AzTrials
AzTrials

Alzheimer DiseasePhase 3RETHINK-ALZNCT04994483

Simufilam 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 88 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

A 52-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 52 weeks. Approximately 750 participants will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. 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
804 participants
Where
88 sitesin 3 countries
Study dates
3 Nov 2021to 2 Oct 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 either 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

88 sites in 3 countries.

88 sites in 3 countries

United States74 sites

  • Albuquerque Neuroscience, Inc

    Albuquerque, New Mexico, 87109

  • Neuro Medical Clinic of Central Louisiana, LLC

    Alexandria, Louisiana, 71301

  • Dent Neurologic Institute

    Amherst, New York, 14226

  • Advanced Research Center, Inc

    Anaheim, California, 92805

  • Topaz Clinical Research

    Apopka, Florida, 32703

  • FutureSearch Trials of Neurology

    Austin, Texas, 78731

  • Senior Adults Specialty Research, Inc

    Austin, Texas, 78757

  • Mountain Neurological Research Center

    Basalt, Colorado, 81621

  • Insight Clinical Trials LLC

    Beachwood, Ohio, 44122

  • Neurology Offices of South Florida

    Boca Raton, Florida, 33428

  • Boynton Beach Medical Research Institute (GMI)

    Boynton Beach, Florida, 33437

  • NeuroScience Research Center, LLC

    Canton, Ohio, 44718

  • Dayton Center for Neurological Disorders

    Centerville, Ohio, 45459

  • MDFirst Research

    Chandler, Arizona, 85286

  • Clinical Research Professionals

    Chesterfield, Missouri, 63005

  • K2 Medical Research - Clermont

    Clermont, Florida, 34711

  • Axiom Research, LLC

    Colton, California, 92324

  • ATP Clinical Research, Inc.

    Costa Mesa, California, 92626

  • CT Clinical Research

    Cromwell, Connecticut, 06416

  • Texas Neurology, PA

    Dallas, Texas, 75206

  • Baylor Scott & White Research Institute

    Dallas, Texas, 75231

  • Arrow Clinical Trials

    Daytona Beach, Florida, 32117

  • Colorado Neurological Research Center, PC

    Denver, Colorado, 80210

  • Rhode Island Mood & Memory Research Institute

    East Providence, Rhode Island, 02914

  • Re:Cognition Health

    Fairfax, Virginia, 22031

  • Neuropsychiatric Research Center of Southwest Florida

    Fort Myers, Florida, 33912

  • CCT Research - Gilbert Neurology Partners

    Gilbert, Arizona, 85297

  • Triad Clinical Trials, LLC

    Greensboro, North Carolina, 27410

  • Velocity Clinical Research, Hallandale Beach

    Hallandale, Florida, 33009

  • Galiz Research

    Hialeah, Florida, 33016

  • Infinity Clinical Research - Sunrise

    Hollywood, Florida, 33024

  • Sun Valley Research Center, Inc.

    Imperial, California, 92251

  • CNS Healthcare - Jacksonville

    Jacksonville, Florida, 32256

  • Mt. Olympus Medical Research, LLC

    Katy, Texas, 77450

  • Charter Research

    Lady Lake, Florida, 32162

  • Senior Clinical Trials

    Laguna Hills, California, 92653

  • Segal Trials - West Broward Outpatient Site

    Lauderhill, Florida, 33319

  • ClinCloud

    Maitland, Florida, 32751

  • Brian Abaluck, LLC

    Malvern, Pennsylvania, 19355

  • Alzheimer's Memory Center

    Matthew, North Carolina, 28105

  • Velocity Clinical Research, Boise

    Meridian, Idaho, 83642

  • Merritt Island Medical Research, LLC

    Merritt Island, Florida, 32952

  • Central Miami Medical Institute (GMI)

    Miami, Florida, 33125

  • New Horizon Research Center

    Miami, Florida, 33165

  • Luminous Clinical Research

    Miami, Florida, 33186

  • Quantam Clinical Trials

    Miami Beach, Florida, 33140

  • South Florida Research Phase I-IV INC

    Miami Springs, Florida, 33166

  • Global Medical Institutes/Scranton Medical Institute - Moosic Division

    Moosic, Pennsylvania, 18507

  • Parker Jewish Institute for Health Care & Rehabilitation

    New Hyde Park, New York, 11040-1433

  • Suncoast Clinical Research, Inc.

    New Port Richey, Florida, 34652

  • Mid Hudson Medical Research

    New Windsor, New York, 12553

  • NY Neurology Associates

    New York, New York, 10003

  • Boston Neuro Research Center

    North Dartmouth, Massachusetts, 02747

  • Renstar Medical Research

    Ocala, Florida, 34470

  • Charter Research

    Orlando, Florida, 32803

  • Combined Research Orlando Phase I-IV

    Orlando, Florida, 32807

  • CCT Research - Papillion Research Center

    Papillion, Nebraska, 68046

  • Xenoscience, Inc.

    Phoenix, Arizona, 85004

  • Progressive Medical Research

    Port Orange, Florida, 32127

  • Summit Research Network, LLC

    Portland, Oregon, 97210

  • Artemis Institute for Clinical Research

    Riverside, California, 92503

  • University of Rochester Medical Center - Alzheimer's Disease Care, Research and Education Program

    Rochester, New York, 14620

  • Green Mountain Research Institute, Inc.

    Rutland, Vermont, 05701

  • Syrentis Clinical Research

    Santa Ana, California, 92705

  • Memory and Brain Wellness Center at Harborview

    Seattle, Washington, 98104

  • Palmetto Clinical Research

    Summerville, South Carolina, 29485

  • Clinical Research of Brandon, LLC (Tampa)

    Tampa, Florida, 33603

  • Stedman Clinical Trials

    Tampa, Florida, 33613

  • Advanced Clinical Institute, Inc

    West Long Branch, New Jersey, 07764

  • Premier Research Institute at Palm Beach Neurology

    West Palm Beach, Florida, 33407

  • Ascension Via Christi Research

    Wichita, Kansas, 67214

  • Grayline Research Center

    Wichita Falls, Texas, 76309

  • Northwestern Medicine Central DuPage Hospital

    Winfield, Illinois, 60190

  • Five Town Neuroscience Research

    Woodmere, New York, 11598

Other trials in United States

Australia9 sites

  • Eastern Health

    Box Hill, Victoria, 3128

  • Delmont Private Hospital

    Glen Iris, Victoria, 3146

  • Austin Health

    Heidelberg, Victoria, 3084

  • The University of Queensland

    Herston, Queensland, 4029

  • KaRa MINDS

    Macquarie Park, New South Wales, 2113

  • The Alfred Hospital

    Melbourne, Victoria, 3004

  • Australian Alzheimer's Research Foundation

    Nedlands, Western Australia, 8009

  • Royal Melbourne Hospital

    Parkville, Victoria, 3050

  • Impact Health Pty Ltd.

    Southport, Queensland, 4215

Other trials in Australia

Canada5 sites

  • LMC Clinical Research - London

    London, Ontario, N6A 5R9

  • Alpha Recherche Clinique

    Québec, G3K 2P8

  • Bluewater Clinical Research Group Inc

    Sarnia, Ontario, N7T 4X3

  • Q & T Research

    Sherbrooke, Quebec, J1J 2G2

  • Diex Research Sherbrooke Inc.

    Sherbrooke, Quebec, J1L0H8

Other trials in Canada

About this study

Official title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Study Evaluating the Safety and Efficacy of Simufilam 100 mg Tablets in Subjects With Mild-to-Moderate Alzheimer's Disease

A 52-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 52 weeks. Approximately 750 participants will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 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 52-week, repeat-dose oral administration in participants with mild-to-moderate AD. Secondary objectives include the assessment of simufilam's effect on neuropsychiatric symptoms and caregiver burden. A third objective is to investigate the effect of simufilam treatment on plasma biomarkers. A limited number of research sites will be invited to participate in the pharmacokinetic (PK) and plasma biomarker sub-study. Collection of PK samples will enable an exposure-response analysis. Approximately 100 subjects will participate (50 per group). Plasma samples will be collected during the Screening Visit and again at Weeks 28 and 52. Change from Baseline for plasma biomarkers represent additional secondary endpoints.

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 magnetic resonance imaging (MRI) during screening to ensure entry criteria are met (unless recent MRI confirms entry criteria). Resting electrocardiograms will be conducted at Baseline (Study Day 1) and Weeks 4, 28, and 52. 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 52 weeks at a dose of 100 mg.

  • PlaceboDrug

    Matching placebo given b.i.d. for 52 weeks.

Study groups in NCT04994483
Study groupRoleWhat they receive
PlaceboPlacebo comparatorMatching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 52 weeks
Receives: Drug: Placebo
Simufilam 100 mgExperimentalSimufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 52 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 52 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 52

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

    The change from baseline to Week 52 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. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.

    Measured: Baseline (Study Day 1) to Week 52

Secondary outcomes (5)

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

    The change from baseline to Week 52 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance.

    Measured: Baseline (Study Day 1) to Week 52

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

    The change from baseline to Week 52 in the NPI, a 12-item study partner interview, which records the frequency and severity of common neuropsychiatric symptoms in dementia, as well as the level of study partner distress due to each of 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 52

  3. Change From Baseline in the Mini-Mental State Exam (MMSE)

    The change from baseline to Week 52 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 52

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

    The change from baseline to Week 52 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 52

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

    The change from baseline to Week 52 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 52

Timeline

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

  1. First posted6 Aug 2021
  2. Study start3 Nov 2021
  3. Primary completion2 Oct 2024
  4. Study completion2 Oct 2024

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
Model description
Approximately 750 patients will be enrolled into the study. All patients will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
804 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04994483
Sponsor's protocol ID
PTI-125-07
Acronym
RETHINK-ALZ
Status last verified
May 2025
First submitted
29 Jul 2021
Last updated
25 May 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 88 sites in 3 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: finished, as of the sponsor's last update on 25 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 88 sites in United States, Australia, Canada. 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 25 May 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 52). 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 NCT04994483, 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 25 May 2025.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in