| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early Alzheimer’s Disease |
|
| 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 |
1.Participant must be in the AD continuum as defined by the 2018 NIA-AA Research Framework; this requires evidence of cerebral amyloidosis (A+) as detailed:a.Must be positive by the PrecivityADAβ blood test prior to proceeding with either the amyloid-PET or CSF assements for confirmation of amyloid pathology. Confirmation of amyloid pathology b is described in criterion 1b below. Participants with a low APS are not eligible for study participation. Prospective participants who are considered to be amyloid positive via either historical amyloid-PET scan or CSF test may forego the initial screen with the PrecivityAD Aβ. b.Confirmation of amyloid pathology as demonstrated either by positive amyloid-PET scan or by a CSF pTau/Aβ42 ratio > 0.024 as measured bythe Elecsys assay. c.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 scan2. Participants must demonstrate a clinical severity consistent with Stages 2, 3 or early 4 as defined in the 2018 NIA-AA Research Framework, also described as mild cognitive impairment and mild dementia. Further, participants must meet the following inclusion criteria to define clinical severity: a.Has mild symptomatology as defined by a screening MMSE score of ≥20 points. b.Has a (CDR-GS) – Global Score of 0.5 to 1.0. c.Has evidence of episodic memory impairment as defined by a RBANS score on the Delayed Memory Index ≤85 or ≤95 as described in the protocol .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.4.Participant is willing and able to give informed consent. Where not permitted by local regulations, participants deemed not able to provide consent by the PI will not be enrolled, where local regulation permit it, a legally authorized representative must provide informed consent on their behalf, and participant must provide assent.5.Participant can be male or female, and is 50 to 85 age inclusive.6.Participant ≤120 kg.7. At screening, female participants must be nonpregnant and nonlactating, and 1 of the following conditions must
apply: a.Participant is not a WOCBP (either surgically sterilized, or physiologically incapable of becoming pregnant, or at least 1y
postmenopausal.b.Participant is a WOCBP and agrees to use an acceptable contraceptive method from screening until12 weeks after the last dose of study drug. Acceptable contraception is defined on the protocol. c.WOCBP must have a serum pregnancy test conducted at screening.8.Male participants must agree to use acceptable contraception and not donate sperm from screening until 12 weeks after the last dose of study drug. Acceptable contraception for the male participant when having sexual intercourse with a WOCBP who is not currently pregnant is defined as using a condom. In addition, WOCBP partners must use hormonal contraceptives or an intrauterine device. Vasectomized male participants should have received medical assessment of surgical success.9. Participant has availability of a person ("study partner") who, in the PI´s opinion, has frequent and sufficient contact with Participant, is able to provide accurate information regarding Participant's cognitive and functional abilities, agrees to
provide information at clinic visits, and signs the necessary consent form. a.The study partner must have sufficient cognitive capacity, in the
Investigator's opinion, to accurately report upon Participant's behaviour, cognitive, and functional abilities; should be in sufficiently good general
health, in the Investigator's opinion, to have a high likelihood of maintaining the same level of interaction with participant and
participation in study procedures throughout the study duration. b.Every effort should be made to have the same study partner participate in all
the study.10.Participant and study partner are fluent in the language of the tests at the study site as assessed by site personnel.11.Participant is
willing and able to complete all aspects of the study as applicable and should be capable of completing assessments either alone or with the
study partner.12.Participant has adequate visual and auditory acuity, in the PI´s opinion, to perform the neuropsychological testing.
13.Participant agrees not to donate blood or blood products for transfusion during the study and 1 year after the final dose. Inclusion criteria for optional Tau-PET, longitudinal Amyloid PET, and WLSA, are described in the protocol. |
|
| E.4 | Principal exclusion criteria |
1.Participant has any evidence of a condition other than AD that may affect cognition2.Participant has history or presence of vascular disease that has the potential to affect cognitive function, or stroke within past 2y,transient ischemic attack within last 180d before screening, or presence on MRI of any cortical stroke regardless age3.Participant has history of cerebrovascular accident, severe clinically significant CNS trauma, history or presence of intracranial tumor, infections that affect brain function, or history of infections with neurologic sequelae4. Participant currently has or has had an acute illness that requires or required IV antibiotics within 30d prior to first study drug admin.5Participant has history or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits, or any ongoing eye disorder per protocol 6.Participant has any history of schizophrenia, schizoaffective disorder, major depression, bipolar disorder, or is at risk of suicide in PI´s
opinion7.Participant has history of alcohol and/or moderate to severe substance use disorder in the past 2y 8.Participant has MRI evidence of
a. >2 lacunar infarcts. b. Territorial infarct >1 cm3. c. White matter hyperintense lesions on the FLAIR sequence per protocol 9.Participant has presence on MRI of microbleeds>5 and/or areas of leptomeningeal hemosiderosis per protocol10.Participant has presence of significant cerebral vascular pathology, as assessed by the MRI central reader11.Participant is unable to tolerate MRI procedures or has a contraindication, those able to tolerate MRI with intermittent use of a low-dose benzodiazepine or anxiolytic may be included in the study.12. Uncontrolled hypertension as defined in the protocol or presence of an abnormal ECG.13.Participant has unstable ventricular dysrhythmias 14.Participant has significant kidney disease per protocol15.Participant has impaired hepatic function per protocol16.Participant is positive for hepatitis B surface Ag per protocol , or history of spirochetal infection. Participants with a positive HCV virus Ab will be allowed if HCV RNA is negative17.Participants with active or latent TB disease should not be enrolled 18. Any chronic active immune disorder requiring systemic immunosuppressive therapy within 1y prior to study enrollment19.Participant has abnormal screening TSH20.Participant has screening folic acid or low vitamin B12 levels that may be contributing to
cognitive impairment21. Participant is positive for presence of APOE e4/e4 genotype.22.Participant has screening Hgb A1c >8% or poorly controlled diabetes23.Participant has contraindication for LP including deformity of the lumbosacral region of the spine that in the PI´s opinion would contraindicate LP for participants in Part 1 and Part 2 who can only be CSF eligible due to regional lack of availability of PET ligands, or consent to the optional LP assessments 24.Participant has clinically significantly abnormal screening blood or urine results that remain abnormal, or has impaired coagulation25.Participant has history of cancer with the exceptions per protocol: 26.Participant has known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins 27.Participant has had any surgery or hospitalization within 30d prior to first study drug admin 28.Participant with other severe or unstable medical condition that could put them at special risk29.Participant resides in a skilled nursing facility, convalescent home, or long-term care facility30. AD medications must not be initiated, modified, or stopped within 60 days prior to screening. 31.Takes any medications known to impair consciousness or cognition10.32Is under investigational active
immunotherapy to prevent or postpone cognitive decline Routinely recommended vaccinations are allowed, as well as any vaccine against
SARS-CoV-2,or is under any passive immunotherapy or other long acting biologic agent that is under evaluation to prevent or postpone cognitive decline within 1y of screening33.Takes investigational drug within 5 half-lives or 90d of screening, whichever is longer34.Previously treated
with medications used for Parkinson symptoms or any other neurodegenerative disorder within 1y of screening35.Typical antipsychotic or neuroleptic medication within 180d of screening except as brief drug for a nonpsychiatric indication, or atypical antipsychotics except with intermittent short term (<1 week) use, which is permitted except within 2d less or 5 half-lives (whichever is longer) prior to any neurocognitive assessment 36.Anti-coagulation medications within 90d of screening per protocol37.Systemic or anticipated systemic immunosuppressive therapy use during the study38.Chronic use of opiates or opioids within 90d of screening39.Stimulant medications ,chronic use of benzodiazepines, barbiturates or hypnotics. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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 24, 48, 72, and 96.
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. |
|
| 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 | 5 |
| 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 States |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| 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 | 2 |
| 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 | 2 |
| 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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