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

Study Overview
=================
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.

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

Conditions
-----------------
Alzheimer Disease

Intervention / Treatment
-----------------
* Drug: Simufilam
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 87 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks | Drug: Placebo<br>* Matching placebo given b.i.d. for 76 weeks<br>|
| Experimental: Simufilam 50 mg<br>Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks | Drug: Simufilam<br>* 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.<br>* Other names: PTI-125;|
| Experimental: Simufilam 100 mg<br>Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks | Drug: Simufilam<br>* 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.<br>* Other names: PTI-125;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation. | Baseline (Study Day 1) to Week 76 | 
| 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 | 
| 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 | 
| 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 | 
| Change from baseline in plasma biomarker SavaDx | SavaDx is a novel plasma biomarker | Baseline (Study Day 1) to Week 76 |