Alzheimer Disease
Conditions
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.
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 76 weeks at a dose of 50 mg or 100 mg.
DRUGPlacebo
Matching placebo given b.i.d. for 76 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 (1:1:1) 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.
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 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 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 for the subject. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 for the subject, as well as the level of study partner distress due to 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 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. Scores range from 0 to 30; lower scores 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. 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 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. Scores range from 0 to 88, with a higher score indicating greater stress or burden. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 Tau Positron Emission Tomography (PET) | Baseline (Study Day 1) to Week 76 | Changes from baseline in tau deposition in the brain |
| Changes From Baseline in Plasma Biomarkers | Baseline (Study Day 1) to Week 76 | Change from baseline in the following plasma biomarkers of AD pathology, neurodegeneration, and neuroinflammation: phospho-tau217 (P-tau217), total tau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). |
| Changes From Baseline in CSF Biomarkers | Baseline (Study Day 1) to Week 76 | Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation: P-tau217, total tau, GFAP, and NfL. |
| Change From Baseline in Plasma Biomarker SavaDx | Baseline (Study Day 1) to Week 76 | Change from baseline in SavaDx, a novel plasma biomarker. |
| Changes From Baseline in Amyloid Positron Emission Tomography (PET) | Baseline (Study Day 1) to Week 76 | Changes from baseline in amyloid deposition in the brain. |
Countries
Canada, Puerto Rico, South Korea, United States
Participant flow
Pre-assignment details
Participation in the study required each subject to have a study partner who also consented to participate for the duration of the subject's participation. Study partners were not considered independent participants. The enrollment number and number of participants detailed below represents the number of subject/study partner dyads.
Participants by arm
| Arm | Count |
|---|---|
| Simufilam 50 mg Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 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 76 weeks at a dose of 50 mg or 100 mg. | 376 |
| Simufilam 100 mg Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 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 76 weeks at a dose of 50 mg or 100 mg. | 374 |
| Placebo Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks
Placebo: Matching placebo given b.i.d. for 76 weeks | 375 |
| Total | 1,125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 33 | 33 | 17 |
| Overall Study | Health issues preventing continuation | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 7 | 6 | 8 |
| Overall Study | Met stopping criteria | 0 | 0 | 1 |
| Overall Study | Noncompliance with study drug | 6 | 2 | 1 |
| Overall Study | Noncompliance with study procedures | 0 | 1 | 1 |
| Overall Study | Physician Decision | 4 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Randomized in error, not treated | 0 | 0 | 2 |
| Overall Study | Sponsor requests subject to be withdrawn | 0 | 0 | 3 |
| Overall Study | Starting alternative treatment | 0 | 1 | 1 |
| Overall Study | Study terminated by sponsor | 70 | 74 | 67 |
| Overall Study | Unavailability/noncompliance of study partner | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 53 | 51 | 55 |
Baseline characteristics
| Characteristic | Simufilam 50 mg | Simufilam 100 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 74.45 years STANDARD_DEVIATION 7.624 | 73.64 years STANDARD_DEVIATION 8.185 | 73.72 years STANDARD_DEVIATION 7.926 | 73.94 years STANDARD_DEVIATION 7.916 |
| Age, Customized 65 to 74 years | 115 Participants | 124 Participants | 131 Participants | 370 Participants |
| Age, Customized <65 years | 47 Participants | 54 Participants | 50 Participants | 151 Participants |
| Age, Customized ≥75 years | 214 Participants | 196 Participants | 194 Participants | 604 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 35 Participants | 20 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 345 Participants | 338 Participants | 350 Participants | 1033 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 21 Participants | 28 Participants | 32 Participants | 81 Participants |
| Race/Ethnicity, Customized Black or African American | 23 Participants | 17 Participants | 21 Participants | 61 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not reported | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 326 Participants | 326 Participants | 313 Participants | 965 Participants |
| Region of Enrollment Canada | 46 participants | 47 participants | 56 participants | 149 participants |
| Region of Enrollment Puerto Rico | 6 participants | 9 participants | 4 participants | 19 participants |
| Region of Enrollment South Korea | 12 participants | 18 participants | 21 participants | 51 participants |
| Region of Enrollment United States | 312 participants | 300 participants | 294 participants | 906 participants |
| Sex: Female, Male Female | 207 Participants | 208 Participants | 214 Participants | 629 Participants |
| Sex: Female, Male Male | 169 Participants | 166 Participants | 161 Participants | 496 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 376 | 2 / 374 | 3 / 373 |
| other Total, other adverse events | 198 / 376 | 184 / 374 | 195 / 373 |
| serious Total, serious adverse events | 61 / 376 | 43 / 374 | 45 / 373 |
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 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).
Time frame: Baseline (Study Day 1) to Week 76
Population: Data are from subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) who completed the assessment. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) | 5.71 score on a scale | Standard Error 0.529 |
| Simufilam 100 mg | Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) | 5.65 score on a scale | Standard Error 0.509 |
| Placebo | Change From Baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) | 5.26 score on a scale | Standard Error 0.506 |
p-value: 0.533595% CI: [-0.96, 1.86]Mixed Models Analysis
p-value: 0.583695% CI: [-0.99, 1.76]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 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 for the subject. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.
Time frame: Baseline (Study Day 1) to Week 76
Population: Data are from subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) whose study partner completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | -7.20 score on a scale | Standard Error 0.646 |
| Simufilam 100 mg | Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | -6.87 score on a scale | Standard Error 0.623 |
| Placebo | Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | -5.63 score on a scale | Standard Error 0.62 |
p-value: 0.076395% CI: [-3.3, 0.17]Mixed Models Analysis
p-value: 0.15395% CI: [-2.93, 0.46]Mixed Models Analysis
Secondary
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. 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 76
Population: Data are from subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) who completed the assessment. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | 1.65 score on a scale | Standard Error 0.186 |
| Simufilam 100 mg | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | 1.76 score on a scale | Standard Error 0.187 |
| Placebo | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | 1.84 score on a scale | Standard Error 0.186 |
Secondary
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.
Time frame: Baseline (Study Day 1) to Week 76
Population: Data are from subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) who completed the assessment. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) | -11.5 score on a scale | Standard Error 0.901 |
| Simufilam 100 mg | Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) | -11.5 score on a scale | Standard Error 0.87 |
| Placebo | Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) | -10.5 score on a scale | Standard Error 0.865 |
Secondary
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. Scores range from 0 to 30; lower scores indicate more severe impairment.
Time frame: Baseline (Study Day 1) to Week 76
Population: Data are from subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) who completed the assessment. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the MMSE | -3.48 score on a scale | Standard Error 0.288 |
| Simufilam 100 mg | Change From Baseline in the MMSE | -3.29 score on a scale | Standard Error 0.277 |
| Placebo | Change From Baseline in the MMSE | -3.35 score on a scale | Standard Error 0.275 |
Secondary
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 for the subject, as well as the level of study partner distress due to 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 76
Population: Data are from subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) whose study partner completed the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the Neuropsychiatric Inventory (NPI) | 1.57 score on a scale | Standard Error 0.574 |
| Simufilam 100 mg | Change From Baseline in the Neuropsychiatric Inventory (NPI) | 1.44 score on a scale | Standard Error 0.556 |
| Placebo | Change From Baseline in the Neuropsychiatric Inventory (NPI) | 0.37 score on a scale | Standard Error 0.551 |
Secondary
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. Scores range from 0 to 88, with a higher score indicating greater stress or burden.
Time frame: Baseline (Study Day 1) to Week 76
Population: Data are from the study partners of subjects in the modified intent-to-treat population (all randomized subjects with baseline plasma P-tau181 ≥44 pg/mL or other evidence of amyloid pathology, e.g., amyloid PET) who completed the assessment. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Change From Baseline in the Zarit Burden Interview (ZBI) | 3.37 score on a scale | Standard Error 0.734 |
| Simufilam 100 mg | Change From Baseline in the Zarit Burden Interview (ZBI) | 4.68 score on a scale | Standard Error 0.711 |
| Placebo | Change From Baseline in the Zarit Burden Interview (ZBI) | 4.40 score on a scale | Standard Error 0.706 |
Other Pre-specified
Change From Baseline in Plasma Biomarker SavaDx
Change from baseline in SavaDx, a novel plasma biomarker.
Time frame: Baseline (Study Day 1) to Week 76
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.
Other Pre-specified
Changes From Baseline in Amyloid Positron Emission Tomography (PET)
Changes from baseline in amyloid deposition in the brain.
Time frame: Baseline (Study Day 1) to Week 76
Population: The overall number of subjects analyzed is the number of subjects who consented to take part in the amyloid PET imaging substudy and for whom there were baseline and Week 76 values. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Changes From Baseline in Amyloid Positron Emission Tomography (PET) | 0.0 µL | Standard Deviation 0.1 |
| Simufilam 100 mg | Changes From Baseline in Amyloid Positron Emission Tomography (PET) | 0.0 µL | Standard Deviation 0.09 |
| Placebo | Changes From Baseline in Amyloid Positron Emission Tomography (PET) | 0.0 µL | Standard Deviation 0.09 |
Other Pre-specified
Changes From Baseline in Brain Volume Via MRI
Changes from baseline in hippocampus, ventricles, and whole brain volume.
Time frame: Baseline (Study Day 1) to Week 76
Population: The overall number of subjects analyzed is the number of subjects who consented to take part in the MRI imaging substudy and for whom there was at least one non-missing post baseline MRI assessment available. MRIs were not conducted in the whole substudy population at Week 76. No data were collected from study partners for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simufilam 50 mg | Changes From Baseline in Brain Volume Via MRI | Ventricular volume | 5459.5 µL | Standard Deviation 4290.67 |
| Simufilam 50 mg | Changes From Baseline in Brain Volume Via MRI | Whole brain volume | -17799.5 µL | Standard Deviation 13360.83 |
| Simufilam 50 mg | Changes From Baseline in Brain Volume Via MRI | Hippocampal volume | -180.7 µL | Standard Deviation 109.82 |
| Simufilam 100 mg | Changes From Baseline in Brain Volume Via MRI | Ventricular volume | 6109.9 µL | Standard Deviation 3766.34 |
| Simufilam 100 mg | Changes From Baseline in Brain Volume Via MRI | Whole brain volume | -19043.6 µL | Standard Deviation 9721.2 |
| Simufilam 100 mg | Changes From Baseline in Brain Volume Via MRI | Hippocampal volume | -192.2 µL | Standard Deviation 110.23 |
| Placebo | Changes From Baseline in Brain Volume Via MRI | Whole brain volume | -17878.6 µL | Standard Deviation 14012.4 |
| Placebo | Changes From Baseline in Brain Volume Via MRI | Hippocampal volume | -186.8 µL | Standard Deviation 114.54 |
| Placebo | Changes From Baseline in Brain Volume Via MRI | Ventricular volume | 6255.1 µL | Standard Deviation 5374.61 |
Other Pre-specified
Changes From Baseline in CSF Biomarkers
Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation: P-tau217, total tau, GFAP, and NfL.
Time frame: Baseline (Study Day 1) to Week 76
Population: The overall number of subjects analyzed is the number of subjects who consented to take part in the CSF biomarker analysis substudy and for whom there were baseline and Week 76 values for each biomarker. CSF samples were not obtained from the whole substudy population at Week 76. No data were collected from study partners for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simufilam 50 mg | Changes From Baseline in CSF Biomarkers | CSF P-Tau 217 | 141.9 pg/mL | Standard Deviation 169.08 |
| Simufilam 50 mg | Changes From Baseline in CSF Biomarkers | CSF Total Tau | 136.7 pg/mL | Standard Deviation 161.1 |
| Simufilam 50 mg | Changes From Baseline in CSF Biomarkers | CSF GFAP | 1939.2 pg/mL | Standard Deviation 2409.36 |
| Simufilam 50 mg | Changes From Baseline in CSF Biomarkers | CSF NfL | 2372.6 pg/mL | Standard Deviation 2494.67 |
| Simufilam 100 mg | Changes From Baseline in CSF Biomarkers | CSF NfL | 1334.9 pg/mL | Standard Deviation 2310.62 |
| Simufilam 100 mg | Changes From Baseline in CSF Biomarkers | CSF P-Tau 217 | 90.5 pg/mL | Standard Deviation 210.38 |
| Simufilam 100 mg | Changes From Baseline in CSF Biomarkers | CSF GFAP | 585.0 pg/mL | Standard Deviation 2062.91 |
| Simufilam 100 mg | Changes From Baseline in CSF Biomarkers | CSF Total Tau | 92.5 pg/mL | Standard Deviation 152.32 |
| Placebo | Changes From Baseline in CSF Biomarkers | CSF NfL | 1535.9 pg/mL | Standard Deviation 3383.45 |
| Placebo | Changes From Baseline in CSF Biomarkers | CSF Total Tau | 28.7 pg/mL | Standard Deviation 140.48 |
| Placebo | Changes From Baseline in CSF Biomarkers | CSF GFAP | 674.8 pg/mL | Standard Deviation 1873.18 |
| Placebo | Changes From Baseline in CSF Biomarkers | CSF P-Tau 217 | 10.8 pg/mL | Standard Deviation 139.2 |
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), total tau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).
Time frame: Baseline (Study Day 1) to Week 76
Population: The overall number of subjects analyzed is the number of subjects who consented to take part in the plasma biomarker analysis substudy and for whom there were baseline and Week 76 values for each biomarker. Plasma samples were not obtained from the whole substudy population at Week 76. No data were collected from study partners for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simufilam 50 mg | Changes From Baseline in Plasma Biomarkers | Plasma GFAP | 636.5 pg/mL | Standard Deviation 1591.37 |
| Simufilam 50 mg | Changes From Baseline in Plasma Biomarkers | Plasma Total Tau | 50.7 pg/mL | Standard Deviation 122.51 |
| Simufilam 50 mg | Changes From Baseline in Plasma Biomarkers | Plasma P-Tau 217 | 43.6 pg/mL | Standard Deviation 121.06 |
| Simufilam 50 mg | Changes From Baseline in Plasma Biomarkers | Plasma NfL | 872.3 pg/mL | Standard Deviation 2023.12 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | Plasma NfL | 321.3 pg/mL | Standard Deviation 1397.74 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | Plasma P-Tau 217 | 4.7 pg/mL | Standard Deviation 15.74 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | Plasma Total Tau | 10.9 pg/mL | Standard Deviation 41.92 |
| Simufilam 100 mg | Changes From Baseline in Plasma Biomarkers | Plasma GFAP | 235.7 pg/mL | Standard Deviation 846.47 |
| Placebo | Changes From Baseline in Plasma Biomarkers | Plasma NfL | 351.4 pg/mL | Standard Deviation 2075.46 |
| Placebo | Changes From Baseline in Plasma Biomarkers | Plasma GFAP | 107.7 pg/mL | Standard Deviation 507.17 |
| Placebo | Changes From Baseline in Plasma Biomarkers | Plasma Total Tau | 7.0 pg/mL | Standard Deviation 39.44 |
| Placebo | Changes From Baseline in Plasma Biomarkers | Plasma P-Tau 217 | 4.0 pg/mL | Standard Deviation 12.36 |
Other Pre-specified
Changes From Baseline in Tau Positron Emission Tomography (PET)
Changes from baseline in tau deposition in the brain
Time frame: Baseline (Study Day 1) to Week 76
Population: The overall number of subjects analyzed is the number of subjects who consented to take part in the tau PET imaging substudy and for whom there were baseline and Week 76 values. No data were collected from study partners for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Simufilam 50 mg | Changes From Baseline in Tau Positron Emission Tomography (PET) | 0.0 µL | Standard Error 0.1 |
| Simufilam 100 mg | Changes From Baseline in Tau Positron Emission Tomography (PET) | 0.0 µL | Standard Error 0.07 |
| Placebo | Changes From Baseline in Tau Positron Emission Tomography (PET) | 0.0 µL | Standard Error 0.1 |