Alzheimer Disease
Conditions
Brief 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.
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 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.
Interventions
DRUGSimufilam
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 52 weeks at a dose of 100 mg.
DRUGPlacebo
Matching placebo given b.i.d. for 52 weeks.
Sponsors
Premier Research
Cassava Sciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomized treatments will be assigned by subject numbers in a randomly generated numeric sequence. Randomization (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.
Intervention model description
Approximately 750 patients will be enrolled into the study. All patients will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks.
Eligibility
Sex/Gender
ALL
Age
50 Years to 87 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | Baseline (Study Day 1) to Week 52 | 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. |
| Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) | Baseline (Study Day 1) to Week 52 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Neuropsychiatric Inventory (NPI) | Baseline (Study Day 1) to Week 52 | 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. |
| Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | Baseline (Study Day 1) to Week 52 | 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. Scores for each domain have a minimum of 0 and a maximum of 3, and the 6 domain scores are summed to give the CDR-SB, which has a minimum score of 0 and a maximum score of 18. Higher scores indicate more severe impairment. |
| Change From Baseline in the Zarit Burden Interview (ZBI) | Baseline (Study Day 1) to Week 52 | 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. Scores range from 0 to 88, with a higher score indicating greater stress or burden. |
| Change From Baseline in the Mini-Mental State Exam (MMSE) | Baseline (Study Day 1) to Week 52 | 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. Scores range from 0 to 30, lower scores indicate more severe impairment. |
| Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) | Baseline (Study Day 1) to Week 52 | The change from baseline to Week 52 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline in Plasma Biomarkers | Baseline (Study Day 1) to Week 52 | Change from baseline in the following plasma biomarkers of AD pathology, neurodegeneration, and neuroinflammation: phospho-tau217 (P-tau217), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and total tau. |
| Changes From Baseline in the Plasma SavaDx Biomarker | Baseline (Study Day 1) to Week 52 | Change from baseline in SavaDx, a novel plasma biomarker |
Countries
Australia, Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simufilam 100 mg Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 52 weeks
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 52 weeks at a dose of 100 mg. | 403 |
| Placebo Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 52 weeks
Placebo: Matching placebo given b.i.d. for 52 weeks. | 401 |
| Total | 804 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 26 | 17 |
| Overall Study | Lack of a reliable study partner | 0 | 1 |
| Overall Study | Lost to Follow-up | 6 | 10 |
| Overall Study | Met MRI exclusion criteria | 0 | 1 |
| Overall Study | Met stopping criteria | 1 | 0 |
| Overall Study | Noncompliance with study drug | 8 | 5 |
| Overall Study | Physician Decision | 5 | 0 |
| Overall Study | Randomized in error, not treated | 4 | 3 |
| Overall Study | Sponsor requests subject to be withdrawn | 2 | 1 |
| Overall Study | Withdrawal by Subject | 41 | 38 |
Baseline characteristics
| Characteristic | Simufilam 100 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 73.72 years STANDARD_DEVIATION 7.911 | 74.31 years STANDARD_DEVIATION 7.555 | 74.02 years STANDARD_DEVIATION 7.737 |
| Age, Customized 65 to 74 years | 126 Participants | 133 Participants | 259 Participants |
| Age, Customized <65 years | 62 Participants | 47 Participants | 109 Participants |
| Age, Customized ≥75 years | 215 Participants | 221 Participants | 436 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 62 Participants | 51 Participants | 113 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 334 Participants | 341 Participants | 675 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 9 Participants | 16 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 8 Participants | 2 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants | 18 Participants | 38 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 366 Participants | 376 Participants | 742 Participants |
| Region of Enrollment Australia | 36 participants | 25 participants | 61 participants |
| Region of Enrollment Canada | 31 participants | 21 participants | 52 participants |
| Region of Enrollment United States | 336 participants | 355 participants | 691 participants |
| Sex: Female, Male Female | 225 Participants | 222 Participants | 447 Participants |
| Sex: Female, Male Male | 178 Participants | 179 Participants | 357 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 399 | 3 / 398 |
| other Total, other adverse events | 161 / 399 | 140 / 398 |
| serious Total, serious adverse events | 52 / 399 | 36 / 398 |
Outcome results
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).
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) | 2.79 score on a scale | Standard Error 0.363 |
| Placebo | Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) | 3.19 score on a scale | Standard Error 0.359 |
p-value: 0.430895% CI: [-1.37, 0.59]Mixed Models Analysis
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.
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | -3.26 score on a scale | Standard Error 0.442 |
| Placebo | Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | -3.76 score on a scale | Standard Error 0.438 |
p-value: 0.403495% CI: [-0.68, 1.7]Mixed Models Analysis
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. Scores for each domain have a minimum of 0 and a maximum of 3, and the 6 domain scores are summed to give the CDR-SB, which has a minimum score of 0 and a maximum score of 18. Higher scores indicate more severe impairment.
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | 1.04 score on a scale | Standard Error 0.138 |
| Placebo | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | 0.85 score on a scale | Standard Error 0.136 |
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.
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) | -5.53 score on a scale | Standard Error 0.605 |
| Placebo | Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) | -6.49 score on a scale | Standard Error 0.598 |
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. Scores range from 0 to 30, lower scores indicate more severe impairment.
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the Mini-Mental State Exam (MMSE) | -1.95 score on a scale | Standard Error 0.223 |
| Placebo | Change From Baseline in the Mini-Mental State Exam (MMSE) | -2.14 score on a scale | Standard Error 0.221 |
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.
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the Neuropsychiatric Inventory (NPI) | 0.54 score on a scale | Standard Error 0.588 |
| Placebo | Change From Baseline in the Neuropsychiatric Inventory (NPI) | 0.90 score on a scale | Standard Error 0.579 |
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. Scores range from 0 to 88, with a higher score indicating greater stress or burden.
Time frame: Baseline (Study Day 1) to Week 52
Population: Data are from subjects in the Intent-to-treat population (all randomized subjects) who completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 100 mg | Change From Baseline in the Zarit Burden Interview (ZBI) | 2.52 score on a scale | Standard Error 0.556 |
| Placebo | Change From Baseline in the Zarit Burden Interview (ZBI) | 2.30 score on a scale | Standard Error 0.551 |
Other Pre-specified
Changes From Baseline in Plasma Biomarkers
Change from baseline in the following plasma biomarkers of AD pathology, neurodegeneration, and neuroinflammation: phospho-tau217 (P-tau217), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and total tau.
Time frame: Baseline (Study Day 1) to Week 52
Population: The overall number of participants analyzed is the number of participants who consented to take part in the biomarker analysis substudy and for whom there were baseline values for each biomarker. Plasma samples were not obtained from the whole substudy population at Week 52.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | P-tau217 | 1.0 pg/mL | Standard Deviation 6.56 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | GFAP | 2.0 pg/mL | Standard Deviation 57.39 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | NfL | 69.3 pg/mL | Standard Deviation 373.43 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | Total tau | 5.5 pg/mL | Standard Deviation 35.62 |
| Placebo | Changes From Baseline in Plasma Biomarkers | Total tau | -2.2 pg/mL | Standard Deviation 41.98 |
| Placebo | Changes From Baseline in Plasma Biomarkers | P-tau217 | -0.4 pg/mL | Standard Deviation 9.77 |
| Placebo | Changes From Baseline in Plasma Biomarkers | NfL | 17.5 pg/mL | Standard Deviation 96.73 |
| Placebo | Changes From Baseline in Plasma Biomarkers | GFAP | 40.2 pg/mL | Standard Deviation 255.14 |
Other Pre-specified
Changes From Baseline in the Plasma SavaDx Biomarker
Change from baseline in SavaDx, a novel plasma biomarker
Time frame: Baseline (Study Day 1) to Week 52
Population: Change from baseline in SavaDx, a novel plasma biomarker, was included in the protocol as part of the secondary analysis as a biomarker which may have been measured. The final SAP, which postdated the protocol, included the analysis of biomarkers as an exploratory/tertiary endpoint. However, analysis of SavaDx was not conducted due to a sponsor decision and therefore, no results are available.