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

Sponsor
Cassava Sciences, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT05026177
Collaborator
Premier Research Group plc (Industry)
1,083
77
3
30.4
14.1
0.5

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
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

Study Type:
Interventional
Anticipated Enrollment :
1083 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Randomized treatments will be assigned by subject numbers in a randomly generated numeric sequence. Randomization (1:1:1) will be stratified by low or high Mini-Mental State Exam (MMSE; 16-20 and 21-27). The randomization code will not be revealed to study subjects, Investigators, clinical staff, study monitors or the Sponsor until all subjects have completed therapy and the database has been finalized and locked.
Primary Purpose:
Treatment
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
Actual Study Start Date :
Nov 18, 2021
Anticipated Primary Completion Date :
Jun 1, 2024
Anticipated Study Completion Date :
Jun 1, 2024

Arms and Interventions

Arm Intervention/Treatment
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

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:
  • PTI-125
  • 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:
  • PTI-125
  • Outcome Measures

    Primary Outcome Measures

    1. 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).

    2. 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

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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.

    6. 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.

    7. 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.

    8. 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

    9. 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

    10. Change from baseline in plasma biomarker SavaDx [Baseline (Study Day 1) to Week 76]

      SavaDx is a novel plasma biomarker

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years to 87 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    6. The subject has been a non-smoker 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.

    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

    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 > 35.0.

    13. History or diagnosis of clinically significant cardiac disease

    14. Prescribed aducanumab.

    15. 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
    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.
    Responsible Party:
    Cassava Sciences, Inc.
    ClinicalTrials.gov Identifier:
    NCT05026177
    Other Study ID Numbers:
    • PTI-125-06
    First Posted:
    Aug 30, 2021
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 6, 2022