| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early Alzheimer’s Disease |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029205 |
| E.1.2 | Term | Nervous system disorders |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of AL002 in participants with Early AD in delaying disease progression compared to standard of care |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of AL002 in participants with Early AD on efficacy as measured by the rate of change in COAs
Pharmacokinetics:
To estimate the concentration of AL002 in participants with Early AD in serum and CSF (when available)
Safety:
To evaluate the safety and tolerability of AL002 in participants with Early AD
Exploratory:
To evaluate the effects of AL002 in participants with Early AD on exploratory PD biomarkers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Key clinical inclusion criteria for the study:
1. Participant must be in the AD continuum as defined by the 2018 NIA-AA 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, the participant meets this requirement without additional evidence needed. ii. If the DMI >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 longitudinal Amyloid PET imaging assessment only
- Inclusion criteria for participants participating in the optional at-home and/or in-clinic WLSA only. |
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| E.4 | Principal 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 area of leptomeningeal hemosiderosis based on central read.
15. Participant has presence of significant cerebral vascular pathology as assessed by the MRI Central Reader.
16. Participant is unable to tolerate MRI procedures (eg, due to anxiety or claustrophobia) or has contraindication to MRI, including but not limited to, the presence of pacemakers that are not MRI compatible, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an MRI scan; or any other clinical history or examination finding that would pose a potential hazard in combination with MRI. Those who are able to tolerate MRI with intermittent use of a low-dose benzodiazepine or anxiolytic are permitted and may be included in the study.
Bullets 17 to 50 (pages 72 to 76) in the protocol for the following:
- Cardiovascular disorders-related exclusion criteria
- Hepatic/renal disorders
- Infections and immune disorders
- Metabolic/endocrine disorders
- General exclusions
- Medication-related exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Disease progression as measured by change from baseline in the CDR-SB
Primary Estimand for Primary Efficacy:
Endpoint: The primary clinical question of interest is what is the potential relative treatment difference between AL002 and placebo, 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CDR will be done at screening, and on weeks 25, 49, 73, and 97.
Also at early termination (ET) and FU (every 4 weeks), but if Clinical Outcomes Assessment have been performed within 12 weeks of the Efficacy FU visit, they do not need to be performed at the Efficacy FU visit.
|
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Change from baseline in MMSE
• Change from baseline in RBANS - Update
• 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
CSF PK concentrations of AL002 (when available)
Safety Endpoints:
Incidences of AEs, including 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 plasma
Changes from baseline in levels of biomarkers related to microglia function in CSF and/or plasma (eg, CSF1R, IL1RN, osteopontin, YKL-40)
Changes from baseline in levels of biomarkers related to AD pathology in CSF and/or plasma (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-PET (for participants who agree to participate in the optional assessment only)
Changes from baseline in brain amyloid burden as assessed by longitudinal Amyloid PET scanning (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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MMSE, RBANS, ADAS-Cog13,and ADCS-ADL-MCI tests performed at weeks 25,49,73, and 97.Part1 PK samples on day 1,8,15,29,43. Part 2 PK samples at weeks: 1,3,5,6,9,13,17,25,37,49,61,73,85,97, ET and SFU/ 8 weeks.
Part 1 CSF at screening and day 43. Part 2 Predose Baseline and at week 49, 73, ET and Early FU/4 weeks. Part 1 ADA samples day 1, 15, 29 and 43.Part 2 at weeks1,3,9,17,25,37,49,61,73,85,97,ET, SFU /8weeks. AEs start being collected at Predose Baseline Visit and subsequent visits . Vital signs will be collected and AEs documented prior to and at the end of infusion. AEs, AESIs, and SAEs will be assessed after the participant signs the informed consent through to 8 weeks after the last dose of study drug.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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