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 (REFOCUS-ALZ)

  • End date
    Jun 15, 2024
  • participants needed
  • sponsor
    Cassava Sciences, Inc.
Updated on 15 October 2022
mini-mental state examination
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.


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 provide plasma for a biomarker sub-study, and those 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. All subjects will undergo magnetic resonance imaging (MRI) during screening to ensure entry criteria are met, 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. Electrocardiograms will be conducted on 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, on 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.

Condition Alzheimer Disease
Treatment Placebo, Simufilam
Clinical Study IdentifierNCT05026177
SponsorCassava Sciences, Inc.
Last Modified on15 October 2022


Yes No Not Sure

Inclusion Criteria

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
The subject has been a non-smoker for at least 3 years
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

Exclusion Criteria

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
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
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 > 35.0
History or diagnosis of clinically significant cardiac disease
Prescribed aducanumab
COVID-19 infection within 3 months of screening. If no history of a prior COVID-19 infection, subject must be fully vaccinated for COVID-19 at least 2 weeks prior to randomization
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