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

Alzheimer Disease Clinical Trial

— RETHINK-ALZ  

Official title:

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Study Evaluating the Safety and Efficacy of Simufilam 100 mg Tablets in Subjects With Mild-to-Moderate Alzheimer's Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04994483
• Other study ID #: PTI-125-07
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 3, 2021
• Est. completion date: October 2024

Study information

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

Clinical Trial Summary

A 52-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 52 weeks. Approximately 750 participants will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 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 52-week, repeat-dose oral administration in participants with mild-to-moderate AD. Secondary objectives include the assessment of simufilam's effect on neuropsychiatric symptoms and caregiver burden. A third objective is to investigate the effect of simufilam treatment on plasma biomarkers. A limited number of research sites will be invited to participate in the pharmacokinetic (PK) and plasma biomarker sub-study. Collection of PK samples will enable an exposure-response analysis. Approximately 100 subjects will participate (50 per group). Plasma samples will be collected during the Screening Visit and again at Weeks 28 and 52. Change from Baseline for plasma biomarkers represent additional secondary endpoints.

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 magnetic resonance imaging (MRI) during screening to ensure entry criteria are met (unless recent MRI confirms entry criteria). Resting electrocardiograms will be conducted at Baseline (Study Day 1) and Weeks 4, 28, and 52. 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: 750
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• 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 either 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 52 weeks at a dose of 100 mg.
• Placebo
Matching placebo given b.i.d. for 52 weeks.

Locations

Country	Name	City	State
Australia	Eastern Health	Box Hill	Victoria
Australia	Delmont Private Hospital	Glen Iris	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	The University of Queensland	Herston	Queensland
Australia	KaRa MINDS	Macquarie Park	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Australian Alzheimer's Research Foundation	Nedlands	Western Australia
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Impact Health Pty Ltd.	Southport	Queensland
Canada	LMC Clinical Research - London	London	Ontario
Canada	Alpha Recherche Clinique	Québec
Canada	Bluewater Clinical Research Group Inc	Sarnia	Ontario
Canada	Diex Research Sherbrooke Inc.	Sherbrooke	Quebec
Canada	Q & T Research	Sherbrooke	Quebec
United States	Albuquerque Neuroscience, Inc	Albuquerque	New Mexico
United States	Neuro Medical Clinic of Central Louisiana, LLC	Alexandria	Louisiana
United States	Dent Neurologic Institute	Amherst	New York
United States	Advanced Research Center, Inc	Anaheim	California
United States	Topaz Clinical Research	Apopka	Florida
United States	FutureSearch Trials of Neurology	Austin	Texas
United States	Senior Adults Specialty Research, Inc	Austin	Texas
United States	Mountain Neurological Research Center	Basalt	Colorado
United States	Insight Clinical Trials LLC	Beachwood	Ohio
United States	Neurology Offices of South Florida	Boca Raton	Florida
United States	Boynton Beach Medical Research Institute (GMI)	Boynton Beach	Florida
United States	NeuroScience Research Center, LLC	Canton	Ohio
United States	Dayton Center for Neurological Disorders	Centerville	Ohio
United States	MDFirst Research	Chandler	Arizona
United States	Clinical Research Professionals	Chesterfield	Missouri
United States	K2 Medical Research - Clermont	Clermont	Florida
United States	Axiom Research, LLC	Colton	California
United States	ATP Clinical Research, Inc.	Costa Mesa	California
United States	CT Clinical Research	Cromwell	Connecticut
United States	Baylor Scott & White Research Institute	Dallas	Texas
United States	Texas Neurology, PA	Dallas	Texas
United States	Arrow Clinical Trials	Daytona Beach	Florida
United States	Colorado Neurological Research Center, PC	Denver	Colorado
United States	Rhode Island Mood & Memory Research Institute	East Providence	Rhode Island
United States	Re:Cognition Health	Fairfax	Virginia
United States	Neuropsychiatric Research Center of Southwest Florida	Fort Myers	Florida
United States	CCT Research - Gilbert Neurology Partners	Gilbert	Arizona
United States	Triad Clinical Trials, LLC	Greensboro	North Carolina
United States	Velocity Clinical Research, Hallandale Beach	Hallandale Beach	Florida
United States	Galiz Research	Hialeah	Florida
United States	Infinity Clinical Research - Sunrise	Hollywood	Florida
United States	Sun Valley Research Center, Inc.	Imperial	California
United States	CNS Healthcare - Jacksonville	Jacksonville	Florida
United States	Mt. Olympus Medical Research, LLC	Katy	Texas
United States	Charter Research	Lady Lake	Florida
United States	Senior Clinical Trials	Laguna Hills	California
United States	Segal Trials - West Broward Outpatient Site	Lauderhill	Florida
United States	ClinCloud	Maitland	Florida
United States	Brian Abaluck, LLC	Malvern	Pennsylvania
United States	Alzheimer's Memory Center	Matthew	North Carolina
United States	Velocity Clinical Research, Boise	Meridian	Idaho
United States	Merritt Island Medical Research, LLC	Merritt Island	Florida
United States	Central Miami Medical Institute (GMI)	Miami	Florida
United States	Luminous Clinical Research	Miami	Florida
United States	New Horizon Research Center	Miami	Florida
United States	Quantam Clinical Trials	Miami Beach	Florida
United States	South Florida Research Phase I-IV INC	Miami Springs	Florida
United States	Global Medical Institutes/Scranton Medical Institute - Moosic Division	Moosic	Pennsylvania
United States	Parker Jewish Institute for Health Care & Rehabilitation	New Hyde Park	New York
United States	Suncoast Clinical Research, Inc.	New Port Richey	Florida
United States	Mid Hudson Medical Research	New Windsor	New York
United States	NY Neurology Associates	New York	New York
United States	Boston Neuro Research Center	North Dartmouth	Massachusetts
United States	Renstar Medical Research	Ocala	Florida
United States	Charter Research	Orlando	Florida
United States	Combined Research Orlando Phase I-IV	Orlando	Florida
United States	CCT Research - Papillion Research Center	Papillion	Nebraska
United States	Xenoscience, Inc.	Phoenix	Arizona
United States	Progressive Medical Research	Port Orange	Florida
United States	Summit Research Network, LLC	Portland	Oregon
United States	Artemis Institute for Clinical Research	Riverside	California
United States	University of Rochester Medical Center - Alzheimer's Disease Care, Research and Education Program	Rochester	New York
United States	Green Mountain Research Institute, Inc.	Rutland	Vermont
United States	Syrentis Clinical Research	Santa Ana	California
United States	Memory and Brain Wellness Center at Harborview	Seattle	Washington
United States	Palmetto Clinical Research	Summerville	South Carolina
United States	Clinical Research of Brandon, LLC (Tampa)	Tampa	Florida
United States	Stedman Clinical Trials	Tampa	Florida
United States	Advanced Clinical Institute, Inc	West Long Branch	New Jersey
United States	Premier Research Institute at Palm Beach Neurology	West Palm Beach	Florida
United States	Ascension Via Christi Research	Wichita	Kansas
United States	Grayline Research Center	Wichita Falls	Texas
United States	Northwestern Medicine Central DuPage Hospital	Winfield	Illinois
United States	Five Town Neuroscience Research	Woodmere	New York

Sponsors (2)

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

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

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 52 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 52
Primary	Change from baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)	The change from baseline to Week 52 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 52
Secondary	Change from baseline in the integrated Alzheimer's Disease Rating Scale (iADRS)	The change from baseline to Week 52 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance.	Baseline (Study Day 1) to Week 52
Secondary	Change from baseline in the Neuropsychiatric Inventory (NPI)	The change from baseline to Week 52 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 each of the 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 52
Secondary	Change from baseline in the Mini-Mental State Exam (MMSE)	The change from baseline to Week 52 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 52
Secondary	Change from baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)	The change from baseline to Week 52 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 52
Secondary	Change from baseline in the Zarit Burden Interview (ZBI)	The change from baseline to Week 52 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 52
Secondary	Changes from baseline in plasma phospho-tau181 (P-tau181) and/or phospho-tau217 (P-tau217), and neurofilament light chain.	Change from baseline in plasma biomarkers of AD pathology, neurodegeneration, and neuroinflammation.	Baseline (Study Day 1) to Week 52
Secondary	Changes from baseline in the plasma SavaDx biomarker	Change from baseline in SavaDx, a novel plasma biomarker	Baseline (Study Day 1) to Week 52