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

Alzheimer Disease Clinical Trial

— REFOCUS-ALZ  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05026177
• Other study ID #: PTI-125-06
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 18, 2021
• Est. completion date: May 2025

Study information

• Verified date: January 2024
• Source: Cassava Sciences, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 1083
• Est. completion date: May 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 87 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• Simufilam
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 Aß42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.
• Placebo
Matching placebo given b.i.d. for 76 weeks

Locations

Country	Name	City	State
Canada	Recherches Neuro-Hippocampe Inc.	Gatineau	Quebec
Canada	True North Clinical Research - Halifax	Halifax	Nova Scotia
Canada	OCT Research ULC DBA Okanagan Clinical Trials	Kelowna	British Columbia
Canada	St. Joseph's Health Care London	London	Ontario
Canada	Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD)	Moncton	New Brunswick
Canada	True North Clinical Research - New Minas	New Minas	Nova Scotia
Canada	Ottawa Memory Clinic	Ottawa	Ontario
Canada	Kawartha Centre - Redefining Healthy Aging	Peterborough	Ontario
Canada	The Centre for Memory and Aging	Toronto	Ontario
Canada	Toronto Memory Program	Toronto	Ontario
Canada	Djavad Mowafaghian Centre for Brain Health	Vancouver	British Columbia
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu	North Gyeongsang Province
Korea, Republic of	Hanyang University Guri Hospital	Guri-si	Gyeonggi-do
Korea, Republic of	Chonnam National University Hospital	Gwangju	Dong-gu
Korea, Republic of	Inha University Medical Center	Incheon	Jung-go
Korea, Republic of	Gachon University Gil Hospital	Namdong-gu	Incheon
Korea, Republic of	Korea University Anam Hospital	Seongbuk-gu	Seoul
Korea, Republic of	HanYang University Hospital	Seongdong-gu	Seoul
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul	Songpa-gu
Puerto Rico	Santa Cruz Behavioral PSC	Bayamón
Puerto Rico	Barbara Diaz Hernandez Md Research, Inc.	San Juan
Puerto Rico	Inspira Clinical Research	San Juan
Puerto Rico	Instituto De Neurologia Dra. Ivonne Fraga	San Juan
United States	Albany Medical Center	Albany	New York
United States	Neurological Associates of Albany	Albany	New York
United States	JEM Research Institute	Atlantis	Florida
United States	Northwest Clinical Research Center	Bellevue	Washington
United States	The Memory Clinic - Bennington	Bennington	Vermont
United States	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida
United States	Clinical Research of Brandon, LLC	Brandon	Florida
United States	Integrative Clinical Trials	Brooklyn	New York
United States	SPRI Clinical Trials Brooklyn	Brooklyn	New York
United States	North County Neurology Associates	Carlsbad	California
United States	Great Lakes Clinical Trials	Chicago	Illinois
United States	Columbus Memory Center, PC	Columbus	Georgia
United States	Ohio State University	Columbus	Ohio
United States	Neurology Consultants of Dallas, PA	Dallas	Texas
United States	Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC	Danbury	Connecticut
United States	Neurology Diagnostics	Dayton	Ohio
United States	Accel Research Sites - NeuroStudies	Decatur	Georgia
United States	Brain Matters Research Inc	Delray Beach	Florida
United States	Velocity Clinical Research, Formerly Clarity Clinical Research	East Syracuse	New York
United States	Neurology Center of New England	Foxboro	Massachusetts
United States	KCA Neurology, PLLC	Franklin	Tennessee
United States	Neuro-Pain Medical Center	Fresno	California
United States	Neurology Center of North Orange County	Fullerton	California
United States	Indago Research and Health Center, Inc.	Hialeah	Florida
United States	Cedar Health Research	Irving	Texas
United States	The Clinical Trial Center	Jenkintown	Pennsylvania
United States	Alphab Global Research	Jupiter	Florida
United States	University of Kentucky Sanders-Brown Center on Aging	Lexington	Kentucky
United States	Healthy Brain Clinic	Long Beach	California
United States	California Research Insitute	Los Angeles	California
United States	K2 Medical Research	Maitland	Florida
United States	ActivMed Practices & Research, LLC	Methuen	Massachusetts
United States	Brainstorm Research	Miami	Florida
United States	Mind Institute at Miami Jewish Health	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Shankle Clinic and Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Boston Center for Memory	Newton	Massachusetts
United States	Neuro-Behavioral Clinical Research (NBCR)	North Canton	Ohio
United States	Health Synergy Clinical Research	Okeechobee	Florida
United States	Clinical Neuroscience Solutions, Inc. dba CNS Healthcare	Orlando	Florida
United States	Advocate Aurora Health	Park Ridge	Illinois
United States	Arizona Neuroscience Research, LLC	Phoenix	Arizona
United States	Banner Alzheimer's Institute	Phoenix	Arizona
United States	Office of Donald S. Marks, M.D., P.C.	Plymouth	Massachusetts
United States	Keystone Clinical Studies, LLC	Plymouth Meeting	Pennsylvania
United States	Quantum Laboratories	Pompano Beach	Florida
United States	Center for Cognitive Health - Portland	Portland	Oregon
United States	Global Medical Institutes, LLC	Princeton	New Jersey
United States	Pacific Research Network, LLC	San Diego	California
United States	Intercoastal Medical Group - Sarasota	Sarasota	Florida
United States	Clinical Endpoints	Scottsdale	Arizona
United States	The Cognitive and Research Center of New Jersey (CRCNJ)	Springfield	New Jersey
United States	Ki Health Partners, LLC	Stamford	Connecticut
United States	Richmond Behavioral Associates	Staten Island	New York
United States	Alzheimer's Research & Treatment Center	Stuart	Florida
United States	Brain Matters Research Inc	Stuart	Florida
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	USF Health - Byrd Alzheimer's Center and Research Institute	Tampa	Florida
United States	Advanced Memory Research Institute of NJ	Toms River	New Jersey
United States	Banner Alzheimer's Institute - Tucson	Tucson	Arizona
United States	MedVadis Research	Waltham	Massachusetts
United States	Alzheimer's Research & Treatment Center	Wellington	Florida
United States	Neurology Specialists of Monmouth County	West Long Branch	New Jersey
United States	Accellacare Research of Winston-Salem	Winston-Salem	North Carolina
United States	Conquest Research	Winter Park	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Cassava Sciences, Inc.	Premier Research Group plc

Countries where clinical trial is conducted

United States,  Canada,  Korea, Republic of,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Baseline (Study Day 1) to Week 76
Primary	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. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.	Baseline (Study Day 1) to Week 76
Secondary	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.	Baseline (Study Day 1) to Week 76
Secondary	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, 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.	Baseline (Study Day 1) to Week 76
Secondary	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. Lower scores indicate more severe impairment.	Baseline (Study Day 1) to Week 76
Secondary	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. Higher scores indicate more severe impairment.	Baseline (Study Day 1) to Week 76
Secondary	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, with a higher score indicating greater stress or burden.	Baseline (Study Day 1) to Week 76
Secondary	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 Aß42	Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation.	Baseline (Study Day 1) to Week 76
Secondary	Changes from baseline in brain volume via MRI	Changes from baseline in hippocampus, ventricles, and whole brain volume.	Baseline (Study Day 1) to Week 76
Secondary	Changes from baseline in amyloid and tau PET	Changes from baseline in amyloid and tau deposition in the brain	Baseline (Study Day 1) to Week 76
Secondary	Changes from baseline in plasma biomarkers P-tau181, P-tau217, and neurofilament light chain	Change from baseline in plasma biomarkers of AD pathology and neurodegeneration	Baseline (Study Day 1) to Week 76
Secondary	Change from baseline in plasma biomarker SavaDx	SavaDx is a novel plasma biomarker	Baseline (Study Day 1) to Week 76