Clinical trial NCT05026177: Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Alzheimer Disease
Lead sponsor: Cassava Sciences, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Premier Research Group plc
First posted: 2021-08-30
Enrollment: 1125
Sex: ALL
Minimum age (years): 50
Maximum age (years): 87
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Key Inclusion Criteria:

1. 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.
2. Evidence for AD pathophysiology, confirmed prior to or during screening.
3. MMSE score ≥ 16 and ≤ 27 at screening.
4. Clinical Dementia Rating - Global Score must be 0.5, 1 or 2.
5. 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.
6. The subject has not been a cigarette smoker or chewed tobacco for at least 3 years.
7. Availability of a study partner.
8. 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.
9. 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 Exclusion Criteria:

1. A neurologic condition other than AD that significantly contributes to the subject's dementia.
2. Any current primary psychiatric diagnosis other than AD if it is likely to confound cognitive assessment or ability to comply with study procedures.
3. 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).
4. Suicidal ideation during the past 3 months or suicidal behavior during the past 12 months.
5. Alcohol or substance use disorder within 2 years of screening.
6. MRI presence of cerebral vascular or other significant pathology.
7. History of transient ischemic attack or stroke within 12 months of screening.
8. Seizure within 12 months of screening.
9. Severe head trauma or head trauma considered likely to be contributing to the subject's cognitive impairment.
10. Sleep apnea that is considered likely to be contributing to the subject's cognitive impairment.
11. Insufficiently controlled diabetes mellitus or hypertension.
12. Body mass index \< 18.5 or \> 37.5.
13. History or diagnosis of clinically significant cardiac disease.
14. Currently or previously prescribed/administered aducanumab, lecanemab, or any anti-amyloid monoclonal antibody, more than 2 doses.

Primary outcomes:
measure: Change from baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12)
timeFrame: Baseline (Study Day 1) to Week 76
measure: Change from baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
timeFrame: Baseline (Study Day 1) to Week 76
Secondary outcomes:
measure: Change from baseline in the integrated Alzheimer's Disease Rating Scale (iADRS)
timeFrame: Baseline (Study Day 1) to Week 76
measure: Change from baseline in the Neuropsychiatric Inventory (NPI)
timeFrame: Baseline (Study Day 1) to Week 76
measure: Change from baseline in the MMSE
timeFrame: Baseline (Study Day 1) to Week 76
measure: Change from baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)
timeFrame: Baseline (Study Day 1) to Week 76
measure: Change from baseline in the Zarit Burden Interview (ZBI)
timeFrame: Baseline (Study Day 1) to Week 76
measure: 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
timeFrame: Baseline (Study Day 1) to Week 76
measure: Changes from baseline in brain volume via MRI
timeFrame: Baseline (Study Day 1) to Week 76
measure: Changes from baseline in amyloid and tau PET
timeFrame: Baseline (Study Day 1) to Week 76
measure: Changes from baseline in plasma biomarkers P-tau181, P-tau217, and neurofilament light chain
timeFrame: Baseline (Study Day 1) to Week 76
measure: Change from baseline in plasma biomarker SavaDx
timeFrame: Baseline (Study Day 1) to Week 76
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Phoenix
country: United States
facility: Arizona Neuroscience Research, LLC
state: Arizona
city: Scottsdale
country: United States
facility: Clinical Endpoints
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Tucson
country: United States
facility: Banner Alzheimer's Institute - Tucson
state: Arizona
city: Carlsbad
country: United States
facility: North County Neurology Associates
state: California
city: Fresno
country: United States
facility: Neuro-Pain Medical Center
state: California
city: Fullerton
country: United States
facility: Neurology Center of North Orange County
state: California
city: Long Beach
country: United States
facility: Healthy Brain Clinic
state: California
city: Los Angeles
country: United States
facility: California Research Insitute
state: California
city: Newport Beach
country: United States
facility: Shankle Clinic and Hoag Memorial Hospital Presbyterian
state: California
city: San Diego
country: United States
facility: Pacific Research Network, LLC
state: California
city: Danbury
country: United States
facility: Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC
state: Connecticut
city: Stamford
country: United States
facility: Ki Health Partners, LLC
state: Connecticut
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Brandon
country: United States
facility: Clinical Research of Brandon, LLC
state: Florida
city: Deerfield Beach
country: United States
facility: Quantum Laboratories
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research Inc
state: Florida
city: Hialeah
country: United States
facility: Indago Research and Health Center, Inc.
state: Florida
city: Jupiter
country: United States
facility: Alphab Global Research
state: Florida
city: Maitland
country: United States
facility: K2 Medical Research
state: Florida
city: Miami
country: United States
facility: Mind Institute at Miami Jewish Health
state: Florida
city: Miami
country: United States
facility: Brainstorm Research
state: Florida
city: Okeechobee
country: United States
facility: Health Synergy Clinical Research
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc. dba CNS Healthcare
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Group - Sarasota
state: Florida
city: Stuart
country: United States
facility: Alzheimer's Research & Treatment Center
state: Florida
city: Stuart
country: United States
facility: Brain Matters Research Inc
state: Florida
city: Tampa
country: United States
facility: USF Health - Byrd Alzheimer's Center and Research Institute
state: Florida
city: Wellington
country: United States
facility: Alzheimer's Research & Treatment Center
state: Florida
city: Winter Park
country: United States
facility: Conquest Research
state: Florida
city: Columbus
country: United States
facility: Columbus Memory Center, PC
state: Georgia
city: Decatur
country: United States
facility: Accel Research Sites - NeuroStudies
state: Georgia
city: Chicago
country: United States
facility: Great Lakes Clinical Trials
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Aurora Health
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Sanders-Brown Center on Aging
state: Kentucky
city: Foxboro
country: United States
facility: Neurology Center of New England
state: Massachusetts
city: Methuen
country: United States
facility: ActivMed Practices & Research, LLC
state: Massachusetts
city: Newton
country: United States
facility: Boston Center for Memory
state: Massachusetts
city: Plymouth
country: United States
facility: Office of Donald S. Marks, M.D., P.C.
state: Massachusetts
city: Waltham
country: United States
facility: MedVadis Research
state: Massachusetts
city: Middletown
country: United States
facility: Patient First MD
state: New Jersey
city: Princeton
country: United States
facility: Global Medical Institutes, LLC
state: New Jersey
city: Springfield
country: United States
facility: The Cognitive and Research Center of New Jersey (CRCNJ)
state: New Jersey
city: Toms River
country: United States
facility: Advanced Memory Research Institute of NJ
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Albany
country: United States
facility: Neurological Associates of Albany
state: New York
city: Brooklyn
country: United States
facility: Integrative Clinical Trials
state: New York
city: Brooklyn
country: United States
facility: SPRI Clinical Trials Brooklyn
state: New York
city: East Syracuse
country: United States
facility: Velocity Clinical Research, Formerly Clarity Clinical Research
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Winston-Salem
country: United States
facility: Accellacare Research of Winston-Salem
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Dayton
country: United States
facility: Neurology Diagnostics
state: Ohio
city: North Canton
country: United States
facility: Neuro-Behavioral Clinical Research (NBCR)
state: Ohio
city: Portland
country: United States
facility: Center for Cognitive Health - Portland
state: Oregon
city: Jenkintown
country: United States
facility: The Clinical Trial Center
state: Pennsylvania
city: Plymouth Meeting
country: United States
facility: Keystone Clinical Studies, LLC
state: Pennsylvania
city: Franklin
country: United States
facility: KCA Neurology, PLLC
state: Tennessee
city: Dallas
country: United States
facility: Neurology Consultants of Dallas, PA
state: Texas
city: Irving
country: United States
facility: Cedar Health Research
state: Texas
city: Bennington
country: United States
facility: The Memory Clinic - Bennington
state: Vermont
city: Bellevue
country: United States
facility: Northwest Clinical Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Kelowna
country: Canada
facility: OCT Research ULC DBA Okanagan Clinical Trials
state: British Columbia
city: Vancouver
country: Canada
facility: Djavad Mowafaghian Centre for Brain Health
state: British Columbia
city: Moncton
country: Canada
facility: Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD)
state: New Brunswick
city: Halifax
country: Canada
facility: True North Clinical Research - Halifax
state: Nova Scotia
city: New Minas
country: Canada
facility: True North Clinical Research - New Minas
state: Nova Scotia
city: London
country: Canada
facility: St. Joseph's Health Care London
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Memory Clinic
state: Ontario
city: Ottawa
country: Canada
facility: Recherches Neuro-Hippocampe Inc.
state: Ontario
city: Peterborough
country: Canada
facility: Kawartha Centre - Redefining Healthy Aging
state: Ontario
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Toronto
country: Canada
facility: The Centre for Memory and Aging
state: Ontario
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
state: Dong-gu
city: Guri-si
country: Korea, Republic of
facility: Hanyang University Guri Hospital
state: Gyeonggi-do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Namdong-gu
country: Korea, Republic of
facility: Gachon University Gil Hospital
state: Incheon
city: Incheon
country: Korea, Republic of
facility: Inha University Medical Center
state: Jung-go
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
state: North Gyeongsang Province
city: Seongbuk-gu
country: Korea, Republic of
facility: Korea University Anam Hospital
state: Seoul
city: Seongdong-gu
country: Korea, Republic of
facility: HanYang University Hospital
state: Seoul
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Songpa-gu
city: Bayamón
country: Puerto Rico
facility: Santa Cruz Behavioral PSC
city: San Juan
country: Puerto Rico
facility: Inspira Clinical Research
city: San Juan
country: Puerto Rico
facility: Barbara Diaz Hernandez Md Research, Inc.
city: San Juan
country: Puerto Rico
facility: Instituto De Neurologia Dra. Ivonne Fraga
Study officials:
affiliation: Cassava Sciences
name: Jim Kupiec, MD
role: STUDY_CHAIR
References: