A Study to Evaluate Efficacy and Safety of Intravenous ACU193 in Participants With Early Alzheimer's Disease (ALTITUDE-AD)

Alzheimer Disease Clinical Trial

— ALTITUDE-AD  

Official title:

A Phase 2/3 Double-Blind, Randomized, Placebo-Controlled Adaptive Design Trial to Evaluate the Efficacy and Safety of Intravenous ACU193 in Early Alzheimer's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06335173
• Other study ID #: ACU193-201
• Secondary ID: 2023-509807-34-0
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 29, 2024
• Est. completion date: January 2031

Study information

• Verified date: April 2024
• Source: Acumen Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary purpose of this study is to evaluate the efficacy of ACU193 infusions administered once every four weeks (Q4W) in slowing cognitive and functional decline as compared to placebo in participants with early Alzheimer's disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2040
• Est. completion date: January 2031
• Est. primary completion date: January 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 90 Years

Eligibility

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 and baseline 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

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• ACU193
Intravenous ACU193
• Placebo
Intravenous Placebo

Locations

Country	Name	City	State
Canada	MoCA Research and Innovations	Greenfield Park	Quebec
Canada	Okanagan Clinical Trials	Kelowna	British Columbia
Canada	Parkwood Institute	London	Ontario
Canada	Hippocampe d/b/a Ottawa Memory Clinic	Ottawa	Ontario
Canada	The Kawartha Regional Memory Clinic (KRMC)	Peterborough	Ontario
Canada	Baycrest - The Rotman Research Institute (RRI)	Toronto	Ontario
Canada	Toronto Memory Program (TMP) (Neurology Research Inc.)	Toronto	Ontario
Canada	University Health Network (UHN) - Toronto Western Hospital (TWH) - Krembil Neuroscience Centre (KNC) - Memory Clinic	Toronto	Ontario
Canada	Office of Alexandre Henri-Bhargava, MD	Victoria	British Columbia
France	Amiens university hospital	Amiens
France	Chu Pellegrin	Bordeaux
France	Hopital Neurologique Pierre Wertheimer	Bron
France	Hôpital de la Timone	Marseille Cedex 05
France	Chu Montpellier	Montpellier
France	Hopital Lariboisiere	Paris
France	Institut de la Mémoire et de la Maladie d'Alzheimer -IM2A	Paris
France	CHU de Rennes, CMRR	Rennes
France	CHU de NANTES-Hôpital Nord Laennec	Saint-Herblain
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
France	Centre de Recherche du Gérontopôle - CHU de Toulouse Hôpital la Grave	Toulouse
Germany	Charité - Universitaetsmedizin Berlin	Berlin
Germany	Pharmakologisches Studienzentrum Chemnitz GmbH	Chemnitz
Germany	University Hospital of Cologne	Cologne
Germany	Saarland University Hospital	Homburg
Germany	Zentralinstitut für seelische Gesundheit	Mannheim
Germany	Technical University of Munich, School of Medicine and Health, Klinikum rechts der Isar	Munich
Germany	Rostock University Medical Center	Rostock
Germany	Praxisgemeinschaft Dr. Springub/Schwarz	Westerstede
Italy	Fondazione Istituto G. Giglio di Cefalù	Cefalù
Italy	Policlinico San Martino	Genova
Italy	Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico	Milano
Italy	Fondazione IRCCS San Gerardo dei Tintori	Monza
Italy	Neurology Clinic	Perugia
Italy	IRCCS Neuromed	Pozzilli
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Italy	Sapienza Università di Roma - AOU Policlinico Umberto I	Roma
Italy	SSD Alzheimer's disease and related dementias	Torino
Italy	A.O. Piafondazione Card. G. Panico	Tricase
Poland	Centrum Medyczne Neuromed	Bydgoszcz
Poland	Krakowska Akademia Neurologii Sp. z o.o.	Krakow
Poland	RCMed	Sochaczew
Poland	Centrum Medyczne Senior	Sopot
Poland	Centrum Medyczne NeuroProtect	Warsaw
Spain	Fundacio ACE	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Fundacion Neuropolis - Hospital Viamed Montecanal	Cuarte de Huerva	Zaragoza
Spain	Cae Oroitu	Getxo
Spain	Hospital Ruber	Madrid
Spain	Policlínica Gipuzkoa	San Sebastian
Spain	Fundacion CITA alzheimer	San Sebastián	Gipuzkoa
Spain	Hospital Universitari General de catalunya	Sant Cugat Del Vallès	Barcelona
Spain	Hospital Victoria Eugenia	Sevilla
Spain	Hospital Universitari i Politècnic La Fe	Valencia
United Kingdom	Re:Cognition Health - Birmingham	Birmingham	West Midlands
United Kingdom	Re:Cognition Health - Bristol	Bristol
United Kingdom	Panthera Biopartners - Enfield	Enfield Town	Greater London
United Kingdom	Re:Cognition Health - Guildford	Guildford	Surrey
United Kingdom	Re:Cognition Health - London	London	Greater London
United Kingdom	St. Pancras Clinical Research Ltd.	London	Greater London
United Kingdom	Neuroclin Glasgow	Motherwell	Lanarkshire
United Kingdom	Re:Cognition Health - Plymouth	Plymouth	Devon
United Kingdom	Panthera Bio-Partners - Preston	Preston	Lancashire
United Kingdom	Panthera Bio-Partners - Rochdale	Rochdale	Greater Manchester
United Kingdom	Panthera Biopartners - Sheffield	Sheffield	Yorkshire
United Kingdom	Re:Cognition Health - Winchester	Winchester	Hampshire
United States	Abington Neurological Associates	Abington	Pennsylvania
United States	Neurological Associates of Albany	Albany	New York
United States	IMA Clinical Research - Albuquerque	Albuquerque	New Mexico
United States	JEM Research Institute	Atlantis	Florida
United States	Senior Adult Specialty Research	Austin	Texas
United States	Gadolin Research, LLC	Beaumont	Texas
United States	Alpine Clinical Research Center	Boulder	Colorado
United States	Bradenton Research Center	Bradenton	Florida
United States	The Neurology Center of Southern California - Carlsbad	Carlsbad	California
United States	Columbus Memory Center	Columbus	Georgia
United States	Gil Fernandez-Yera, MD, PA	Coral Gables	Florida
United States	Neurology Clinic. P.C	Cordova	Tennessee
United States	Kerwin Medical Center	Dallas	Texas
United States	Accel Research- Neurostudies	Decatur	Georgia
United States	CenExel - iResearch Atlanta	Decatur	Georgia
United States	Brain Matters Research	Delray Beach	Florida
United States	The Mile High Research Center	Denver	Colorado
United States	Rhode Island Mood and Memory	East Providence	Rhode Island
United States	Neurology Center of North Orange County	Fullerton	California
United States	Hattiesburg Clinic - Memory Center	Hattiesburg	Mississippi
United States	Coral Clinical Research	Homestead	Florida
United States	Irvine Medical Research	Irvine	California
United States	The Alliance for Multispecialty Research LLC (AMR)	Knoxville	Tennessee
United States	K2 Medical Research - Villages	Lady Lake	Florida
United States	Cleveland Clinic - Lou Ruvo Center for Brain Health (CCLRCBH)	Lakewood	Ohio
United States	Las Vegas Medical Research Center	Las Vegas	Nevada
United States	Healthy Brain Research	Long Beach	California
United States	AMC Research	Matthews	North Carolina
United States	Finlay Medical Research	Miami	Florida
United States	Verus Clinical Research	Miami	Florida
United States	Collier Neurologic Specialists (CNS), L.L.C.	Naples	Florida
United States	Yale School of Medicine - Alzheimer's Disease Research Unit (ADRU)	New Haven	Connecticut
United States	Neurological Institute of New York	New York	New York
United States	Boston Center for Memory	Newton	Massachusetts
United States	Keystone Clinical Research	Norristown	Pennsylvania
United States	Office of Jeffrey S. Ross, MD	Northbrook	Illinois
United States	Research Center for Clinical Studies, LLC	Norwalk	Connecticut
United States	Ocala Health - Family Care Specialists - Ocala I	Ocala	Florida
United States	IMA Clinical Research - Phoenix	Phoenix	Arizona
United States	Donald S. Marks, MD. P.C.	Plymouth	Massachusetts
United States	Progressive Medical Research	Port Orange	Florida
United States	Summit Research Network	Portland	Oregon
United States	ActivMed Practices and Research	Portsmouth	New Hampshire
United States	Princeton Psychiatric Center	Princeton	New Jersey
United States	Sharp Mesa Vista Hospital	San Diego	California
United States	Syrentis Clinical Research	Santa Ana	California
United States	CenExel - iResearch Savannah	Savannah	Georgia
United States	CenExel - California Neuroscience Research Medical Group, Inc (CNR)	Sherman Oaks	California
United States	The Cognitive and Research Center of New Jersey	Springfield	New Jersey
United States	Alzheimer's Research and Treatment Center - Stuart	Stuart	Florida
United States	SUNY Upstate Medical University - Upstate University Hospital (SUNY Health Science Center)	Syracuse	New York
United States	K2 Medical Research - Tampa	Tampa	Florida
United States	Charter Research - Lady Lake	The Villages	Florida
United States	CenExel - Advanced Memory Research Institute of NJ	Toms River	New Jersey
United States	Re:Cognition Health - Fairfax	Washington	District of Columbia
United States	Alzheimers Research and Treatment Center - Wellington	Wellington	Florida
United States	KU Wichita Center for Clinical Research	Wichita	Kansas
United States	Charter Research - Winter Park	Winter Park	Florida
United States	Conquest Research	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Acumen Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	Effect of ACU193 on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by iADRS		Baseline up to Week 80
Secondary	Effect of ACU193 on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by ADCS-iADL		Baseline up to Week 80
Secondary	Effect of ACU193 on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by ADAS-Cog13		Baseline up to Week 80
Secondary	Effect of ACU193 on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by CDR-SB		Baseline up to Week 80
Secondary	Effect of ACU193 on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by MMSE		Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	Number of Participants with Treatment-Related Adverse Events (TEAEs)		Baseline up to Week 80
Secondary	Number of Participants with Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)		Baseline up to Week 80
Secondary	Number of Participants who Discontinue or Withdraw due to TEAE		Baseline up to Week 80
Secondary	Number of Participants with Anti-Drug Antibodies (ADA) and Neutralizing Antibodies		Baseline up to Week 80
Secondary	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)		Baseline up to Week 80
Secondary	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.	Baseline up to Week 80
Secondary	Serum Concentration of ACU193		Pre-dose and multiple timepoints post dose up to 80 weeks
Secondary	Concentration of ACU193 in Cerebrospinal Fluid (CSF)		Up to Week 76
Secondary	CSF Concentrations of ACU193 in a Subset of Participants		Up to Week 76
Secondary	Correlation Between ACU193 Exposure with Clinical Efficacy Measures	Correlation between ACU193 exposure and clinical outcomes (including iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE) will be assessed in this study.	Baseline up to 80 weeks
Secondary	Change From Baseline in Amyloid Plaque Load or Deposition Measured by Positron Emission Tomography (PET) in Centiloids		Baseline up to Week 76
Secondary	Change from Baseline in Volumetric Magnetic Resonance Imaging (vMRI) of Whole Brain Volume, Ventricular Volume, and Volume of Selected Regions of Interest		Baseline up to Week 76
Secondary	Target Engagement Assessed by Measurement of ACU193- Amyloid-ß oligomer (AßO) Complex in CSF		Up to Week 76
Secondary	Change from Baseline in CSF Concentrations of Amyloid, Tau and Other Neurodegenerative Biomarkers		Baseline up to Week 76
Secondary	Change from Baseline in CSF Concentrations of Amyloid, Tau, and Other Neurodegenerative Biomarkers in a Subset of Participants		Baseline up to Week 76
Secondary	Change from Baseline in Blood Concentrations of Amyloid, Tau, and Other Neurodegenerative Biomarkers		Baseline up to Week 76
Secondary	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.	Up to 80 weeks