REFOCUS-ALZ: Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 3 |
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 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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Placebo Comparator: Placebo Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks |
Drug: Placebo
Matching placebo given b.i.d. for 76 weeks
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Experimental: Simufilam 50 mg Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks |
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 Aβ42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.
Other Names:
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Experimental: Simufilam 100 mg Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks |
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 Aβ42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.
Other Names:
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Outcome Measures
Primary Outcome Measures
- 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
- 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 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 sores 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.
- 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), 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.
- 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 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
Eligibility Criteria
Criteria
Key Inclusion Criteria:
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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.
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Evidence for AD pathophysiology, confirmed prior to or during screening
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MMSE score ≥ 16 and ≤ 27 at screening.
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Clinical Dementia Rating - Global Score must be 0.5, 1 or 2.
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If receiving background AD medications, the dosing regimen must be stable for at least 12 weeks prior to randomization.
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The subject has been a non-smoker for at least 3 years.
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Availability of a study partner
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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.
Key Exclusion Criteria:
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A neurologic condition other than AD that significantly contributes to the subject's dementia.
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Any current primary psychiatric diagnosis other than AD if it is likely to confound cognitive assessment or ability to comply with study procedures
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Geriatric Depression Scale (15-item) score > 8
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Suicidal ideation during the past 3 months or suicidal behavior during the past 12 months
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Alcohol or substance use disorder within 2 years of screening
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MRI presence of cerebral vascular or other significant pathology
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History of transient ischemic attack or stroke within 12 months of screening
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Seizure within 12 months of screening.
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Severe head trauma or head trauma considered likely to be contributing to the subject's cognitive impairment.
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Sleep apnea that is considered likely to be contributing to the subject's cognitive impairment.
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Insufficiently controlled diabetes mellitus or hypertension
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Body mass index < 18.5 or > 35.0.
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History or diagnosis of clinically significant cardiac disease
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Prescribed aducanumab.
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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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Banner Alzheimer's Institute | Phoenix | Arizona | United States | 85006 |
2 | Arizona Neuroscience Research, LLC | Phoenix | Arizona | United States | 85032 |
3 | Clinical Endpoints | Scottsdale | Arizona | United States | 85258 |
4 | Banner Sun Health Research Institute | Sun City | Arizona | United States | 85351 |
5 | Banner Alzheimer's Institute - Tucson | Tucson | Arizona | United States | 85718 |
6 | North County Neurology Associates | Carlsbad | California | United States | 92011 |
7 | Neuro-Pain Medical Center | Fresno | California | United States | 93710 |
8 | Neurology Center of North Orange County | Fullerton | California | United States | 92835 |
9 | California Research Insitute | Los Angeles | California | United States | 90027 |
10 | Shankle Clinic and Hoag Memorial Hospital Presbyterian | Newport Beach | California | United States | 92663 |
11 | Pacific Research Network, LLC | San Diego | California | United States | 92103 |
12 | University of California - San Francisco: Memory and Aging Center | San Francisco | California | United States | 94158 |
13 | Nuvance Health Medical Practice CT, Inc. - Associated Neurologists, PC | Danbury | Connecticut | United States | 06810 |
14 | Ki Health Partners, LLC | Stamford | Connecticut | United States | 06905 |
15 | JEM Research Institute | Atlantis | Florida | United States | 33462 |
16 | Parkinson's Disease and Movement Disorders Center of Boca Raton | Boca Raton | Florida | United States | 33486 |
17 | Clinical Research of Brandon, LLC | Brandon | Florida | United States | 33511 |
18 | Brain Matters Research Inc | Delray Beach | Florida | United States | 33445 |
19 | Indago Research and Health Center, Inc. | Hialeah | Florida | United States | 33012 |
20 | Mind Institute at Miami Jewish Health | Miami | Florida | United States | 33137 |
21 | Brainstorm Research | Miami | Florida | United States | 33176 |
22 | Health Synergy Clinical Research | Okeechobee | Florida | United States | 34972 |
23 | Medical Research Group of Central Florida | Orange City | Florida | United States | 32763 |
24 | Clinical Neuroscience Solutions, Inc. dba CNS Healthcare | Orlando | Florida | United States | 32801 |
25 | Quantum Laboratories | Pompano Beach | Florida | United States | 33064 |
26 | Intercoastal Medical Group - Sarasota | Sarasota | Florida | United States | 34239 |
27 | Alzheimer's Research & Treatment Center | Stuart | Florida | United States | 34997 |
28 | Brain Matters Research Inc | Stuart | Florida | United States | 34997 |
29 | USF Health - Byrd Alzheimer's Center and Research Institute | Tampa | Florida | United States | 33613 |
30 | Alzheimer's Research & Treatment Center | Wellington | Florida | United States | 33414 |
31 | Conquest Research | Winter Park | Florida | United States | 32789 |
32 | Columbus Memory Center, PC | Columbus | Georgia | United States | 31909 |
33 | Accel Research Sites - NeuroStudies | Decatur | Georgia | United States | 30030 |
34 | Great Lakes Clinical Trials | Chicago | Illinois | United States | 60640 |
35 | Advocate Aurora Health | Park Ridge | Illinois | United States | 60068 |
36 | University of Kentucky Sanders-Brown Center on Aging | Lexington | Kentucky | United States | 40504 |
37 | ActivMed Practices & Research, LLC | Methuen | Massachusetts | United States | 01844 |
38 | Boston Center for Memory | Newton | Massachusetts | United States | 02459 |
39 | Office of Donald S. Marks, M.D., P.C. | Plymouth | Massachusetts | United States | 02360 |
40 | MedVadis Research | Waltham | Massachusetts | United States | 02451 |
41 | Global Medical Institutes, LLC | Princeton | New Jersey | United States | 08540 |
42 | The Cognitive and Research Center of New Jersey (CRCNJ) | Springfield | New Jersey | United States | 07081 |
43 | Advanced Memory Research Institute of NJ | Toms River | New Jersey | United States | 08755 |
44 | Neurology Specialists of Monmouth County | West Long Branch | New Jersey | United States | 07764 |
45 | Albany Medical Center | Albany | New York | United States | 12208 |
46 | Neurological Associates of Albany | Albany | New York | United States | 12208 |
47 | Michael I Weintraub, MD, PC | Briarcliff Manor | New York | United States | 10510 |
48 | Integrative Clinical Trials | Brooklyn | New York | United States | 11229 |
49 | SPRI Clinical Trials Brooklyn | Brooklyn | New York | United States | 11235 |
50 | Clarity Clinical Research | East Syracuse | New York | United States | 13057 |
51 | Richmond Behavioral Associates | Staten Island | New York | United States | 10312 |
52 | Accellacare Research of Winston-Salem | Winston-Salem | North Carolina | United States | 27103 |
53 | Ohio State University | Columbus | Ohio | United States | 43210 |
54 | Neurology Diagnostics | Dayton | Ohio | United States | 45459 |
55 | Neuro-Behavioral Clinical Research (NBCR) | North Canton | Ohio | United States | 44720 |
56 | Center for Cognitive Health - Portland | Portland | Oregon | United States | 97225 |
57 | The Clinical Trial Center | Jenkintown | Pennsylvania | United States | 19046 |
58 | Keystone Clinical Studies, LLC | Plymouth Meeting | Pennsylvania | United States | 19462 |
59 | KCA Neurology, PLLC | Franklin | Tennessee | United States | 37067 |
60 | Neurology Consultants of Dallas, PA | Dallas | Texas | United States | 75243 |
61 | The Memory Clinic - Bennington | Bennington | Vermont | United States | 05201 |
62 | Northwest Clinical Research Center | Bellevue | Washington | United States | 98007 |
63 | Medical College of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
64 | OCT Research ULC DBA Okanagan Clinical Trials | Kelowna | British Columbia | Canada | V1Y 2Z9 |
65 | Centre Hospitalier Universitaire Dr-Georges-L.-Dumont (CHUDGLD) | Moncton | New Brunswick | Canada | E1C 2Z3 |
66 | True North Clinical Research - Halifax | Halifax | Nova Scotia | Canada | B3S 1N2 |
67 | True North Clinical Research - New Minas | New Minas | Nova Scotia | Canada | B4N 3R7 |
68 | The Centre for Memory and Aging | Toronto | Ontariop | Canada | |
69 | St. Joseph's Health Care London | London | Ontario | Canada | N6C 0A7 |
70 | Ottawa Memory Clinic | Ottawa | Ontario | Canada | K1Z 1G3 |
71 | Kawartha Centre - Redefining Healthy Aging | Peterborough | Ontario | Canada | K9H2P4 |
72 | Toronto Memory Program | Toronto | Ontario | Canada | M3B 2S7 |
73 | Recherches Neuro-Hippocampe Inc. | Gatineau | Quebec | Canada | J8T 8J1 |
74 | Santa Cruz Behavioral PSC | Bayamón | Puerto Rico | 00961 | |
75 | Inspira Clinical Research | San Juan | Puerto Rico | 00918 | |
76 | Barbara Diaz Hernandez Md Research, Inc. | San Juan | Puerto Rico | 00926 | |
77 | Instituto De Neurologia Dra. Ivonne Fraga | San Juan | Puerto Rico |
Sponsors and Collaborators
- Cassava Sciences, Inc.
- Premier Research Group plc
Investigators
- Study Chair: Jim Kupiec, MD, Cassava Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PTI-125-06