Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease
- Registration Number
- NCT05026177
- Lead Sponsor
- Cassava Sciences, Inc.
- Brief 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 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.
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1125
- 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.
- 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.
Key
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks Simufilam 100 mg Simufilam Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks Simufilam 50 mg Simufilam Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks
- Primary Outcome Measures
Name Time Method Change from baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) Baseline (Study Day 1) to Week 76 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).
Change from baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Baseline (Study Day 1) to Week 76 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. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.
- Secondary Outcome Measures
Name Time Method Change from baseline in the integrated Alzheimer's Disease Rating Scale (iADRS) Baseline (Study Day 1) to Week 76 The change from baseline to Week 76 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance.
Change from baseline in the Neuropsychiatric Inventory (NPI) Baseline (Study Day 1) to Week 76 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, as well as the level of study partner distress due to these neuropsychiatric problems. Scores range from 0 to 144, with higher scores indicating more frequent and severe symptoms, and greater levels of partner distress.
Change from baseline in the Zarit Burden Interview (ZBI) Baseline (Study Day 1) to Week 76 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, with a higher score indicating greater stress or burden.
Changes from baseline in CSF neurogranin, neurofilament light chain, total tau, phospho-tau181 (P-tau181) and/or phospho-tau217 (P-tau217), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and Aβ42 Baseline (Study Day 1) to Week 76 Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation.
Change from baseline in the MMSE Baseline (Study Day 1) to Week 76 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. Lower scores indicate more severe impairment.
Change from baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) Baseline (Study Day 1) to Week 76 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. Higher scores indicate more severe impairment.
Changes from baseline in brain volume via MRI Baseline (Study Day 1) to Week 76 Changes from baseline in hippocampus, ventricles, and whole brain volume.
Changes from baseline in amyloid and tau PET Baseline (Study Day 1) to Week 76 Changes from baseline in amyloid and tau deposition in the brain
Changes from baseline in plasma biomarkers P-tau181, P-tau217, and neurofilament light chain Baseline (Study Day 1) to Week 76 Change from baseline in plasma biomarkers of AD pathology and neurodegeneration
Change from baseline in plasma biomarker SavaDx Baseline (Study Day 1) to Week 76 SavaDx is a novel plasma biomarker
Trial Locations
- Locations (87)
Parkinson's Disease and Movement Disorders Center of Boca Raton
🇺🇸Boca Raton, Florida, United States
Clinical Research of Brandon, LLC
🇺🇸Brandon, Florida, United States
Quantum Laboratories
🇺🇸Deerfield Beach, Florida, United States
Brain Matters Research Inc
🇺🇸Stuart, Florida, United States
Indago Research and Health Center, Inc.
🇺🇸Hialeah, Florida, United States
Alphab Global Research
🇺🇸Jupiter, Florida, United States
K2 Medical Research
🇺🇸Maitland, Florida, United States
Mind Institute at Miami Jewish Health
🇺🇸Miami, Florida, United States
Brainstorm Research
🇺🇸Miami, Florida, United States
Health Synergy Clinical Research
🇺🇸Okeechobee, Florida, United States
Clinical Neuroscience Solutions, Inc. dba CNS Healthcare
🇺🇸Orlando, Florida, United States
Intercoastal Medical Group - Sarasota
🇺🇸Sarasota, Florida, United States
Alzheimer's Research & Treatment Center
🇺🇸Wellington, Florida, United States
USF Health - Byrd Alzheimer's Center and Research Institute
🇺🇸Tampa, Florida, United States
Conquest Research
🇺🇸Winter Park, Florida, United States
Columbus Memory Center, PC
🇺🇸Columbus, Georgia, United States
Accel Research Sites - NeuroStudies
🇺🇸Decatur, Georgia, United States
Great Lakes Clinical Trials
🇺🇸Chicago, Illinois, United States
Advocate Aurora Health
🇺🇸Park Ridge, Illinois, United States
University of Kentucky Sanders-Brown Center on Aging
🇺🇸Lexington, Kentucky, United States
Neurology Center of New England
🇺🇸Foxboro, Massachusetts, United States
ActivMed Practices & Research, LLC
🇺🇸Methuen, Massachusetts, United States
Boston Center for Memory
🇺🇸Newton, Massachusetts, United States
Office of Donald S. Marks, M.D., P.C.
🇺🇸Plymouth, Massachusetts, United States
MedVadis Research
🇺🇸Waltham, Massachusetts, United States
Patient First MD
🇺🇸Middletown, New Jersey, United States
Global Medical Institutes, LLC
🇺🇸Princeton, New Jersey, United States
The Cognitive and Research Center of New Jersey (CRCNJ)
🇺🇸Springfield, New Jersey, United States
Advanced Memory Research Institute of NJ
🇺🇸Toms River, New Jersey, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Neurological Associates of Albany
🇺🇸Albany, New York, United States
Integrative Clinical Trials
🇺🇸Brooklyn, New York, United States
SPRI Clinical Trials Brooklyn
🇺🇸Brooklyn, New York, United States
Velocity Clinical Research, Formerly Clarity Clinical Research
🇺🇸East Syracuse, New York, United States
Richmond Behavioral Associates
🇺🇸Staten Island, New York, United States
Accellacare Research of Winston-Salem
🇺🇸Winston-Salem, North Carolina, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Neurology Diagnostics
🇺🇸Dayton, Ohio, United States
Neuro-Behavioral Clinical Research (NBCR)
🇺🇸North Canton, Ohio, United States
Center for Cognitive Health - Portland
🇺🇸Portland, Oregon, United States
The Clinical Trial Center
🇺🇸Jenkintown, Pennsylvania, United States
Keystone Clinical Studies, LLC
🇺🇸Plymouth Meeting, Pennsylvania, United States
KCA Neurology, PLLC
🇺🇸Franklin, Tennessee, United States
Neurology Consultants of Dallas, PA
🇺🇸Dallas, Texas, United States
Cedar Health Research
🇺🇸Irving, Texas, United States
The Memory Clinic - Bennington
🇺🇸Bennington, Vermont, United States
Northwest Clinical Research Center
🇺🇸Bellevue, Washington, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
OCT Research ULC DBA Okanagan Clinical Trials
🇨🇦Kelowna, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health
🇨🇦Vancouver, British Columbia, Canada
Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD)
🇨🇦Moncton, New Brunswick, Canada
True North Clinical Research - Halifax
🇨🇦Halifax, Nova Scotia, Canada
True North Clinical Research - New Minas
🇨🇦New Minas, Nova Scotia, Canada
St. Joseph's Health Care London
🇨🇦London, Ontario, Canada
Ottawa Memory Clinic
🇨🇦Ottawa, Ontario, Canada
Recherches Neuro-Hippocampe Inc.
🇨🇦Ottawa, Ontario, Canada
Kawartha Centre - Redefining Healthy Aging
🇨🇦Peterborough, Ontario, Canada
Toronto Memory Program
🇨🇦Toronto, Ontario, Canada
The Centre for Memory and Aging
🇨🇦Toronto, Ontario, Canada
Chonnam National University Hospital
🇰🇷Gwangju, Dong-gu, Korea, Republic of
Hanyang University Guri Hospital
🇰🇷Guri-si, Gyeonggi-do, Korea, Republic of
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Gyeonggi-do, Korea, Republic of
Gachon University Gil Hospital
🇰🇷Namdong-gu, Incheon, Korea, Republic of
Inha University Medical Center
🇰🇷Incheon, Jung-go, Korea, Republic of
Kyungpook National University Chilgok Hospital
🇰🇷Daegu, North Gyeongsang Province, Korea, Republic of
Korea University Anam Hospital
🇰🇷Seongbuk-gu, Seoul, Korea, Republic of
HanYang University Hospital
🇰🇷Seongdong-gu, Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Songpa-gu, Korea, Republic of
Santa Cruz Behavioral PSC
🇵🇷Bayamón, Puerto Rico
Inspira Clinical Research
🇵🇷San Juan, Puerto Rico
Barbara Diaz Hernandez Md Research, Inc.
🇵🇷San Juan, Puerto Rico
Instituto De Neurologia Dra. Ivonne Fraga
🇵🇷San Juan, Puerto Rico
Banner Alzheimer's Institute
🇺🇸Phoenix, Arizona, United States
Arizona Neuroscience Research, LLC
🇺🇸Phoenix, Arizona, United States
Clinical Endpoints
🇺🇸Scottsdale, Arizona, United States
Banner Sun Health Research Institute
🇺🇸Sun City, Arizona, United States
Banner Alzheimer's Institute - Tucson
🇺🇸Tucson, Arizona, United States
North County Neurology Associates
🇺🇸Carlsbad, California, United States
Neuro-Pain Medical Center
🇺🇸Fresno, California, United States
Neurology Center of North Orange County
🇺🇸Fullerton, California, United States
Healthy Brain Clinic
🇺🇸Long Beach, California, United States
California Research Insitute
🇺🇸Los Angeles, California, United States
Shankle Clinic and Hoag Memorial Hospital Presbyterian
🇺🇸Newport Beach, California, United States
Pacific Research Network, LLC
🇺🇸San Diego, California, United States
Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC
🇺🇸Danbury, Connecticut, United States
Ki Health Partners, LLC
🇺🇸Stamford, Connecticut, United States
JEM Research Institute
🇺🇸Atlantis, Florida, United States