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Alzheimer DiseasePhase 3REFOCUS-ALZNCT05026177

Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease

A Phase 3 study testing Simufilam in people with Alzheimer Disease, run by Cassava Sciences, Inc. at 89 sites in 4 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

A 76-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 76 weeks. Approximately 1083 participants will be randomized (1:1:1) to receive either placebo, 50 mg tablets of simufilam, or 100 mg tablets of simufilam, twice daily, for 76… Read more about this study

Who is it for?
Ages 50 to 87 years
Conditions the study is for
Alzheimer Disease
What is being tested?
Simufilam
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,125 participants
Where
89 sitesin 4 countries
Study dates
18 Nov 2021to 30 Dec 2024
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 87 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Meets National Institute on Aging and Alzheimer's Association Research Framework criteria for individuals in clinical Stage 4 or 5 of the Alzheimer's continuum.
  • Evidence for AD pathophysiology, confirmed prior to or during screening.
  • MMSE score ≥ 16 and ≤ 27 at screening.
  • Clinical Dementia Rating - Global Score must be 0.5, 1 or 2.
  • If receiving background AD medications, the dosing regimen must be stable for at least 12 weeks prior to randomization. Chronic medications for conditions other than AD (such as depression) must be prescribed at a stable dose for at least 4 weeks prior to screening.
  • The subject has not been a cigarette smoker or chewed tobacco for at least 3 years.
Show all 9Show fewer
  • Availability of a study partner.
  • Individuals who have participated in a clinical study with an investigational drug targeting the underlying AD process may be permitted to participate in this study.
  • Completed a COVID-19 vaccine primary series ("fully vaccinated") at least 2 weeks prior to randomization or had an unambiguous COVID-19 infection diagnosed more than 3 months before the start of the Screening Period.

Who cannot join

  • A neurologic condition other than AD that significantly contributes to the subject's dementia.
  • Any current primary psychiatric diagnosis other than AD if it is likely to confound cognitive assessment or ability to comply with study procedures.
  • Geriatric Depression Scale (15-item) score > 8 (Note - a subject with a score > 8 may continue in screening if, in the judgment of the Investigator, the elevated score is not attributed to a major depressive episode).
  • Suicidal ideation during the past 3 months or suicidal behavior during the past 12 months.
  • Alcohol or substance use disorder within 2 years of screening.
  • MRI presence of cerebral vascular or other significant pathology.
Show all 14Show fewer
  • History of transient ischemic attack or stroke within 12 months of screening.
  • Seizure within 12 months of screening.
  • Severe head trauma or head trauma considered likely to be contributing to the subject's cognitive impairment.
  • Sleep apnea that is considered likely to be contributing to the subject's cognitive impairment.
  • Insufficiently controlled diabetes mellitus or hypertension.
  • Body mass index < 18.5 or > 37.5.
  • History or diagnosis of clinically significant cardiac disease.
  • Currently or previously prescribed/administered aducanumab, lecanemab, or any anti-amyloid monoclonal antibody, more than 2 doses.

Trial locations and contacts

89 sites in 4 countries.

89 sites in 4 countries

United States65 sites

  • Albany Medical Center

    Albany, New York, 12208

  • Neurological Associates of Albany

    Albany, New York, 12208

  • JEM Research Institute

    Atlantis, Florida, 33462

  • Northwest Clinical Research Center

    Bellevue, Washington, 98007

  • The Memory Clinic - Bennington

    Bennington, Vermont, 05201

  • Parkinson's Disease and Movement Disorders Center of Boca Raton

    Boca Raton, Florida, 33486

  • Clinical Research of Brandon, LLC

    Brandon, Florida, 33511

  • Integrative Clinical Trials

    Brooklyn, New York, 11229

  • SPRI Clinical Trials Brooklyn

    Brooklyn, New York, 11235

  • North County Neurology Associates

    Carlsbad, California, 92011

  • Great Lakes Clinical Trials

    Chicago, Illinois, 60640

  • Columbus Memory Center, PC

    Columbus, Georgia, 31909

  • Ohio State University

    Columbus, Ohio, 43210

  • Neurology Consultants of Dallas, PA

    Dallas, Texas, 75243

  • Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC

    Danbury, Connecticut, 06810

  • Neurology Diagnostics

    Dayton, Ohio, 45459

  • Accel Research Sites - NeuroStudies

    Decatur, Georgia, 30030

  • Quantum Laboratories

    Deerfield Beach, Florida, 33442

  • Brain Matters Research Inc

    Delray Beach, Florida, 33445

  • Velocity Clinical Research, Formerly Clarity Clinical Research

    East Syracuse, New York, 13057

  • Neurology Center of New England

    Foxborough, Massachusetts, 02035

  • KCA Neurology, PLLC

    Franklin, Tennessee, 37067

  • Neuro-Pain Medical Center

    Fresno, California, 93710

  • Neurology Center of North Orange County

    Fullerton, California, 92835

  • Indago Research and Health Center, Inc.

    Hialeah, Florida, 33012

  • Cedar Health Research

    Irving, Texas, 75062

  • The Clinical Trial Center

    Jenkintown, Pennsylvania, 19046

  • Alphab Global Research

    Jupiter, Florida, 33458

  • University of Kentucky Sanders-Brown Center on Aging

    Lexington, Kentucky, 40504

  • Healthy Brain Clinic

    Long Beach, California, 90804

  • California Research Insitute

    Los Angeles, California, 90027

  • K2 Medical Research

    Maitland, Florida, 32751

  • ActivMed Practices & Research, LLC

    Methuen, Massachusetts, 01844

  • Mind Institute at Miami Jewish Health

    Miami, Florida, 33137

  • Brainstorm Research

    Miami, Florida, 33176

  • Patient First MD

    Middletown, New Jersey, 07748

  • Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Shankle Clinic and Hoag Memorial Hospital Presbyterian

    Newport Beach, California, 92663

  • Boston Center for Memory

    Newton, Massachusetts, 02459

  • Neuro-Behavioral Clinical Research (NBCR)

    North Canton, Ohio, 44720

  • Health Synergy Clinical Research

    Okeechobee, Florida, 34972

  • Clinical Neuroscience Solutions, Inc. dba CNS Healthcare

    Orlando, Florida, 32801

  • Advocate Aurora Health

    Park Ridge, Illinois, 60068

  • Banner Alzheimer's Institute

    Phoenix, Arizona, 85006

  • Arizona Neuroscience Research, LLC

    Phoenix, Arizona, 85032

  • Office of Donald S. Marks, M.D., P.C.

    Plymouth, Massachusetts, 02360

  • Keystone Clinical Studies, LLC

    Plymouth Meeting, Pennsylvania, 19462

  • Center for Cognitive Health - Portland

    Portland, Oregon, 97225

  • Global Medical Institutes, LLC

    Princeton, New Jersey, 08540

  • Pacific Research Network, LLC

    San Diego, California, 92103

  • Intercoastal Medical Group - Sarasota

    Sarasota, Florida, 34239

  • Clinical Endpoints

    Scottsdale, Arizona, 85258

  • The Cognitive and Research Center of New Jersey (CRCNJ)

    Springfield, New Jersey, 07081

  • Ki Health Partners, LLC

    Stamford, Connecticut, 06905

  • Richmond Behavioral Associates

    Staten Island, New York, 10312

  • Alzheimer's Research & Treatment Center

    Stuart, Florida, 34997

  • Brain Matters Research Inc

    Stuart, Florida, 34997

  • Banner Sun Health Research Institute

    Sun City, Arizona, 85351

  • USF Health - Byrd Alzheimer's Center and Research Institute

    Tampa, Florida, 33613

  • Advanced Memory Research Institute of NJ

    Toms River, New Jersey, 08755

  • Banner Alzheimer's Institute - Tucson

    Tucson, Arizona, 85718

  • MedVadis Research

    Waltham, Massachusetts, 02451

  • Alzheimer's Research & Treatment Center

    Wellington, Florida, 33414

  • Accellacare Research of Winston-Salem

    Winston-Salem, North Carolina, 27103

  • Conquest Research

    Winter Park, Florida, 32789

Other trials in United States

Canada11 sites

  • True North Clinical Research - Halifax

    Halifax, Nova Scotia, B3S 1N2

  • OCT Research ULC DBA Okanagan Clinical Trials

    Kelowna, British Columbia, V1Y 2Z9

  • St. Joseph's Health Care London

    London, Ontario, N6C 0A7

  • Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD)

    Moncton, New Brunswick, E1C 2Z3

  • True North Clinical Research - New Minas

    New Minas, Nova Scotia, B4N 3R7

  • Ottawa Memory Clinic

    Ottawa, Ontario, K1Z 1G3

  • Recherches Neuro-Hippocampe Inc.

    Ottawa, Ontario, K1Z 1G3

  • Kawartha Centre - Redefining Healthy Aging

    Peterborough, Ontario, K9H2P4

  • Toronto Memory Program

    Toronto, Ontario, M3B 2S7

  • The Centre for Memory and Aging

    Toronto, Ontario

  • Djavad Mowafaghian Centre for Brain Health

    Vancouver, British Columbia, V6T 1Z3

Other trials in Canada

South Korea9 sites

  • Kyungpook National University Chilgok Hospital

    Daegu, North Gyeongsang Province, 61469

  • Hanyang University Guri Hospital

    Guri-si, Gyeonggi-do, 11923

  • Chonnam National University Hospital

    Gwangju, Dong-gu, 61469

  • Inha University Medical Center

    Incheon, Jung-go, 22332

  • Gachon University Gil Hospital

    Namdong-gu, Incheon, 21565

  • Korea University Anam Hospital

    Seongbuk-gu, Seoul, 02841

  • HanYang University Hospital

    Seongdong-gu, Seoul, 04763

  • Seoul National University Bundang Hospital

    Seongnam-si, Gyeonggi-do, 13620

  • Asan Medical Center

    Seoul, Songpa-gu, 05505

Other trials in South Korea

Puerto Rico4 sites

  • Santa Cruz Behavioral PSC

    Bayamón, 00961

  • Inspira Clinical Research

    San Juan, 00918

  • Barbara Diaz Hernandez Md Research, Inc.

    San Juan, 00926

  • Instituto De Neurologia Dra. Ivonne Fraga

    San Juan

Other trials in Puerto Rico

About this study

Official title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 76-week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects With Mild-to-Moderate Alzheimer's Disease

A 76-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 76 weeks. Approximately 1083 participants will be randomized (1:1:1) to receive either placebo, 50 mg tablets of simufilam, or 100 mg tablets of simufilam, twice daily, for 76 weeks. Clinic visits will occur 4 weeks after the baseline visit, and then every 12 weeks until the end of the study. The safety of simufilam, and its efficacy in enhancing cognition and slowing cognitive and functional decline will be evaluated.

Read the detailed description

The primary objective of this study is to investigate the safety and efficacy of simufilam (PTI-125) in enhancing cognition and slowing cognitive and functional decline following 76-week, repeat-dose oral administration in participants with mild-to-moderate AD. Secondary objectives are to assess neuropsychiatric symptoms and to replicate the cerebrospinal fluid (CSF) biomarker effects observed in the two Phase 2 studies (PTI-125-03 and PTI-125-02) after 76 weeks of simufilam treatment. A third objective is to investigate the effect of simufilam treatment on plasma biomarkers as well as anatomical correlates of disease progression (brain volume [hippocampus, ventricles and whole brain]; and amyloid and tau deposition in the brain). A limited number of research sites will be invited to participate in sub-studies to assess the impact of simufilam on anatomical and biomarker endpoints, including: change from Baseline in CSF biomarkers (30 subjects/group); brain volume via magnetic resonance imaging (MRI) (50 subjects/group); and amyloid and tau positron emission tomography (PET) (40 and 50 subjects/group, respectively). Participants in both PET sub-studies will be required to have an MRI during the Screening Period and provide plasma for a biomarker sub-study. Participants in the tau PET sub-study will also provide additional plasma for a pharmacokinetic (PK) exposure response analysis. Changes from baseline for these imaging and fluid biomarkers represent additional secondary endpoints. The 90 subjects (30 per group) in the CSF sub-study will undergo lumbar puncture during the Screening Period and again at the Week 76 End-of-Treatment Visit to collect CSF biomarkers.

Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the Columbia Suicide Severity Rating Scale at every visit. Subjects will undergo MRI during screening to ensure entry criteria are met (unless recent MRI confirms entry criteria); however, 150 subjects (50 subjects per treatment group) will also undergo repeat MRI assessments at Weeks 40 and 76 to assess both long-term safety and drug impact on brain volume as noted above. Resting electrocardiograms will be conducted at Baseline (Study Day 1) and Weeks 4, 40 and 76. A complete physical and neurological examination will be performed at screening, and brief examinations will be performed at all other visits. Weight will be measured during the Screening Period, at Baseline (Study Day 1) and at all other visits.

An independent Data Safety Monitoring Board (DSMB) will meet periodically to review subject safety assessments and determine if dosing may continue. A charter will be developed with specific guidance for the DSMB.

Being tested
Simufilam, Placebo
Medical subject headings
Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SimufilamDrug

    Also called PTI-125

    Simufilam is a novel drug candidate designed to treat and slow the progression of AD. Simufilam binds with femtomolar affinity to an altered conformation of filamin A that is present in the brain of patients with AD and critical to the toxicity of Aβ42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.

  • PlaceboDrug

    Matching placebo given b.i.d. for 76 weeks

Study groups in NCT05026177
Study groupRoleWhat they receive
PlaceboPlacebo comparatorMatching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks
Receives: Drug: Placebo
Simufilam 50 mgExperimentalSimufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks
Receives: Drug: Simufilam
Simufilam 100 mgExperimentalSimufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks
Receives: Drug: Simufilam

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12)

    The change from baseline to Week 76 in the ADAS-Cog12, a psychometrician-administered battery comprised of several cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Scores range from 0 (best) to 80 (worst).

    Measured: Baseline (Study Day 1) to Week 76

  2. Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)

    The change from baseline to Week 76 in the ADCS-ADL, a 23-item study partner questionnaire that covers both basic activities of daily living (ADL) and more complex ADL or instrumental ADL for the subject. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.

    Measured: Baseline (Study Day 1) to Week 76

Secondary outcomes (5)

  1. Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS)

    The change from baseline to Week 76 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance.

    Measured: Baseline (Study Day 1) to Week 76

  2. Change From Baseline in the Neuropsychiatric Inventory (NPI)

    The change from baseline to Week 76 in the NPI, a 12-item study partner interview, which records the frequency and severity of common neuropsychiatric symptoms in dementia for the subject, as well as the level of study partner distress due to the neuropsychiatric problems. Scores range from 0 to 144, with higher scores indicating more frequent and severe symptoms, and greater levels of partner distress.

    Measured: Baseline (Study Day 1) to Week 76

  3. Change From Baseline in the MMSE

    The change from baseline to Week 76 in the MMSE, a set of standardized questions covering several target areas: orientation, registration, attention and calculation, short-term verbal recall, naming, repetition, 3-step command, reading, writing, and visuospatial cognitive assessment. Scores range from 0 to 30; lower scores indicate more severe impairment.

    Measured: Baseline (Study Day 1) to Week 76

  4. Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)

    The change from baseline to Week 76 in the CDR-SB, which characterizes 6 domains of cognitive and functional performance applicable to AD and related dementias: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Scores for each domain have a minimum of 0 and a maximum of 3, and the 6 domain scores are summed to give the CDR-SB, which has a minimum score of 0 and a maximum score of 18. Higher scores indicate more severe impairment.

    Measured: Baseline (Study Day 1) to Week 76

  5. Change From Baseline in the Zarit Burden Interview (ZBI)

    The change from baseline to Week 76 in the ZBI, a 22-item study partner questionnaire designed to assess the stress or burden experienced by caregivers of people with dementia. Scores range from 0 to 88, with a higher score indicating greater stress or burden.

    Measured: Baseline (Study Day 1) to Week 76

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Aug 2021
  2. Study start18 Nov 2021
  3. Primary completion30 Dec 2024
  4. Study completion30 Dec 2024

Why it stopped: Sponsor decision

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
1,125 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05026177
Sponsor's protocol ID
PTI-125-06
Acronym
REFOCUS-ALZ
Status last verified
Sep 2025
First submitted
9 Aug 2021
Last updated
22 Sep 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Kupiec JW, Porsteinsson AP, Turner RS, Hendrix S, Mallinckrodt C, Khan A, Cohen I, Liss J, Clarnette R, Park KH, Hernandez AM, Burns LH. Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease. J Prev Alzheimers Dis. 2026 Mar;13(3):100469. doi: 10.1016/j.tjpad.2025.100469. Epub 2026 Jan 6.

    PubMed 41500915

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Simufilam in people with Alzheimer Disease, run by Cassava Sciences, Inc. at 89 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 22 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 89 sites in United States, Canada, South Korea, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Sep 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) (time frame: Baseline (Study Day 1) to Week 76). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05026177, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2025.

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