Early Alzheimer's Disease
Conditions
Brief summary
This study is being conducted to evaluate the safety and efficacy of ALZ-801 in Early Alzheimer's disease (AD) subjects with the APOE4/4 genotype. This is a double-blind, randomized trial with one dose of ALZ-801 compared to placebo.
Detailed description
This is a multi-center, double-blind study that will evaluate 265 mg twice daily (BID) of ALZ-801, an oral tablet, over 78 weeks as a treatment for subjects (50-80 years old) with Early AD who are homozygous for the ε4 allele of the apolipoprotein gene (APOE4 homozygous or APOE4/4). The primary efficacy outcome assessment is a measure of cognition (ADAS-cog 13). Additional measures of global and functional impairments will also be assessed. Imaging and soluble biomarkers of AD and neurodegeneration will be measured and a sub-study to evaluate cerebrospinal fluid (CSF) biomarkers is also included.
Interventions
ALZ-801 tablet 265 mg once daily in the evening for the first 2 weeks, then ALZ-801 tablet 265 mg BID
Placebo tablet BID
Sponsors
National Institute on Aging (NIA)
Alzheon Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a multi-center Phase 3, randomized, double-blind, placebo-controlled, parallel-group study.
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of MCI or Mild Dementia due to AD consistent with the National Institute on Aging-Alzheimer's Association (NIA-AA) Working Group Criteria. * Homozygous for the ε4 allele of the apolipoprotein E gene (APOE4/4). * MMSE score at Screening of 22 to 30 (inclusive). * CDR - Global score of 0.5 or 1 and CDR Memory Box Score of ≥ 0.5. * RBANS delayed memory index score ≤ 85. * Evidence of progressive memory loss over the last 12 months per investigator assessment
Exclusion criteria
* Brain magnetic resonance imaging (MRI) indicative of significant abnormality per central reader, other than AD related atrophy. Computed tomography (CT) scan acceptable for subjects who cannot undergo MRI. * Diagnosis of neurodegenerative disorder other than AD. * Diagnosis of major depressive disorder (MDD) within one year prior to screening. * Currently taking memantine or has taken memantine within 12 weeks prior to the Baseline Visit. * History of suicidal behavior within one year prior to screening or has ongoing suicidal ideation. * History of seizures, excluding febrile seizures of childhood or a single distant seizure (\> 5 years). * Medically confirmed history of recent cerebral infarct or transient ischemic attack within one year prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Cognitive Efficacy Endpoint (ADAS-Cog13) | Baseline to Week 78 | Change from baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-Cog13) scores. The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. |
| Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Entire study: approximately 82 weeks. (first dose of study drug until end of Safety Follow-up Visit at 28 +/- 7 days after the last dose (ie, 78-week treatment period plus 4-weeks follow-up after last dose up to total of 82 weeks) | Safety and tolerability as measured by incidence, nature and severity of treatment emergent adverse events (TEAE), serious TEAEs, and TEAEs leading to withdrawal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Endpoint (A-IADL-W) | Baseline to Week 78 | Change from baseline in Amsterdam - Instrumental Activities of Daily Living scores calculated using the weighted average method (A-IADL-W score). The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at detecting deficits in complex functions at the early stages of AD. Instrumental ADL can be described as the activities necessary to function independently in society. These activities include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday tasks, determined by multiple cognitive processes and controlled processing. They can be distinguished from basic ADL, which include basic self-care skills. The A-IADL-W has a score range of 0-100 and is calculated as follows: (sum of all scores / number of questions scored) × 25. For A-IADL-W, higher scores indicates worse functioning or more impairment. |
| Key Secondary Endpoint (CDR-SB) | Baseline to Week 78 | Change from baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) scores. CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. |
| Functional Assessment (DAD) | Baseline to Week 78 | Change from baseline in Disability Assessment for Dementia (DAD)scores. The DAD consists of 40 items with a score range of 0-100 to evaluate the basic and instrumental activities of daily living of subjects with dementia. It is administered through an interview with the caregiver. Higher DAD scores indicate less disability or better function. |
| Global Cognition Assessment (MMSE) | Baseline to Week 78 | Change from baseline in Mini-Mental State Examination (MMSE) score. The MMSE is a measure of global cognition that is widely used for clinical staging of Alzheimer's Disease. It consists of 11 domains items for a score range of 0-30 to assess general cognitive function. Higher score on MMSE means better cognitive skills. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Imaging Biomarker Endpoint - DTI in White Matter Mean Diffusivity (Bilateral Fornix) | Baseline to Week 78 | Change from baseline in Bilateral Fornix White Matter Mean Diffusivity as measured by Diffusion Tensor Imaging - Magnetic Resonance Imaging (DTI-MRI). The mean diffusivity (MD) is the average of the three main diffusion values (eigenvalues) obtained from the diffusion tensor imaging (DTI). It is expressed as mm2/s. This unit quantifies the average rate of water diffusion across all directions within a tissue, providing an overall measure of tissue microstructural properties. Lower MD value suggests better maintenance of microstructural integrity of a given brain tissue. Positive treatment effects of ALZ-801 on DTI would present as lower mean diffusivity compared with the placebo group. |
| Imaging Biomarker Endpoint - White Matter Fractional Anisotropy (Bilateral Fornix) | Baseline to Week 78 | Change from baseline in Bilateral Fornix White Matter Fractional Anisotropy as measured by Diffusion Tensor Imaging - Magnetic Resonance Imaging (DTI-MRI). Fractional anisotropy (FA) is a unitless, scalar value that measures the degree of anisotropic (directional) water diffusion within a voxel, ranging from 0 to 1. A value of 0 indicates perfectly isotropic (equal in all directions) diffusion, while a value of 1 indicates perfectly anisotropic (directional) diffusion. Higher FA value suggests better maintenance of microstructural integrity of a given brain tissue. Positive treatment effects of ALZ-801 on DTI would present as higher FA in the ALZ-801 group compared with the placebo group. |
| Cognitive Efficacy Endpoint (ADAS-Cog 13) - MCI Subgroup | Baseline to Week 78 | Change from baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-cog 13) scores at 78 weeks. The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. |
| Cognitive Efficacy Endpoint (ADAS-Cog 13) - Mild Alzheimer's Disease(Mild AD) Subgroup | Baseline to Week 78 | Change from baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-cog 13) scores at 78 weeks. The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. |
| A-IADL-W - MCI Subgroup | Baseline to Week 78 | Change from baseline in Amsterdam - Instrumental Activities of Daily Living scores calculated using the weighted average method (A-IADL-W score). The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at detecting deficits in complex functions at the early stages of AD. Instrumental ADL can be described as the activities necessary to function independently in society. These activities include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday tasks, determined by multiple cognitive processes and controlled processing. They can be distinguished from basic ADL, which include basic self-care skills. The A-IADL-W has a score range of 0-100 and is calculated as follows: (sum of all scores / number of questions scored) × 25. For A-IADL-W, higher scores indicates worse functioning or more impairment. |
| A-IADL-W - Mild AD Subgroup | Baseline to Week 78 | Change from baseline in Amsterdam - Instrumental Activities of Daily Living scores calculated using the weighted average method (A-IADL-W score). The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at detecting deficits in complex functions at the early stages of AD. Instrumental ADL can be described as the activities necessary to function independently in society. These activities include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday tasks, determined by multiple cognitive processes and controlled processing. They can be distinguished from basic ADL, which include basic self-care skills. The A-IADL-W has a score range of 0-100 and is calculated as follows: (sum of all scores / number of questions scored) × 25. For A-IADL-W, higher scores indicates worse functioning or more impairment. |
| CDR-SB - MCI Subgroup | Baseline to Week 78 | Change from baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) scores. CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. |
| CDR-SB - Mild AD Subgroup | Baseline to Week 78 | Change from baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) scores. CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. |
| Functional Assessment (DAD) - MCI Subgroup | Baseline to Week 78 | Change from baseline in Disability Assessment for Dementia (DAD)scores. The DAD consists of 40 items with a score range of 0-100 to evaluate the basic and instrumental activities of daily living of subjects with dementia. It is administered through an interview with the caregiver. Higher DAD scores indicate less disability or better function. |
| Functional Assessment (DAD) - Mild AD Subgroup | Baseline to Week 78 | Change from baseline in Disability Assessment for Dementia (DAD)scores. The DAD consists of 40 items with a score range of 0-100 to evaluate the basic and instrumental activities of daily living of subjects with dementia. It is administered through an interview with the caregiver. Higher DAD scores indicate less disability or better function. |
| Global Cognition Assessment (MMSE) - MCI Subgroup | Baseline to Week 78 | Change from baseline in Mini-Mental State Examination (MMSE) score. The MMSE is a measure of global cognition that is widely used for clinical staging of Alzheimer's Disease. It consists of 11 domains items for a score range of 0-30 to assess general cognitive function. Higher score on MMSE means better cognitive skills. |
| Imaging Biomarker Endpoint (Hippocampal Volume) | Baseline to Week 78 | Change from baseline in total (bilateral) hippocampal volume (HV) (uL) as measured by Magnetic Resonance Imaging (MRI). HV atrophy is an early event in AD patients, especially in APOE4/4 homozygotes who show accelerated atrophy compared to APOE3/3 patients with Early AD. HV may be a marker of synaptic loss and neurodegeneration. |
| Hippocampal Volume (MCI Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) hippocampal volume (HV) (uL) as measured by Magnetic Resonance Imaging (MRI). HV atrophy is an early event in AD patients, especially in APOE4/4 homozygotes who show accelerated atrophy compared to APOE3/3 patients with Early AD. HV may be a marker of synaptic loss and neurodegeneration. |
| Hippocampal Volume (Mild AD Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) hippocampal volume (HV) (uL) as measured by Magnetic Resonance Imaging (MRI). HV atrophy is an early event in AD patients, especially in APOE4/4 homozygotes who show accelerated atrophy compared to APOE3/3 patients with Early AD. HV may be a marker of synaptic loss and neurodegeneration. |
| Cortical Thickness (Whole Cortex) (MCI Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. |
| Cortical Thickness (Whole Cortex) (Mild AD Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. |
| Cortical Thickness (Mayo Index) (MCI Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. The Mayo Index refers specifically to the measurement of cortical thickness in the medial temporal lobe versus the whole cortex. |
| Cortical Thickness (Mayo Index) (Mild AD Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. The Mayo Index refers specifically to the measurement of cortical thickness in the medial temporal lobe versus the whole cortex. |
| Whole Brain Volume (MCI Subgroup) | Baseline to Week 78 | Change from baseline in whole brain volume (uL) as measured by Magnetic Resonance Imaging (MRI). |
| Whole Brain Volume (Mild AD Subgroup) | Baseline to Week 78 | Change from baseline in whole brain volume (uL) as measured by Magnetic Resonance Imaging (MRI). |
| Ventricular Volume (MCI Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) ventricular volume (uL) as measured by Magnetic Resonance Imaging (MRI). |
| Ventricular Volume (Mild AD Subgroup) | Baseline to Week 78 | Change from baseline in total (bilateral) ventricular volume (uL) as measured by Magnetic Resonance Imaging (MRI). |
| Global Cognition Assessment (MMSE) - Mild AD Subgroup | Baseline to Week 78 | Change from baseline in Mini-Mental State Examination (MMSE) score. The MMSE is a measure of global cognition that is widely used for clinical staging of Alzheimer's Disease. It consists of 11 domains items for a score range of 0-30 to assess general cognitive function. Higher score on MMSE means better cognitive skills. |
| Imaging Biomarker Endpoint (Cortical Thickness [Whole Cortex]) | Baseline to Week 78 | Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. |
| Imaging Biomarker Endpoint (Cortical Thickness [Mayo Index]) | Baseline to Week 78 | Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. The Mayo Index refers specifically to the measurement of cortical thickness in the medial temporal lobe. |
| Imaging Biomarker Endpoint (Whole Brain Volume) | Baseline to Week 78 | Change from baseline in whole brain volume (uL) as measured by Magnetic Resonance Imaging (MRI). |
| Imaging Biomarker Endpoint (Ventricular Volume) | Baseline to Week 78 | Change from baseline in total (bilateral) ventricular volume (uL) as measured by Magnetic Resonance Imaging (MRI). |
| Imaging Biomarker Endpoint - DTI in Grey Matter Mean Diffusivity - Bilateral Caudate | Baseline to Week 78 | Change from baseline in Grey Matter Mean Diffusivity (Bilateral Caudate) as measured by Diffusion Tensor Imaging - Magnetic Resonance Imaging (DTI-MRI). The mean diffusivity (MD) is the average of the three main diffusion values (eigenvalues) obtained from the diffusion tensor imaging (DTI). It is expressed as mm2/s. This unit quantifies the average rate of water diffusion across all directions within a tissue, providing an overall measure of tissue microstructural properties. Lower MD value suggests better maintenance of microstructural integrity of a given brain tissue. Positive treatment effects of ALZ-801 on DTI would present as lower mean diffusivity compared with the placebo group. |
Countries
Canada, Czechia, France, Germany, Iceland, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects in the placebo treatment arm will receive placebo tablets BID throughout the study
Placebo Comparator: Placebo: Placebo tablet BID | 162 |
| ALZ-801 ALZ-801 265 mg BID tablet orally. Subjects will receive placebo in the morning and one table of ALZ-801 265mg tablet in the evening during the first two weeks of the study; thereafter, they will receive a 265mg tablet BID.
Experimental: ALZ-801: ALZ-801 tablet 265 mg BID | 163 |
| Total | 325 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 11 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | not otherwise specified | 2 | 3 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 11 |
Baseline characteristics
| Characteristic | Placebo | Total | ALZ-801 |
|---|---|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 5.93 | 68.5 years STANDARD_DEVIATION 6.14 | 68.4 years STANDARD_DEVIATION 6.36 |
| Age, Customized 50 to <=65 | 46 Participants | 95 Participants | 49 Participants |
| Age, Customized >65 to 80 | 116 Participants | 230 Participants | 114 Participants |
| Alzheimer's Diagnosis based on MMSE Mild Alzheimer's Disease (Mild AD) MMSE 22-26 | 102 Participants | 198 Participants | 96 Participants |
| Alzheimer's Diagnosis based on MMSE Mild cognitive impairment (MCI) MMSE 27-30 | 60 Participants | 127 Participants | 67 Participants |
| Baseline Clinical Outcomes Assessments (Safety Population) ADAS-Cog13 | 24.31 units on a scale STANDARD_DEVIATION 8.86 | 23.93 units on a scale STANDARD_DEVIATION 8.56 | 23.554 units on a scale STANDARD_DEVIATION 8.26 |
| Baseline Clinical Outcomes Assessments (Safety Population) A-IADL-W | 17.46 units on a scale STANDARD_DEVIATION 20.65 | 16.73 units on a scale STANDARD_DEVIATION 19.55 | 16.00 units on a scale STANDARD_DEVIATION 18.42 |
| Baseline Clinical Outcomes Assessments (Safety Population) CDR-SB | 2.97 units on a scale STANDARD_DEVIATION 1.45 | 3.00 units on a scale STANDARD_DEVIATION 1.49 | 3.04 units on a scale STANDARD_DEVIATION 1.53 |
| Baseline Clinical Outcomes Assessments (Safety Population) DAD | 93.0 units on a scale STANDARD_DEVIATION 10.34 | 93.2 units on a scale STANDARD_DEVIATION 10.13 | 93.3 units on a scale STANDARD_DEVIATION 9.94 |
| Baseline Clinical Outcomes Assessments (Safety Population) MMSE | 25.1 units on a scale STANDARD_DEVIATION 2.7 | 25.3 units on a scale STANDARD_DEVIATION 2.7 | 25.5 units on a scale STANDARD_DEVIATION 2.7 |
| Concomitant AChEI No | 100 Participants | 209 Participants | 109 Participants |
| Concomitant AChEI Yes | 62 Participants | 116 Participants | 54 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 13 Participants | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 14 Participants | 25 Participants | 11 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 7 Participants | 12 Participants | 5 Participants |
| Race/Ethnicity, Customized Multiple Races | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 141 Participants | 288 Participants | 147 Participants |
| Race/Ethnicity, Customized Race Not Reported/Missing | 9 Participants | 18 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 145 Participants | 289 Participants | 144 Participants |
| Sex: Female, Male Female | 82 Participants | 167 Participants | 85 Participants |
| Sex: Female, Male Male | 80 Participants | 158 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 162 | 0 / 163 |
| other Total, other adverse events | 94 / 162 | 104 / 163 |
| serious Total, serious adverse events | 13 / 162 | 15 / 163 |
Outcome results
Primary
Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE)
Safety and tolerability as measured by incidence, nature and severity of treatment emergent adverse events (TEAE), serious TEAEs, and TEAEs leading to withdrawal.
Time frame: Entire study: approximately 82 weeks. (first dose of study drug until end of Safety Follow-up Visit at 28 +/- 7 days after the last dose (ie, 78-week treatment period plus 4-weeks follow-up after last dose up to total of 82 weeks)
Population: Safety Population: subjects who took at least 1 dose of any study drug are included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | TEAE | 137 Participants |
| Placebo | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Study drug related TEAE | 44 Participants |
| Placebo | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Serious TEAE | 13 Participants |
| Placebo | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Serious study drug related TEAE | 0 Participants |
| Placebo | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | TEAE leading to discontinuation of study drug | 4 Participants |
| Placebo | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Study drug related TEAE leading to study drug discontinuation | 1 Participants |
| ALZ-801 | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | TEAE leading to discontinuation of study drug | 13 Participants |
| ALZ-801 | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | TEAE | 140 Participants |
| ALZ-801 | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Serious study drug related TEAE | 1 Participants |
| ALZ-801 | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Study drug related TEAE | 75 Participants |
| ALZ-801 | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Study drug related TEAE leading to study drug discontinuation | 10 Participants |
| ALZ-801 | Incidence, Nature, and Severity of Treatment Emergent Adverse Events (TEAE) | Serious TEAE | 14 Participants |
Primary
Primary Cognitive Efficacy Endpoint (ADAS-Cog13)
Change from baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-Cog13) scores. The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 78
Population: Full Analysis Set (FAS): The FAS includes all study subjects who received at least one dose of the study drug, had at least one baseline assessment and any post baseline efficacy assessment. All primary and secondary clinical efficacy analyses are conducted on this population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Primary Cognitive Efficacy Endpoint (ADAS-Cog13) | 4.40 Score on a scale | Standard Error 0.69 |
| ALZ-801 | Primary Cognitive Efficacy Endpoint (ADAS-Cog13) | 3.89 Score on a scale | Standard Error 0.69 |
Comparison: The null hypothesis was change from baseline (CBL) of ADAS-Cog13 in the ALZ-801 arm was not different from the placebo arm. The alternative hypothesis was that the CBL of ADAS-Cog13 in ALZ-801 arm was different.~A Mixed-Effect Model Repeated Measure (MMRM) model was used with fixed terms for treatment, gender, age group, disease severity based on baseline MMSE (≤ 26 vs. \> 26), concomitant AD medications, visit, and treatment by visit interaction and baseline ADAS-Cog 13 values as covariates.p-value: 0.6058MMRM
Secondary
Functional Assessment (DAD)
Change from baseline in Disability Assessment for Dementia (DAD)scores. The DAD consists of 40 items with a score range of 0-100 to evaluate the basic and instrumental activities of daily living of subjects with dementia. It is administered through an interview with the caregiver. Higher DAD scores indicate less disability or better function.
Time frame: Baseline to Week 78
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Functional Assessment (DAD) | -9.2 score on a scale | Standard Error 1.7 |
| ALZ-801 | Functional Assessment (DAD) | -6.5 score on a scale | Standard Error 1.7 |
Comparison: The same MMRM method applied to the primary efficacy endpoint was used to evaluate the between-treatment difference for the additional secondary endpoints. The hypothesis testing was done without control for type I errors due to multiple comparisons, and the p-value was considered nominal.p-value: 0.2763MMRM
Secondary
Global Cognition Assessment (MMSE)
Change from baseline in Mini-Mental State Examination (MMSE) score. The MMSE is a measure of global cognition that is widely used for clinical staging of Alzheimer's Disease. It consists of 11 domains items for a score range of 0-30 to assess general cognitive function. Higher score on MMSE means better cognitive skills.
Time frame: Baseline to Week 78
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Global Cognition Assessment (MMSE) | -2.03 score on a scale | Standard Error 0.33 |
| ALZ-801 | Global Cognition Assessment (MMSE) | -1.60 score on a scale | Standard Error 0.33 |
Comparison: The same MMRM method applied to the primary efficacy endpoint was used to evaluate the between-treatment difference for the additional secondary endpoints. The hypothesis testing was done without control for type I errors due to multiple comparisons, and the p-value was considered nominal.p-value: 0.4484MMRM
Secondary
Key Secondary Endpoint (A-IADL-W)
Change from baseline in Amsterdam - Instrumental Activities of Daily Living scores calculated using the weighted average method (A-IADL-W score). The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at detecting deficits in complex functions at the early stages of AD. Instrumental ADL can be described as the activities necessary to function independently in society. These activities include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday tasks, determined by multiple cognitive processes and controlled processing. They can be distinguished from basic ADL, which include basic self-care skills. The A-IADL-W has a score range of 0-100 and is calculated as follows: (sum of all scores / number of questions scored) × 25. For A-IADL-W, higher scores indicates worse functioning or more impairment.
Time frame: Baseline to Week 78
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Key Secondary Endpoint (A-IADL-W) | 13.59 score on a scale | Standard Error 2.02 |
| ALZ-801 | Key Secondary Endpoint (A-IADL-W) | 13.60 score on a scale | Standard Error 2 |
Comparison: The A-IADL-W is one of 2 key secondary endpoints. The key secondary efficacy endpoints were to be compared only after the comparison of the primary endpoint has reached statistical significance. Because the primary endpoint did not reach statistical significance, the comparisons for the key secondary endpoints are descriptive only.~The same MMRM method applied to the primary efficacy endpoint was used to evaluate the between-treatment difference for the key secondary endpoints.p-value: 0.9966MMRM
Secondary
Key Secondary Endpoint (CDR-SB)
Change from baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) scores. CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 78
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Key Secondary Endpoint (CDR-SB) | 1.36 score on a scale | Standard Error 0.21 |
| ALZ-801 | Key Secondary Endpoint (CDR-SB) | 1.05 score on a scale | Standard Error 0.22 |
Comparison: The CDR-SB is one of 2 key secondary endpoints. The key secondary efficacy endpoints were to be compared only after the comparison of the primary endpoint has reached statistical significance. Because the primary endpoint did not reach statistical significance, the comparisons for the key secondary endpoints are descriptive only.~The same MMRM method applied to the primary efficacy endpoint was used to evaluate the between-treatment difference for the key secondary endpoints.p-value: 0.309MMRM
Other Pre-specified
A-IADL-W - MCI Subgroup
Change from baseline in Amsterdam - Instrumental Activities of Daily Living scores calculated using the weighted average method (A-IADL-W score). The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at detecting deficits in complex functions at the early stages of AD. Instrumental ADL can be described as the activities necessary to function independently in society. These activities include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday tasks, determined by multiple cognitive processes and controlled processing. They can be distinguished from basic ADL, which include basic self-care skills. The A-IADL-W has a score range of 0-100 and is calculated as follows: (sum of all scores / number of questions scored) × 25. For A-IADL-W, higher scores indicates worse functioning or more impairment.
Time frame: Baseline to Week 78
Population: FAS MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | A-IADL-W - MCI Subgroup | 4.84 score on a scale | Standard Error 2.45 |
| ALZ-801 | A-IADL-W - MCI Subgroup | 1.43 score on a scale | Standard Error 2.5 |
p-value: 0.2682MMRM
Other Pre-specified
A-IADL-W - Mild AD Subgroup
Change from baseline in Amsterdam - Instrumental Activities of Daily Living scores calculated using the weighted average method (A-IADL-W score). The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at detecting deficits in complex functions at the early stages of AD. Instrumental ADL can be described as the activities necessary to function independently in society. These activities include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday tasks, determined by multiple cognitive processes and controlled processing. They can be distinguished from basic ADL, which include basic self-care skills. The A-IADL-W has a score range of 0-100 and is calculated as follows: (sum of all scores / number of questions scored) × 25. For A-IADL-W, higher scores indicates worse functioning or more impairment.
Time frame: Baseline to Week 78
Population: FAS Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | A-IADL-W - Mild AD Subgroup | 18.55 score on a scale | Standard Error 2.21 |
| ALZ-801 | A-IADL-W - Mild AD Subgroup | 22.20 score on a scale | Standard Error 2.21 |
p-value: 0.2178MMRM
Other Pre-specified
CDR-SB - MCI Subgroup
Change from baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) scores. CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 78
Population: FAS MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CDR-SB - MCI Subgroup | 0.63 score on a scale | Standard Error 0.26 |
| ALZ-801 | CDR-SB - MCI Subgroup | -0.02 score on a scale | Standard Error 0.27 |
p-value: 0.0533MMRM
Other Pre-specified
CDR-SB - Mild AD Subgroup
Change from baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) scores. CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 78
Population: FAS Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CDR-SB - Mild AD Subgroup | 1.84 score on a scale | Standard Error 0.23 |
| ALZ-801 | CDR-SB - Mild AD Subgroup | 1.97 score on a scale | Standard Error 0.24 |
p-value: 0.6854MMRM
Post Hoc
Cerebellar Volume
Change from baseline in total (bilateral) cerebellar volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cerebellar Volume | -577.0 microliters | Standard Error 62.5 |
| ALZ-801 | Cerebellar Volume | -427.2 microliters | Standard Error 64.7 |
Comparison: Analysis of the volumetric MRI outcomes were performed using the same MMRM approach described for analysis of the primary clinical endpoint. The MMRM model included treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 years or \> 65 years), gender, disease severity based on baseline MMSE, baseline volumetric MRI value, visit, and treatment by visit interaction. The MRI magnet strength (1.5 or 3 Tesla) was also included as a covariate in the model.p-value: 0.0966MMRM
Post Hoc
Cerebellar Volume (MCI Subgroup)
Change from baseline in total (bilateral) cerebellar volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cerebellar Volume (MCI Subgroup) | -566.8 microliters | Standard Error 91.78 |
| ALZ-801 | Cerebellar Volume (MCI Subgroup) | -428.8 microliters | Standard Error 94.09 |
p-value: 0.22MMRM
Post Hoc
Cerebellar Volume (Mild AD Subgroup)
Change from baseline in total (bilateral) cerebellar volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cerebellar Volume (Mild AD Subgroup) | -583.6 microliters | Standard Error 68.62 |
| ALZ-801 | Cerebellar Volume (Mild AD Subgroup) | -426.2 microliters | Standard Error 75.18 |
p-value: 0.1005MMRM
Other Pre-specified
Cognitive Efficacy Endpoint (ADAS-Cog 13) - MCI Subgroup
Change from baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-cog 13) scores at 78 weeks. The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 78
Population: FAS MCI subgroup: all study subjects in the MCI subgroup who received at least one dose of the study drug, had at least one baseline assessment and any post baseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cognitive Efficacy Endpoint (ADAS-Cog 13) - MCI Subgroup | 4.10 Score on a scale | Standard Error 0.81 |
| ALZ-801 | Cognitive Efficacy Endpoint (ADAS-Cog 13) - MCI Subgroup | 1.97 Score on a scale | Standard Error 0.83 |
p-value: 0.0416MMRM
Other Pre-specified
Cognitive Efficacy Endpoint (ADAS-Cog 13) - Mild Alzheimer's Disease(Mild AD) Subgroup
Change from baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-cog 13) scores at 78 weeks. The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 78
Population: FAS Mild AD subgroup: all study subjects in the Mild AD subgroup who received at least one dose of the study drug, had at least one baseline assessment and any post baseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cognitive Efficacy Endpoint (ADAS-Cog 13) - Mild Alzheimer's Disease(Mild AD) Subgroup | 4.79 score on a scale | Standard Error 0.75 |
| ALZ-801 | Cognitive Efficacy Endpoint (ADAS-Cog 13) - Mild Alzheimer's Disease(Mild AD) Subgroup | 5.66 score on a scale | Standard Error 0.75 |
p-value: 0.3945MMRM
Other Pre-specified
Cortical Thickness (Mayo Index) (MCI Subgroup)
Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. The Mayo Index refers specifically to the measurement of cortical thickness in the medial temporal lobe versus the whole cortex.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cortical Thickness (Mayo Index) (MCI Subgroup) | -0.117 mm | Standard Error 0.007 |
| ALZ-801 | Cortical Thickness (Mayo Index) (MCI Subgroup) | -0.084 mm | Standard Error 0.007 |
p-value: 0.0002MMRM
Other Pre-specified
Cortical Thickness (Mayo Index) (Mild AD Subgroup)
Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. The Mayo Index refers specifically to the measurement of cortical thickness in the medial temporal lobe versus the whole cortex.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cortical Thickness (Mayo Index) (Mild AD Subgroup) | -0.123 mm | Standard Error 0.006 |
| ALZ-801 | Cortical Thickness (Mayo Index) (Mild AD Subgroup) | -0.109 mm | Standard Error 0.006 |
p-value: 0.0699MMRM
Other Pre-specified
Cortical Thickness (Whole Cortex) (MCI Subgroup)
Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cortical Thickness (Whole Cortex) (MCI Subgroup) | -0.059 mm | Standard Error 0.004 |
| ALZ-801 | Cortical Thickness (Whole Cortex) (MCI Subgroup) | -0.038 mm | Standard Error 0.004 |
p-value: <0.0001MMRM
Other Pre-specified
Cortical Thickness (Whole Cortex) (Mild AD Subgroup)
Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cortical Thickness (Whole Cortex) (Mild AD Subgroup) | -0.061 mm | Standard Error 0.003 |
| ALZ-801 | Cortical Thickness (Whole Cortex) (Mild AD Subgroup) | -0.054 mm | Standard Error 0.003 |
p-value: 0.0985MMRM
Other Pre-specified
Functional Assessment (DAD) - MCI Subgroup
Change from baseline in Disability Assessment for Dementia (DAD)scores. The DAD consists of 40 items with a score range of 0-100 to evaluate the basic and instrumental activities of daily living of subjects with dementia. It is administered through an interview with the caregiver. Higher DAD scores indicate less disability or better function.
Time frame: Baseline to Week 78
Population: FAS MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Functional Assessment (DAD) - MCI Subgroup | -6.3 score on a scale | Standard Error 1.9 |
| ALZ-801 | Functional Assessment (DAD) - MCI Subgroup | -0.2 score on a scale | Standard Error 2 |
p-value: 0.0161MMRM
Other Pre-specified
Functional Assessment (DAD) - Mild AD Subgroup
Change from baseline in Disability Assessment for Dementia (DAD)scores. The DAD consists of 40 items with a score range of 0-100 to evaluate the basic and instrumental activities of daily living of subjects with dementia. It is administered through an interview with the caregiver. Higher DAD scores indicate less disability or better function.
Time frame: Baseline to Week 78
Population: FAS Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Functional Assessment (DAD) - Mild AD Subgroup | -11.1 score on a scale | Standard Error 1.8 |
| ALZ-801 | Functional Assessment (DAD) - Mild AD Subgroup | -11.6 score on a scale | Standard Error 1.8 |
p-value: 0.8387MMRM
Other Pre-specified
Global Cognition Assessment (MMSE) - MCI Subgroup
Change from baseline in Mini-Mental State Examination (MMSE) score. The MMSE is a measure of global cognition that is widely used for clinical staging of Alzheimer's Disease. It consists of 11 domains items for a score range of 0-30 to assess general cognitive function. Higher score on MMSE means better cognitive skills.
Time frame: Baseline to Week 78
Population: FAS MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Global Cognition Assessment (MMSE) - MCI Subgroup | -1.4 Score on a scale | Standard Error 0.4 |
| ALZ-801 | Global Cognition Assessment (MMSE) - MCI Subgroup | -0.5 Score on a scale | Standard Error 0.4 |
p-value: 0.079595% CI: [-0.103, 1.845]MMRM
Other Pre-specified
Global Cognition Assessment (MMSE) - Mild AD Subgroup
Change from baseline in Mini-Mental State Examination (MMSE) score. The MMSE is a measure of global cognition that is widely used for clinical staging of Alzheimer's Disease. It consists of 11 domains items for a score range of 0-30 to assess general cognitive function. Higher score on MMSE means better cognitive skills.
Time frame: Baseline to Week 78
Population: FAS Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Global Cognition Assessment (MMSE) - Mild AD Subgroup | -2.6 score on a scale | Standard Error 0.4 |
| ALZ-801 | Global Cognition Assessment (MMSE) - Mild AD Subgroup | -2.7 score on a scale | Standard Error 0.4 |
p-value: 0.816995% CI: [-1.07, 0.845]MMRM
Other Pre-specified
Hippocampal Volume (MCI Subgroup)
Change from baseline in total (bilateral) hippocampal volume (HV) (uL) as measured by Magnetic Resonance Imaging (MRI). HV atrophy is an early event in AD patients, especially in APOE4/4 homozygotes who show accelerated atrophy compared to APOE3/3 patients with Early AD. HV may be a marker of synaptic loss and neurodegeneration.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population MCI Subgroup: this population included all subjects in the MCI subgroup with an evaluable baseline vMRI assessment who had received at least 1 dose of study drug and had at least 1 evaluable post-baseline imaging vMRI assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Hippocampal Volume (MCI Subgroup) | -411.2 microliters | Standard Error 29.6 |
| ALZ-801 | Hippocampal Volume (MCI Subgroup) | -303.1 microliters | Standard Error 30.16 |
p-value: 0.0042MMRM
Other Pre-specified
Hippocampal Volume (Mild AD Subgroup)
Change from baseline in total (bilateral) hippocampal volume (HV) (uL) as measured by Magnetic Resonance Imaging (MRI). HV atrophy is an early event in AD patients, especially in APOE4/4 homozygotes who show accelerated atrophy compared to APOE3/3 patients with Early AD. HV may be a marker of synaptic loss and neurodegeneration.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population Mild AD Subgroup: this population included all subjects with an evaluable baseline vMRI assessment who had received at least 1 dose of study drug and had at least 1 evaluable post-baseline imaging vMRI assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Hippocampal Volume (Mild AD Subgroup) | -423.2 microliters | Standard Error 23.27 |
| ALZ-801 | Hippocampal Volume (Mild AD Subgroup) | -371.8 microliters | Standard Error 24.75 |
p-value: 0.1145MMRM
Other Pre-specified
Imaging Biomarker Endpoint (Cortical Thickness [Mayo Index])
Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration. The Mayo Index refers specifically to the measurement of cortical thickness in the medial temporal lobe.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint (Cortical Thickness [Mayo Index]) | -0.121 mm | Standard Error 0.005 |
| ALZ-801 | Imaging Biomarker Endpoint (Cortical Thickness [Mayo Index]) | -0.099 mm | Standard Error 0.005 |
Comparison: Analysis of the volumetric MRI outcomes were performed using the same MMRM approach described for analysis of the primary clinical endpoint. The MMRM model included treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 years or \> 65 years), gender, disease severity based on baseline MMSE, baseline volumetric MRI value, visit, and treatment by visit interaction. The MRI magnet strength (1.5 or 3 Tesla) was also included as a covariate in the model.p-value: 0.004MMRM
Other Pre-specified
Imaging Biomarker Endpoint (Cortical Thickness [Whole Cortex])
Change from baseline in total (bilateral) cortical thickness (mm) as measured by MRI. Brain MRI studies in Alzheimer's Disease patients show progressive cortical atrophy, reflecting progressive neurodegeneration.
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint (Cortical Thickness [Whole Cortex]) | -0.060 mm | Standard Error 0.003 |
| ALZ-801 | Imaging Biomarker Endpoint (Cortical Thickness [Whole Cortex]) | -0.048 mm | Standard Error 0.003 |
Comparison: Analysis of the volumetric MRI outcomes were performed using the same MMRM approach described for analysis of the primary clinical endpoint. The MMRM model included treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 years or \> 65 years), gender, disease severity based on baseline MMSE, baseline volumetric MRI value, visit, and treatment by visit interaction. The MRI magnet strength (1.5 or 3 Tesla) was also included as a covariate in the model.p-value: 0.002MMRM
Other Pre-specified
Imaging Biomarker Endpoint - DTI in Grey Matter Mean Diffusivity - Bilateral Caudate
Change from baseline in Grey Matter Mean Diffusivity (Bilateral Caudate) as measured by Diffusion Tensor Imaging - Magnetic Resonance Imaging (DTI-MRI). The mean diffusivity (MD) is the average of the three main diffusion values (eigenvalues) obtained from the diffusion tensor imaging (DTI). It is expressed as mm2/s. This unit quantifies the average rate of water diffusion across all directions within a tissue, providing an overall measure of tissue microstructural properties. Lower MD value suggests better maintenance of microstructural integrity of a given brain tissue. Positive treatment effects of ALZ-801 on DTI would present as lower mean diffusivity compared with the placebo group.
Time frame: Baseline to Week 78
Population: DTI-MRI Population defined as all participants who had an evaluable baseline DTI-MRI assessment, received at least one dose of study drug, and had at least one evaluable post-baseline DTI-MRI assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint - DTI in Grey Matter Mean Diffusivity - Bilateral Caudate | 0.000028 square millimeters per second (mm²/s) | Standard Error 0.00000775 |
| ALZ-801 | Imaging Biomarker Endpoint - DTI in Grey Matter Mean Diffusivity - Bilateral Caudate | 0.000007439 square millimeters per second (mm²/s) | Standard Error 0.00000792 |
Comparison: Analysis of the DTI-MRI outcomes were performed using the same MMRM approach described for analysis of the primary clinical endpoint. The MMRM model included treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 years or \> 65 years), gender, disease severity based on baseline MMSE, baseline DTI-MRI value, visit, and treatment by visit interaction. The MRI magnet strength (1.5 or 3 Tesla) was also included as a covariate in the model.p-value: 0.05495% CI: [-0.0000432, 3.7e-7]MMRM
Other Pre-specified
Imaging Biomarker Endpoint - DTI in White Matter Mean Diffusivity (Bilateral Fornix)
Change from baseline in Bilateral Fornix White Matter Mean Diffusivity as measured by Diffusion Tensor Imaging - Magnetic Resonance Imaging (DTI-MRI). The mean diffusivity (MD) is the average of the three main diffusion values (eigenvalues) obtained from the diffusion tensor imaging (DTI). It is expressed as mm2/s. This unit quantifies the average rate of water diffusion across all directions within a tissue, providing an overall measure of tissue microstructural properties. Lower MD value suggests better maintenance of microstructural integrity of a given brain tissue. Positive treatment effects of ALZ-801 on DTI would present as lower mean diffusivity compared with the placebo group.
Time frame: Baseline to Week 78
Population: DTI-MRI Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint - DTI in White Matter Mean Diffusivity (Bilateral Fornix) | 0.0000237 square millimeters per second (mm²/s) | Standard Error 0.0000058 |
| ALZ-801 | Imaging Biomarker Endpoint - DTI in White Matter Mean Diffusivity (Bilateral Fornix) | 0.000000843 square millimeters per second (mm²/s) | Standard Error 0.00000593 |
p-value: 0.006495% CI: [-0.0000391, -0.0000065]MMRM
Other Pre-specified
Imaging Biomarker Endpoint (Hippocampal Volume)
Change from baseline in total (bilateral) hippocampal volume (HV) (uL) as measured by Magnetic Resonance Imaging (MRI). HV atrophy is an early event in AD patients, especially in APOE4/4 homozygotes who show accelerated atrophy compared to APOE3/3 patients with Early AD. HV may be a marker of synaptic loss and neurodegeneration.
Time frame: Baseline to Week 78
Population: The Imaging Biomarker population included all subjects with an evaluable baseline vMRI assessment who had received at least 1 dose of study drug and had at least 1 evaluable post-baseline imaging vMRI assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint (Hippocampal Volume) | -418.5 microliters | Standard Error 21.46 |
| ALZ-801 | Imaging Biomarker Endpoint (Hippocampal Volume) | -345.0 microliters | Standard Error 22.01 |
Comparison: Analysis of the volumetric MRI outcomes were performed using the same MMRM approach described for analysis of the primary clinical endpoint. The MMRM model included treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 years or \> 65 years), gender, disease severity based on baseline MMSE, baseline volumetric MRI value, visit, and treatment by visit interaction. The MRI magnet strength (1.5 or 3 Tesla) was also included as a covariate in the model.p-value: 0.0174MMRM
Other Pre-specified
Imaging Biomarker Endpoint (Ventricular Volume)
Change from baseline in total (bilateral) ventricular volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint (Ventricular Volume) | 5186.3 microliters | Standard Error 256.19 |
| ALZ-801 | Imaging Biomarker Endpoint (Ventricular Volume) | 4028.9 microliters | Standard Error 262.86 |
p-value: 0.0018MMRM
Other Pre-specified
Imaging Biomarker Endpoint - White Matter Fractional Anisotropy (Bilateral Fornix)
Change from baseline in Bilateral Fornix White Matter Fractional Anisotropy as measured by Diffusion Tensor Imaging - Magnetic Resonance Imaging (DTI-MRI). Fractional anisotropy (FA) is a unitless, scalar value that measures the degree of anisotropic (directional) water diffusion within a voxel, ranging from 0 to 1. A value of 0 indicates perfectly isotropic (equal in all directions) diffusion, while a value of 1 indicates perfectly anisotropic (directional) diffusion. Higher FA value suggests better maintenance of microstructural integrity of a given brain tissue. Positive treatment effects of ALZ-801 on DTI would present as higher FA in the ALZ-801 group compared with the placebo group.
Time frame: Baseline to Week 78
Population: DTI-MRI Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint - White Matter Fractional Anisotropy (Bilateral Fornix) | -0.0154 Units on a scale (fractions 0-1) | Standard Error 0.00332 |
| ALZ-801 | Imaging Biomarker Endpoint - White Matter Fractional Anisotropy (Bilateral Fornix) | -0.002089 Units on a scale (fractions 0-1) | Standard Error 0.00336 |
p-value: 0.046595% CI: [0.0001469, 0.01876]MMRM
Other Pre-specified
Imaging Biomarker Endpoint (Whole Brain Volume)
Change from baseline in whole brain volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Imaging Biomarker Endpoint (Whole Brain Volume) | -17877.0 microliters | Standard Error 955.98 |
| ALZ-801 | Imaging Biomarker Endpoint (Whole Brain Volume) | -15056.0 microliters | Standard Error 979.86 |
Comparison: Analysis of the volumetric MRI outcomes were performed using the same MMRM approach described for analysis of the primary clinical endpoint. The MMRM model included treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 years or \> 65 years), gender, disease severity based on baseline MMSE, baseline volumetric MRI value, visit, and treatment by visit interaction. The MRI magnet strength (1.5 or 3 Tesla) was also included as a covariate in the model.p-value: 0.04MMRM
Other Pre-specified
Ventricular Volume (MCI Subgroup)
Change from baseline in total (bilateral) ventricular volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ventricular Volume (MCI Subgroup) | 4490.5 microliters | Standard Error 343.65 |
| ALZ-801 | Ventricular Volume (MCI Subgroup) | 3178.2 microliters | Standard Error 350.44 |
p-value: 0.0029MMRM
Other Pre-specified
Ventricular Volume (Mild AD Subgroup)
Change from baseline in total (bilateral) ventricular volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ventricular Volume (Mild AD Subgroup) | 5630.4 microliters | Standard Error 274.91 |
| ALZ-801 | Ventricular Volume (Mild AD Subgroup) | 4573.4 microliters | Standard Error 294.71 |
p-value: 0.0065MMRM
Other Pre-specified
Whole Brain Volume (MCI Subgroup)
Change from baseline in whole brain volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population MCI Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Whole Brain Volume (MCI Subgroup) | -17559.5 microliters | Standard Error 1417.91 |
| ALZ-801 | Whole Brain Volume (MCI Subgroup) | -13715.7 microliters | Standard Error 1449.14 |
p-value: 0.0267MMRM
Other Pre-specified
Whole Brain Volume (Mild AD Subgroup)
Change from baseline in whole brain volume (uL) as measured by Magnetic Resonance Imaging (MRI).
Time frame: Baseline to Week 78
Population: Imaging Biomarker Population Mild AD Subgroup
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Whole Brain Volume (Mild AD Subgroup) | -18081.4 microliters | Standard Error 1056.74 |
| ALZ-801 | Whole Brain Volume (Mild AD Subgroup) | -15917.1 microliters | Standard Error 1143.24 |
p-value: 0.1386MMRM