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| ID | Type | Description | Link |
|---|---|---|---|
| R44AG060878 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients.
This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients. A total of sixty (60) patients will be enrolled in the study. Patients will receive Placebo, 50 mg or 100 mg b.i.d. of PTI-125. The objective of this study are to investigate the safety, and biomarkers of PTI-125 following 28-day repeat oral administration.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo Cohort | Placebo Comparator | Subjects administered placebo oral tablets twice daily (BID) |
|
| Simufilam (PTI-125) 100 mg tablets Cohort | Experimental | Subjects administered simufilam (PTI-125) 100 mg oral tablets twice daily (BID) |
|
| Simufilam (PTI-125) 50 mg tablets Cohort | Experimental | Subjects administered simufilam (PTI-125) 50 mg oral tablets twice daily (BID) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo oral tablet | Drug | Oral placebo tablet |
| |
| Simufilam 100 mg tablet |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in CSF Abeta42 | Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid levels of Amyloid beta42 | Screening to Day 28 |
| Change From Baseline in CSF Total Tau. | Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid total tau. | Screening to Day 28 |
| Change From Baseline in CSF P-tau181 | Change from Baseline (screening) to Day 28 in cerebrospinal fluid P-tau181 | Screening to Day 28 |
| Change From Baseline in CSF Neurogranin | Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurogranin | Screening to Day 28 |
| Change From Baseline in CSF Neurofilament Light Chain | Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurofilament light chain | Screening to Day 28 |
| Change From Baseline in CSF YKL-40 | Change from Baseline (screening) in cerebrospinal fluid YKL-40 | Screening to Day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Paired Associates Learning Test | Cognitive test assessing episodic memory. Boxes are displayed on the screen and are "opened" in a randomized order. One or more of them contains a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. The number of boxes increases progressively to a total of 8. |
| Measure | Description | Time Frame |
|---|---|---|
| Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA linkages to these two receptors were assessed by densitometric quantitation of immunoblot bands of each receptor (detected by a specific antibody) in anti-FLNA precipitates. The measure is noted as a ratio to total FLNA. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lindsay Burns, PhD | Cassava Sciences, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cognitive Clinical Trials | Gilbert | Arizona | 85296 | United States | ||
| Cognitive Clinical Trials |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33188449 | Derived | Sever S. Role of actin cytoskeleton in podocytes. Pediatr Nephrol. 2021 Sep;36(9):2607-2614. doi: 10.1007/s00467-020-04812-z. Epub 2020 Nov 13. |
| Label | URL |
|---|---|
| Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Cohort | Subjects administered placebo oral tablets twice daily (BID) |
| FG001 | Simufilam (PTI-125), 100 mg Tablets Cohort | Subjects administered simufilam 100 mg oral tablets twice daily (BID) |
| FG002 | Simufilam (PTI-125), 50 mg Tablets Cohort | Subjects administered simufilam 50 mg oral tablets twice daily (BID) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Placebo Cohort | Subjects administered matching placebo tablets twice daily for 28 days. |
| BG001 | Simufilam (PTI-125), 100 mg Tablets Cohort | Subjects administered 100 mg simufilam tablets twice daily for 28 days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in CSF Abeta42 | Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid levels of Amyloid beta42 | As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | Posted | Mean | Standard Deviation | pg/mL | Screening to Day 28 |
|
28 days
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo Cohort | Subjects administered placebo tablets twice daily (BID) for 28 days. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Medra | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nadav Friedmann, PhD, MD, Chief Medical Officer | Cassava Sciences, Inc. | 512-501-1900 | nfriedmann@cassavasciences.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 28, 2019 | Mar 30, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 12, 2020 | May 6, 2021 | SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 10, 2019 | Mar 30, 2021 | ICF_002.pdf |
Not provided
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C000719508 | Simufilam |
| D013607 | Tablets |
| ID | Term |
|---|---|
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
Not provided
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Approximately sixty (60) patients will be enrolled into the study and randomized to one of three cohorts. Cohorts will receive placebo or PTI-125 at 50 or 100 mg b.i.d. (n=20 per group)
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The sponsor, participant, care provider, investigator including sub-investigators and outcomes assessors will be blinded to throughout the study which includes using an Integrated Web Response System (IWRS) and electronic data capture (EDC) to ensure blinding during the study.
| Drug |
Simufilam 100 mg oral tablet |
|
|
| Simufilam 50 mg oral tablet | Drug | Simufilam 50 mg oral tablet |
|
|
| Day 1 to Day 28 |
| Spatial Working Memory Test | Cognitive assessment of spatial working memory: A number of colored squares (boxes) are shown on the screen. By selecting the boxes and using a process of elimination, the subject should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The number of boxes is gradually increased to a total of 8 for the subjects to search. The colors and positions of the boxes are changed from trial to trial to discourage stereotyped search strategies. | Day 1 to Day 28 |
| CSF IL-6, sTREM2, HMGB1, Albumin, IgG | Change from Baseline (screening sample) to Day 28 in secondary CSF biomarkers of neuroinflammation and blood-brain barrier integrity | Screening to Day 28 |
| Day 1 to Day 28 |
| Plasma P-tau181 | Percent change in plasma P-tau181 | Day 1 to Day 28 |
| Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker | SavaDx is a novel plasma biomarker | Day 1 to Day 28 |
| Surprise |
| Arizona |
| 85374 |
| United States |
| Optimus U | Miami | Florida | 33125 | United States |
| IMIC, Inc. | Palmetto Bay | Florida | 33157 | United States |
| Cognitive Clinical Trials | Bellevue | Nebraska | 68005 | United States |
| Cognitive Clinical Trials | Omaha | Nebraska | 68116 | United States |
| Advanced Memory Research Institute | Toms River | New Jersey | 08755 | United States |
| Centex Studies, Inc. | Houston | Texas | 77058 | United States |
| Centex Studies, Inc. | McAllen | Texas | 78504 | United States |
| BG002 | Simufilam (PTI-125), 50 mg Tablets Cohort | Subjects administered 50 mg simufilam tablets twice daily for 28 days. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| CSF total tau/Aβ42 ratio | Mean | Standard Deviation | ratio |
|
| Mini-Mental State Exam (MMSE) | The MMSE is a is a widely used test of cognitive function among the elderly; it includes tests of orientation, attention, memory, language and visual-spatial skills. It is often used to stage Alzheimer's disease. The scale ranges from 0 to 30. No errors = 30. | Mean | Standard Deviation | units on a scale |
|
| Taking cholinesterase inhibitor or memantine | Count of Participants | Participants |
|
| Heterozygous APOE4 | Count of Participants | Participants |
|
| Homozygous APOE4 | Count of Participants | Participants |
|
| Paired Associates Learning total errors | Boxes are displayed on the screen and are "opened" in a randomized order. One or more of them contains a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. The number of boxes increases progressively to a total of 8. | The least impaired patients (11 or fewer errors, representing a ceiling effect) and patients with 54 or more errors (very poor performance suggesting not understanding the task) were removed from the analysis. Also removed were the 3 patients with no detectable drug in plasma, 2 patients with ≥25% non-compliance by pill counts, one patient with no baseline test and one who did not understand instructions per rater notes. | Mean | Standard Deviation | errors |
|
| Spatial Working Memory total errors | A number of colored squares (boxes) are shown on the screen. By selecting the boxes and using a process of elimination, the subject should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The number of boxes is gradually increased to a total of 8 for the subjects to search. The colors and positions of the boxes are changed from trial to trial to discourage stereotyped search strategies. | Removed from analysis were the 3 patients with no detectable drug in plasma, 2 patients with ≥25% non-compliance by pill counts, one patient with no baseline test and one who did not understand instructions per rater notes | Mean | Standard Deviation | errors |
|
| CSF Aβ42 | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF total tau | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF P-tau181 | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF neurogranin | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF Neurofilament Light Chain | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF YKL-40 | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF IL-6 | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF sTREM2 | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF HMGB1 | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | pg/mL |
|
| CSF/plasma albumin ratio | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | ratio |
|
| CSF/plasma IgG ratio | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | ratio |
|
| Lymphocyte filamin A - α7nAChR, Ratio to total filamin A | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | ratio |
|
| Lymphocyte filamin A - TLR4, Ratio to total filamin A | One subject is missing a CSF sample. Three others had no detectable simufilam in plasma and were excluded from analyses. | Mean | Standard Deviation | ratio |
|
simufilam 100 mg tablets BID for 28 days
| OG002 | Simufilam (PTI-125), 50 mg Tablets Cohort | simufilam 50 mg tablets BID for 28 days |
|
|
|
| Primary | Change From Baseline in CSF Total Tau. | Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid total tau. | As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | Posted | Mean | Standard Deviation | pg/mL | Screening to Day 28 |
|
|
|
|
| Primary | Change From Baseline in CSF P-tau181 | Change from Baseline (screening) to Day 28 in cerebrospinal fluid P-tau181 | As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | Posted | Mean | Standard Deviation | pg/mL | Screening to Day 28 |
|
|
|
|
| Primary | Change From Baseline in CSF Neurogranin | Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurogranin | As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | Posted | Mean | Standard Deviation | pg/mL | Screening to Day 28 |
|
|
|
|
| Primary | Change From Baseline in CSF Neurofilament Light Chain | Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurofilament light chain | As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | Posted | Mean | Standard Deviation | pg/mL | Screening to Day 28 |
|
|
|
|
| Primary | Change From Baseline in CSF YKL-40 | Change from Baseline (screening) in cerebrospinal fluid YKL-40 | As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | Posted | Mean | Standard Deviation | pg/mL | Screening to Day 28 |
|
|
|
|
| Secondary | Paired Associates Learning Test | Cognitive test assessing episodic memory. Boxes are displayed on the screen and are "opened" in a randomized order. One or more of them contains a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. The number of boxes increases progressively to a total of 8. | The least impaired patients (11 or fewer errors, representing a ceiling effect) and patients with 54 or more errors (very poor performance suggesting not understanding the task) were removed from the analysis. Also removed were the 3 patients with no detectable drug in plasma, 2 patients with ≥25% non-compliance by pill counts, one patient with no baseline test and one who did not understand instructions per rater notes. | Posted | Mean | Standard Deviation | Change from Day 1 in total errors | Day 1 to Day 28 |
|
|
|
|
| Secondary | Spatial Working Memory Test | Cognitive assessment of spatial working memory: A number of colored squares (boxes) are shown on the screen. By selecting the boxes and using a process of elimination, the subject should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The number of boxes is gradually increased to a total of 8 for the subjects to search. The colors and positions of the boxes are changed from trial to trial to discourage stereotyped search strategies. | Removed from analysis were the 3 patients with no detectable drug in plasma, 2 patients with ≥25% non-compliance by pill counts, one patient with no baseline test and one who did not understand instructions per rater notes. | Posted | Mean | Standard Deviation | Change from Day 1 in total errors | Day 1 to Day 28 |
|
|
|
|
| Secondary | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | Change from Baseline (screening sample) to Day 28 in secondary CSF biomarkers of neuroinflammation and blood-brain barrier integrity | Three subjects who had no detectable simufilam in plasma at return visits were removed from analyses (two in the 100 mg arm and one in the 50 mg arm). As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. | Posted | Mean | Standard Deviation | pg/mL; optical density for albumin & IgG | Screening to Day 28 |
|
|
|
|
| Other Pre-specified | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA linkages to these two receptors were assessed by densitometric quantitation of immunoblot bands of each receptor (detected by a specific antibody) in anti-FLNA precipitates. The measure is noted as a ratio to total FLNA. | Three subjects who had no detectable simufilam in plasma at any return visit were removed from analyses (two in the 100 mg arm and one in the 50 mg arm). As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. Two additional subjects in the 50 mg arm were missing Day 1 blood samples. | Posted | Mean | Standard Deviation | ratio to total FLNA | Day 1 to Day 28 |
|
|
|
|
| Other Pre-specified | Plasma P-tau181 | Percent change in plasma P-tau181 | For plasma p-tau181 only: 4 subjects (1 in placebo, 2 in 50 mg and 1 in 100 mg arms) were removed because Coefficients of Variation (CVs) between duplicate measurements for either Day 1 or Day 28 samples were >15% on repeat assay (both Day 1 & Day 28 for a subject were repeated if CVs of either Day 1 or Day 28 were >11%). Two outliers were removed (1 in placebo [1.2 to 4.8 pg/ml] and 1 in 100 mg [2.1 to 5.1 pg/ml] arms) for increases >150% & > 2.5 pg/mL. Missing Day 1 blood samples: 2 in 50 mg. | Posted | Mean | Standard Deviation | Percent change | Day 1 to Day 28 |
|
|
|
|
| Other Pre-specified | Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker | SavaDx is a novel plasma biomarker | One subject in the 50 mg arm and two subjects in the 100 mg arm were omitted because these subjects showed no detectable plasma simufilam at any return visit. Two additional subjects in the 50 mg group were missing baseline plasma samples. | Posted | Mean | Standard Deviation | Percent change | Day 1 to Day 28 |
|
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 12 |
| 22 |
| EG001 | Simufilam (PTI-125), 100 mg Tablets Cohort | Subjects administered simufilam 100 mg tablets twice daily (BID) for 28 days. | 0 | 21 | 0 | 21 | 9 | 21 |
| EG002 | Simufilam (PTI-125), 50 mg Tablets Cohort | Subjects administered simufilam 50 mg tablets twice daily (BID) for 28 days. | 0 | 21 | 0 | 21 | 4 | 21 |
| Fatigue | Metabolism and nutrition disorders | Medra | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Medra | Systematic Assessment |
|
| Any adverse event | General disorders | Medra | Systematic Assessment |
|
Not provided
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
In a secondary analysis removing two subjects with no detectable simufilam in plasma, P<0.0001 and CFB was -19.8. |
| This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0012 | P value adjusted for multiplicity of 6 co-primary endpoints (p<0.008 required for significance). | Superiority | In a secondary analysis removing one subject with no detectable simufilam in plasma, P=0.001 and CFB was -14.9. |
In a secondary analysis removing two subjects with no detectable simufilam in plasma, P=0.003 and CFB was -3.2. |
| This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.002 | P value adjusted for multiplicity of 6 co-primary endpoints (p<0.008 required for significance). | Superiority | In a secondary analysis removing one subject with no detectable simufilam in plasma, P=0.003 and CFB was -2.5. |
In a secondary analysis removing two subjects with no detectable simufilam in plasma, P=0.0002 and CFB was -681. |
| This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0005 | P value adjusted for multiplicity of 6 co-primary endpoints (p<0.008 required for significance). | Superiority | In a secondary analysis removing one subject with no detectable simufilam in plasma, P=0.0005 and CFB was -527. |
In a secondary analysis removing two subjects with no detectable simufilam in plasma, P=0.0002 and CFB was -78.5. |
| This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0058 | P value adjusted for multiplicity of 6 co-primary endpoints (p<0.008 required for significance). | Superiority | In a secondary analysis removing one subject with no detectable simufilam in plasma, P=0.0008 and CFB was -51.0. |
In a secondary analysis removing two subjects with no detectable simufilam in plasma, P=0.0001 and CFB was -23.7. |
| This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan). | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0001 | P value adjusted for multiplicity of 6 co-primary endpoints (p<0.008 required for significance). | Superiority | In a secondary analysis removing one subject with no detectable simufilam in plasma, P=0.0002 and CFB was -20.9. |
This study was not powered for statistical significance on cognitive measures. |
| Effect size |
| 0.37 |
| 2-Sided |
Reported effect size vs. placebo was calculated with Hedge's g (for groups of 20 or fewer) but was identical when calculated by Cohen's d. |
| Other |
This study was not powered for statistical significance on cognitive measures. |
| Effect size |
| 0.25 |
| 2-Sided |
Reported effect size vs. placebo was calculated with Hedge's g (for groups of 20 or fewer) but was identical when calculated by Cohen's d. |
| Other |
|
| CSF HMGB1 |
|
| CSF albumin |
|
| CSF IgG |
|
This analysis is for IL-6. |
| ANCOVA |
General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. |
| 0.019 |
Secondary CSF biomarkers were not adjusted for multiplicity. |
| Superiority |
| This analysis is for sTREM2. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0002 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for sTREM2. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0007 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for HMGB1. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0001 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for HMGB1. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0001 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for albumin. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.0001 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for albumin. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.046 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for Immunoglobulin G. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.012 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
| This analysis is for Immunoglobulin G. | ANCOVA | General Linear Model for the analysis of covariance (ANCOVA) with a two-sided 95% confidence interval and baseline measurement as the covariate. | 0.014 | Secondary CSF biomarkers were not adjusted for multiplicity. | Superiority |
|
| Change from baseline in FLNA linkage to alpha7nAChR in subject lymphocytes. FLNA linkage to alpha7nAChR was expressed as ratios of densitometric units of immunoblot bands of alpha7nAChR (probed with a specific antibody) to densitometric units of total FLNA. | ANOVA | ANOVA was used instead of ANCOVA due to the range in baseline values; it was deemed more appropriate to compare to each subject's own baseline value. | 0.009 | As secondary endpoints, lymphocyte biomarkers were not adjusted for multiplicity. | Superiority |
| Change from baseline in FLNA linkage to TLR4 in subject lymphocytes. FLNA linkage to TLR4 was expressed as the ratio of densitometric units of immunoblot bands of TLR4 (probed with a specific antibody) to densitometric units of total FLNA. | ANOVA | ANOVA was used instead of ANCOVA due to the range in baseline values; it was deemed more appropriate to compare to each subject's own baseline value. | 0.01 | As secondary endpoints, lymphocyte biomarkers were not adjusted for multiplicity. | Superiority |
| Change from baseline in FLNA linkage to TLR4 in subject lymphocytes. FLNA linkage to TLR4 was expressed as the ratio of densitometric units of immunoblot bands of TLR4 (probed with a specific antibody) to densitometric units of total FLNA. | ANOVA | ANOVA was used instead of ANCOVA due to the range in baseline values; it was deemed more appropriate to compare to each subject's own baseline value. | 0.01 | As secondary endpoints, lymphocyte biomarkers were not adjusted for multiplicity. | Superiority |
| 0.02 |
| Superiority |
| ANOVA | This p value is for the main effect of treatment of the ANOVA. | 0.009 | Superiority |
| Superiority |