A Study to Evaluate Efficacy and Safety of Intravenous Sabirnetug in Participants With Early Alzheimer's Disease (ALTITUDE-AD)

Phase 2Active Not RecruitingNCT06335173

Acumen Pharmaceuticals542 enrolled

Overview

The primary purpose of this study is to evaluate the efficacy of sabirnetug infusions administered once every four weeks (Q4W) in slowing cognitive and functional decline as compared to placebo in participants with early Alzheimer's disease.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

542

Conditions

Alzheimer Disease

Interventions

sabirnetugDRUG

Intravenous sabirnetug

PlaceboDRUG

Intravenous Placebo

Eligibility

Sex: ALLMin age: 50 YearsMax age: 90 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Body weight of at least 30 kilograms (kg) (66 pounds \[lbs\]) and no more than 160 kg (352 lbs) at Screening * Must consent to apolipoprotein E4 (APOE4) genotype status assessment * Must meet all of the following criteria 1. National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) or probable AD 2. Screening score between 22 and 30 (inclusive) on the Mini-Mental State Examination (MMSE) 3. Screening score of 0.5 or 1.0 on the Clinical Dementia Rating Global Score (CDR-GS) and Screening score ≥0.5 on the CDR Memory Box score 4. Evidence of cerebral amyloid accumulation by either PET scan or CSF * If using cholinesterase inhibitors or memantine to treat symptoms related to AD, doses must be stable for at least three months (12 weeks) prior to Baseline and every attempt should be made to keep them at stable doses throughout the study * Must have a reliable informant or study partner who is willing and able to perform all the roles as specified in the study partner Informed Consent Form (ICF) * Female participants must be surgically sterile or be at least one-year post-menopausal. Male participants with a female partner of child-bearing potential must use adequate contraception Exclusion Criteria: * Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI * MRI of the brain that is inconsistent with MCI or AD or results showing greater than four ARIA-H, presence of any ARIA-E, or superficial siderosis * History of significant or unstable neurological disease, other than AD, which may affect cognition or ability to complete the study, such as other dementias, serious infection of the brain, significant head trauma, uncontrolled seizures, stroke, or Parkinson´s disease * Current serious or unstable clinically important illness that, in the judgment of the site investigator, is likely to affect cognitive assessment including visual and hearing impairment or affect the participant's safety or ability to complete the study * Malignant disease in the last five years except for resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal posttreatment prostate-specific antibody (PSA) * Geriatric Depression Scale-Short Form (GDS-SF) score \>10 or current symptoms meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), criteria for major depressive disorder or any current primary psychiatric diagnosis other than AD if, in the judgment of the site 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 * Suicide risk, as determined by meeting any of the following criteria: 1. Any suicide attempt or preparatory acts/behavior on the C-SSRS Baseline/Screening in the last six months 2. Suicidal ideation in the last six months as defined by a positive response to Question 5 (Suicidal Ideation) on the C-SSRS Baseline/Screening 3. Significant risk of suicide, as judged by the site investigator * Conditions that may affect cognitive assessments during the study * Alcohol use disorder and/or substance use disorder within the last five years

Locations (68)

Outcomes

Primary Outcomes

Change from Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) Score

iADRS is a validated composite of cognition and function made up of Alzheimer's Disease Assessment Scale - Cognitive Subscale 13-item (ADAS-Cog13) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living scale (ADCS-iADL). ADAS-Cog13 is a rater-administered instrument consisting of 13 items assessing cognitive function areas most typically impaired in AD. ADAS-Cog13 scores range from 0 to 85, with higher scores indicating a greater deficit of global cognition. The ADCS-iADL is a subset of the 23-item ADCS-ADL (items 6a and 7 to 23). The iADLs are more complex skills required to successfully live independently. iADL-items score ranges from 0 to 59 (lower scores indicating greater impairment). The iADRS is calculated as a linear combination of total scores from the ADAS-Cog13 and ADCS-iADL. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance.

Time frame: Baseline up to Week 80

Secondary Outcomes

Change from Baseline in ADCS-iADL Score

The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire to be answered by a participant's study partner, where a participant's performance level is rated over the last 4 weeks, based on a set of performance descriptions. The ADCS-iADL is a subset of the 23-item ADCS-ADL (items 6a and 7 to 23). The iADLs are more complex skills required to successfully live independently, and include shopping, keeping appointments, traveling outside of the home, making a meal or snack, and reading and writing. The iADL-items score ranges from 0 to 59 with lower scores indicating greater impairment.

Time frame: Baseline up to Week 80

Change from Baseline in ADAS-Cog13 Score

ADAS-Cog is a rater-administered instrument, designed to assess the severity of dysfunction in cognition, characteristic of persons with AD. The ADAS-Cog13, the cognitive subscale of the ADAS, consists of 13 items assessing cognitive function areas most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, and digit cancellation. The scores range from 0 to 85, with higher scores indicating a greater deficit of global cognition.

Data from ClinicalTrials.gov

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The Neurology Center of Southern California - Carlsbad

Carlsbad, California, United States

Neurology Center of North Orange County

Fullerton, California, United States

Irvine Medical Research

Irvine, California, United States

Healthy Brain Research

Long Beach, California, United States

Syrentis Clinical Research

Santa Ana, California, United States

CenExel - California Neuroscience Research Medical Group, Inc (CNR)

Sherman Oaks, California, United States

Research Center for Clinical Studies, LLC

Norwalk, Connecticut, United States

Re:Cognition Health - Fairfax

Washington D.C., District of Columbia, United States

JEM Research Institute

Atlantis, Florida, United States

Bradenton Research Center

Bradenton, Florida, United States

...and 58 more locations

Time frame: Baseline up to Week 80

Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB)

The CDR is obtained through semi-structured interviews of individuals with AD and informants. The ratings are obtained in six domains: memory, orientation, judgment \& problem-solving, community affairs, home \& hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. CDR-SB score is obtained by summing each of the domain scores, with scores ranging from 0 to 18. Higher scores reflect greater cognitive and functional impairment.

Time frame: Baseline up to Week 80

Change from Baseline in Mini-Mental State Examination (MMSE)

MMSE is a standard staging and assessment tool in AD, designed for grading the cognitive state of individuals with AD. The scale comprises tasks concerning orientation, memory, attention, language, and praxis to evaluate an individual's cognitive state. MMSE total score ranges from 0 to 30, with lower scores indicative of greater cognitive impairment.

Time frame: Baseline up to Week 80

Change from Baseline in Quality of Life in Alzheimer's Disease (QoL-AD)

The QOL-AD tool is a 13-item assessment with each question scored on a 4-point scale where 1 = poor quality of life and 4 = excellent quality of life. Scores range from 13 to 52 with higher scores indicating better quality of life.

Time frame: Baseline up to Week 80

Change from Baseline in Neuropsychiatric Inventory Questionnaire (NPI-Q) Score

NPI-Q is a validated questionnaire completed by informants about participants for whom they care. Each of the 12 NPI-Q domains contains a survey question (answered in Yes/No) that reflects the cardinal symptoms of that domain. If the domain response is "Yes," the informant then rates the severity of the symptoms present within the last month on a 3-point scale and the distress of the symptom using a 5-point scale. The total NPI-Q severity score is the sum of the individual severity scores for each symptom and ranges from 0 to 36, with higher scores indicating more severe behavioral impairment. The total NPI-Q distress score is the sum of the individual distress scores for each symptom and ranges from 0 to 60, with higher scores indicating greater caregiver distress.

Time frame: Baseline up to Week 80

Change from Baseline in EuroQoL 5-Dimension 5-Level (EQ-5D-5L)

EQ-5D-5L is a self-report survey that measures quality of life. The EQ-5D-5L consists of an EQ-5D descriptive system and EQ visual analog scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels, each assigned a unique 1-digit number: no problems, slight problems, moderate problems, severe problems, and extreme problems. The digits are combined into a 5-digit number that describes the participant's health state. The EQ VAS records the participant's health on a vertical visual analog scale, where the endpoints are labeled 0= the best health you can imagine, and 100= the worst health you can imagine.

Time frame: Baseline up to Week 80

Change from Baseline in Resource Utilization in Dementia (RUD)

The RUD questionnaire is a standardized tool and the most widely used instrument for resource use data collection in dementia, enabling comparison of costs of care across countries with differing health care provisions. It is designed to collect data on formal and informal care resource use and to be useful in different care settings, across different countries and care systems, and in both clinical studies and observational cost-of-illness studies.

Time frame: Baseline up to Week 80

Change from Baseline in Zarit Burden Interview (ZBI)

ZBI consists of 22 items. Twenty-one of the items are designed to measure several aspects of burden, whereas Item 22 is a global measure of burden. Response options for each item range from 0-4, and total scores range from 0-88, with higher scores indicating greater self-reported burden.

Time frame: Baseline up to Week 80

Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by iADRS

Time frame: Baseline up to Week 80

Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by ADCS-iADL

Time frame: Baseline up to Week 80

Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by ADAS-Cog13

Time frame: Baseline up to Week 80

Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by CDR-SB

Time frame: Baseline up to Week 80

Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by MMSE

Time frame: Baseline up to Week 80

Percentage of Participants with No Clinical Progression at One Year

No clinical progression in participants will be defined as no decline in CDR-SB score. The CDR is obtained through semi-structured interviews of individuals with AD and informants. The ratings are obtained in six domains: memory, orientation, judgment \& problem-solving, community affairs, home \& hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. CDR-SB score is obtained by summing each of the domain scores, with scores ranging from 0 to 18. Higher scores reflect greater cognitive and functional impairment.

Time frame: Baseline up to Week 80

Number of Participants with Treatment-Related Adverse Events (TEAEs)

Time frame: Baseline up to Week 80

Number of Participants with Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)

Time frame: Baseline up to Week 80

Number of Participants who Discontinue or Withdraw due to TEAE

Time frame: Baseline up to Week 80

Number of Participants with Anti-Drug Antibodies (ADA) and Neutralizing Antibodies

Time frame: Baseline up to Week 80

Number of Participants with Amyloid-Related Imaging Abnormality with Edema/Effusions (ARIA-E) and ARIA with Hemorrhage/Hemosiderin Deposition (ARIA-H) as Measured by Magnetic Resonance Imaging (MRI)

Time frame: Baseline up to Week 80

Number of Participants with Suicidal Ideation and Behavior as Measured by Columbia-Suicide Severity Rating Scale (C-SSRS)

The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). Greater lethality or potential lethality of suicidal behaviors (endorsed on the behavior subscale) indicates increased risk.

Time frame: Baseline up to Week 80

Serum Concentration of sabirnetug

Time frame: Pre-dose and multiple timepoints post dose up to 80 weeks

Concentration of sabirnetug in Cerebrospinal Fluid (CSF)

Time frame: Up to Week 76

CSF Concentrations of ACU193 in a Subset of Participants

Time frame: Up to Week 76

Correlation Between sabirnetug Exposure with Clinical Efficacy Measures

Correlation between sabirnetug exposure and clinical outcomes (including iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE) will be assessed in this study.

Time frame: Baseline up to 80 weeks

Change From Baseline in Amyloid Plaque Load or Deposition Measured by Positron Emission Tomography (PET) in Centiloids

Time frame: Baseline up to Week 76

Change from Baseline in Volumetric Magnetic Resonance Imaging (vMRI) of Whole Brain Volume, Ventricular Volume, and Volume of Selected Regions of Interest

Time frame: Baseline up to Week 76

Target Engagement Assessed by Measurement of sabirnetug- Amyloid-β oligomer (AβO) Complex in CSF

Time frame: Up to Week 76

Change from Baseline in CSF Concentrations of Amyloid, Tau and Other Neurodegenerative Biomarkers

Time frame: Baseline up to Week 76

Change from Baseline in CSF Concentrations of Amyloid, Tau, and Other Neurodegenerative Biomarkers in a Subset of Participants

Time frame: Baseline up to Week 76

Change from Baseline in Blood Concentrations of Amyloid, Tau, and Other Neurodegenerative Biomarkers

Time frame: Baseline up to Week 76

Correlation Between Change in Biomarker that Reflect Disease Progression and Clinical Changes

Assessment of the correlation between change in clinical outcomes (iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE) and change in biomarker (amyloid PET) will be determined by computing Pearson's correlation coefficient for each treatment group.

Time frame: Up to 80 weeks