within the last five years.

Primary outcomes:
measure: Incidence and Nature of Treatment-Related Adverse Events (AE) or Serious Adverse Events (SAE) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE)
timeFrame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD)
measure: Change in Clinical Laboratory Tests
timeFrame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD)
measure: Changes in 12-Lead ECGs
timeFrame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD)
measure: Changes in the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD)
measure: Changes in Magnetic Resonance Imaging (MRI)
timeFrame: Baseline (predose) up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD)
Secondary outcomes:
measure: Estimate Blood Levels of ACU193
timeFrame: Up to 140 days post dose
measure: Estimate Maximum Blood Levels of ACU193
timeFrame: Up to 140 days post dose.
measure: Estimate Time to Reach Maximum Blood Levels of ACU193
timeFrame: Up to 140 days post dose.
measure: Estimate Blood Levels of ACU193
timeFrame: Up to 140 days post dose.
measure: Estimate Clearance of ACU193
timeFrame: Up to 140 days post dose
measure: Estimate Volume of Distribution of ACU193
timeFrame: Up to 140 days post dose
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Clinical Endpoints
state: Arizona
city: Anaheim
country: United States
facility: Orange County Research Institute
state: California
city: Newport Beach
country: United States
facility: Hoag Hospital Newport Beach
state: California
city: Hallandale Beach
country: United States
facility: Velocity Clinical Research
state: Florida
city: Lady Lake
country: United States
facility: Charter Research
state: Florida
city: Miami
country: United States
facility: Columbus Clinical Services
state: Florida
city: Orlando
country: United States
facility: Combined Research Orlando Phase I-IV
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Tampa
country: United States
facility: Santos Research Center
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Decatur
country: United States
facility: iResearch Atlanta
state: Georgia
city: Toms River
country: United States
facility: Advanced Memory Research Institute of NJ
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: Matthews
country: United States
facility: AMC Research
state: North Carolina
city: Abington
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Dallas
country: United States
facility: Kerwin Medical Center
state: Texas
city: Houston
country: United States
facility: Clinical Trials Network
state: Texas
Study officials:
affiliation: Acumen Pharmaceuticals, Inc.
name: Eric Siemers, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Acumen Pharmaceuticals, Inc.
name: Russell Barton
role: STUDY_DIRECTOR
References: