Alzheimers Disease - Neurodegenerative disease - Dementia
Conditions
Interventions
Description of Study Procedures:
Screening Period
Participants will be consented and screened within 8 weeks prior to the Predose
Baseline Visit or to Day 1 to determine eligibility. Participants wil
Sponsors
Alector Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Participant must be in the AD continuum as defined by the 2018 NIAAA Research Framework; this requires evidence of cerebral amyloidosis (A+). This evidence requirement can be satisfied by any one of the following 3 pathways: a. Historical Amyloid PET may be allowed to fulfill this criterion if it meets all of the following: i. Must utilize either [18F]florbetaben, [18F]florbetapir, or [18F]flutametamol. ii. Must have adequate scan parameters and image quality as determined by the central imaging reader. iii. Must have the raw data available to send to the core PET laboratory. iv. Must have been read as positive (elevated amyloid) by the core PET laboratory. b. Historical CSF measurements may be allowed to fulfill this criterion after review by the Medical Monitor. At a minimum, documentation of historical CSF testing must contain the following details: i. Identification of which laboratory did the testing. ii. Identity of the type of assay used. iii. Reference ranges for the values reported. c. If historical testing is not available, the participant must undergo a 2-step verification of amyloid positivity: i. As an initial screen for cerebral amyloidosis, the participant must have a high or intermediate APS as measured by the PrecivityAD Aβ blood test. Participants with a low APS are not eligible for study participation. (Note: Historical studies that do not meet the full criteria in a. or b. may still be considered sufficient, after consultation with the Medical Monitor, to allow a participant to forego PrecivityAD screening and thus allow the participant to proceed to steps outlined in 1.c.ii - amyloid confirmation.). ii. Participants need confirmation of amyloid positivity with either: o New positive Amyloid PET scan o New positive CSF pTau/Aβ42 o Participants who do not have confirmation of amyloid pathology based on an initial Amyloid PET scan may opt to have a second assessment with CSF. Participants who do not have confirmation of amyloid pathology on an initial CSF pTau/Aβ42 measurement may opt to have a second assessment with an Amyloid PET scan. 2. Participant has evidence of episodic memory impairment as demonstrated by the RBANS-Update DMI score: i. If the DMI score is 85 and <=95, the participant may still be considered for participation if they have a history of cognitive and functional decline consistent with diagnosis of Early AD. Agreement between the Investigator and the Medical Monitor that the participant meets criteria for clinical severity consistent with mild cognitive impairment or mild dementia due to Early AD must be documented prior to randomization. 3. If Participant is receiving symptomatic AD medications, the dosing regimen must have been stable for 60days prior to screening not expected to change during study, and must not be initiated, modified, or stopped within 90 days prior to screening start. Bullets 4 to 19 (pages 69 to 70) in the protocol for the following: - General inclusion criteria for the study - Inclusion criteria for participants participating in the optional Tau PET imaging assessment with [18F]MK-6240 only - Inclusion criteria for participants participating in the optional longitudin
Exclusion criteria
Exclusion criteria: Central nervous system (CNS) disorders-related exclusion criteria: 1. Participant has any evidence of a condition other than AD that may affect cognition, including but not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, Parkinson's disease, corticobasal degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy, frontotemporal degeneration, Huntington disease, normal pressure hydrocephalus, hypoxic injury, seizure disorder, static encephalopathy, closed brain injury, or developmental disability. 2. Participant has history or presence of vascular disease that has the potential to affect cognitive function (eg, clinically significant carotid, vertebral stenosis, or plaque; aortic aneurysm; intracranial aneurysm; macro-hemorrhage; arteriovenous malformation). 3. Participant has a history or presence of cerebrovascular accident within the past 2 years, or recent transient ischemic attack within 180 days before screening, or has radiologic evidence of any cortical stroke regardless of age. 4. Participant has history of severe, clinically significant (persistent neurologic deficit or structural brain damage) CNS trauma (eg, cerebral contusion). 5. Participant has history or presence of intracranial tumor (eg, glioma, except for benign brain tumors that, in the opinion of the Investigator, are not likely to impair cognition). 6. Participant has ongoing infections that may affect brain function (eg, human immunodeficiency virus [HIV], syphilis, neuroborreliosis, viral or bacterial meningitis/encephalitis), or history of infections that resulted in neurologic sequelae. 7. Participant currently has or has had an acute illness that requires or required IV antibiotics within 30 days prior to first study drug administration. 8. Participant has history or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits (eg, multiple sclerosis, lupus erythematosus, antiphospholipid antibody syndrome, Behçet disease). 9. Participant has any of the following eye conditions: a history or presence of uveitis, a serious chronic inflammatory condition of the eye, a current eye infection, or any ongoing eye disorder requiring anticipated invasive eye procedures or injectable medical therapy (eg, ranibizumab or aflibercept for macular degeneration or diabetic eye disease) during the study period. 10. Participant has any history of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder. a. A history of major depression is acceptable if no episode has been reported within the previous 2 years. Treatment with antidepressant medications is allowed. 11. Participant is at risk of suicide in the Investigator's opinion. 12. Participant has history of alcohol and/or moderate to severe substance use disorder (according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) within the past 2 years. a. Nicotine use is allowed. Imaging-related exclusion criteria: 13. Participant has MRI evidence of a. >2 lacunar infarcts. b. Any territorial infarct >1 cm3. c. White matter hyperintense lesions on the FLAIR sequence that correspond to an overall Fazekas score of 3. 14. Participant has presence on MRI of >5 microbleeds and/or >1 ar
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Efficacy Endpoint: • Disease progression as measured by change of baseline in the CDR-SB Primary Efficacy Estimand for primary efficacy: • Endpoint: The primary clinical question of interest is what the potential relative treatment difference between AL002 and placebo is, across all post-baseline timepoints in adult patients with Early AD while on study medication, regardless of other interventions. The estimand is described by the following attributes: Treatment condition: while on treatment (hypothetical strategy) regardless of other interventions (treatment policy strategy). Target population: adult patients with Early AD as defined as a percentage by the protocol inclusion/exclusion criteria. Primary endpoint: change from baseline in CDR-SB score to Weeks 25, 49, 73, and 97. Accounting for intercurrent events: a composite strategy will be used to handle intercurrent events as below: - hypothetical strategy for handling premature study drug discontinuation for any reason, - treatment policy strategy for handling all other intercurrent events.Population -level summary: the percent reduction of the relative to placebo group clinical decline (eg, increase in CDR-SB). The proportional treatment effect), comparing each dose level to placebo. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Efficacy Endpoints: • Change from baseline in MMSE • Change from baseline in RBANS - Updtae • Change from baseline in ADAS- Cog13 • Change from baseline in ADCS-ADL-MCI • Change from baseline in ADCOMS Secondary Efficacy Estimands: The main estimand for the secondary efficacy objectives is defined with similar attributes as for the primary estimand except that it is endpoint specific. The treatment effect is defined as a percentage reduction of the placebo group clinical decline. Pharmacokinetic Endpoints: • Serum PK concentrations of AL002 and relevant PK parameters • CSFa PK concentrations of AL002 (when available) • Incidence of ADAs Safety Endpoints: • Incidences of AEs, AESIs, and SAEs • Changes from baseline in vital signs, physical findings, neurological findings, ophthalmological findings, ECG, and clinical laboratory results • C SSRS • MRI abnormalities Exploratory PD Biomarker Endpoints: • Changes from baseline in levels of sTREM2 in CSF and/or plasmaa • Changes from baseline in levels of biomarkers related to microglia function in CSF and/or plasmaa (eg, CSF1R, IL1RN, osteopontin, YKL-40) • Changes from baseline in levels of biomarkers related to AD pathology in CSF and/or plasmaa (eg, Aβ40, Aβ42, pTau, tTau) • Changes from baseline in levels of neurodegeneration biomarkers in plasma and CSFa (eg, NfL) • Changes from baseline in brain volume, assessed by volumetric MRI • Changes from baseline in brain pathological tau burden as assessed by Tau-PETb (for participants who agree to participate in the optional assessment only) • Changes from baseline in sleep and movement measurements via the MC10 device (for participants who agree to participate in the optional assessment only) • Changes from baseline in speech measurements via the WLSA (for participants who agree to participate in the optional assessment only) | — |
Countries
Netherlands
Outcome results
None listed