| 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 |
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| 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 |
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| 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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Participant must be in the Alzheimer’s continuum as defined by the 2018 NIA-AA Research Framework; this requires evidence of cerebral amyloidosis (A+) as detailed in the following:a.Must be positive by the APTUS™-Aβ blood test prior to proceeding with either the amyloid-PET or CSF studies for confirmation of amyloid beta (Aβ) pathology. Demonstration of amyloid pathology by amyloid-PET or CSF phosphorylated tau (pTau)/ amyloid beta (1-42) (Aβ42) ratio is required. Participants with a positive historical amyloid-PET scan that has been collected ≤24 months prior to the start of screening and that meets the acceptable criteria for a historical amyloid-PET scan as outlined in Inclusion Criteria 1b will not be tested by APTUS™-Aβ. Participants with a validated positive historical amyloid-PET scans are considered positive for cerebral Aβ pathology without further testing. b.Has evidence of the AD amyloid pathology, as demonstrated either by positive amyloid-PET scan or by a CSF pTau/Aβ42 ratio > 0.024 as measured by the Roche Elecsys assay. Historical amyloid-PET may be allowed to fulfil this criterion; historical CSF measurements will not be allowed to fulfil this criterion.2.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 ≥22 points. b.Has a Clinical Dementia Rating – 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 ≤85.3.If Participant is receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening.4.Participant is willing and able to give informed consent. If the study participant is not competent, 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 years of age, inclusive.6.Participant weighs between 45 to 120 kg, inclusive.7. At screening, female participants must be nonpregnant and nonlactating, and 1 of the following conditions must apply: a.Participant is not a woman of childbearing potential (WOCBP) (either surgically sterilized, or physiologically incapable of becoming pregnant, or at least 1-year postmenopausal.b.Participant is a WOCBP and agrees to use an acceptable contraceptive method from screening until 8 weeks after the last dose of study treatment. Acceptable contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom, or the sole sexual partner to a vasectomized male. Vasectomized males must have received medical assessment of surgical success. In addition, total abstinence, in accordance with the lifestyle of Participant, is acceptable. 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 8 weeks after the last dose of study treatment. 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 behavior, cognitive, and functional abilities.The study partner 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 is fluent in the language of the tests used 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. Inclusion criteria for optional Tau-PET, longitudinal Amyloid PET, and WLSA, are described in the protocol |
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| 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 2 years, or ischemic attack within last 6 months3.Participant has history of severe, clinically significant CNS trauma, or history or presence of intracranial tumor, or presence of infections that affect brain function or history of infections with neurologic sequelae4.Participant has history or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits, or uveitis with medical intervention, chronic inflammatory or degenerative condition of the eye, current eye infection, any ongoing eye disorder requiring injectable medical therapy or planned invasive eye procedure during the study5.Participant has history of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder, or is at risk of suicide in the PI´s opinion6.Participant has history of alcohol and/or substance use disorder within the past 2 years7.Participant has MRI evidence of a. >2 lacunar infarcts. b. Any territorial infarct >1 cm3. c. White matter hyperintense lesions on the FLAIR sequence as per protocol 8.Participant has presence on MRI of microbleeds>5 and/or areas of leptomeningeal hemosiderosis as per protocol9.Participant has presence of significant cerebral vascular pathology, or any cortical stroke regardless of age as assessed by the MRI central reader10.Participant is unable to tolerate MRI procedures or has a contraindication11.Participant has uncontrolled hypertension or has a history or presence of an abnormal ECG12.Participant has history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias13.Participant has significant kidney disease as per protocol14.Participant has impaired hepatic function as per protocol15.Participant is positive for hepatitis B surface Ag, total hepatitis B core antibody, HIV-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS. Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative16.Participants with active or latent TB disease should not be enrolled in the trial17. Any chronic active immune disorder requiring systemic immunosuppressive therapy within 1 year prior to study enrollment18.Participant has abnormal screening thyroid function tests19.Participant has screening folic acid or low vitamin B12 levels that may be contributing to cognitive impairment20.Participant has screening hemoglobin A1c >8% or poorly controlled insulin dependent diabetes21.Participant has deformity of the lumbosacral region of the spine that in the PI´s opinion would contraindicate LP in those who can only be CSF eligible due to regional lack of availability of PET ligands, or in those who are in Part 122.Participant has clinically significantly abnormal screening blood or urine results that remain abnormal, or has impaired coagulation23.Participant has history of cancer except: a. Is clinically cured. Is not being actively treated and is not likely to require treatment in next 3 years. c. Low probability of recurrence d. Prostate cancer, without progression in the past 2 years24.Participant has known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins25.Participant with other severe or unstable medical condition that could put participant at special risk26.Participant resides in a skilled nursing facility, convalescent home, or long-term care facility27.Takes any medications known to impair consciousness or cognition28.Is under investigational active immunotherapy to prevent or postpone cognitive decline, or is under any passive immunotherapy or other long acting biologic agent that is under evaluation to prevent or postpone cognitive decline within 1 year of screening29.Takes investigational treatment within 5 half-lives or 3 months of screening, whichever is longer30.Previously treated with medications used to treat Parkinsonian symptoms or any other neurodegenerative disorder within 1 year of screening31.Typical antipsychotic or neuroleptic medication within 6 months of screening except as brief treatment for a nonpsychiatric indication, or atypical antipsychotics except with intermittent short term (<1 week) use, which is permitted except within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive assessment 32.Anti-coagulation medications within 3 months of screening33.Systemic immunosuppressive therapy use or anticipated systemic immunosuppressive therapy use during the study34.Chronic use of opiates or opioids within 3 months of screening35.Stimulant medications within 1 month of screening and throughout the study36.Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before screening |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Disease progression as measured by the CDR-SB
Primary Efficacy Estimand:
Treatment Policy: All observed values of the primary variable (CDR-SB) will be used regardless of whether or not the participant interrupted study intervention, permanently discontinued study intervention, or took a prohibited medication. The hazard ratio will be used as the summary measure to assess the efficacy of AL002 as compared to standard of care in participants with Early AD in delaying disease progression. |
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| 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.
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Rate of change in MMSE
• Rate of change in RBANS
• Rate of change in ADAS- Cog13
• Rate of change in ADCS-ADL-MCI
• Rate of change in ADCOMS
• Change from baseline to Week 48, 72, & 96 in CDR-SB
• Change from baseline to Week 48, 72, & 96 in MMSE
• Change from baseline to Week 48, 72, & 96 in RBANS
• Change from baseline to Week 48, 72, & 96 in ADAS- Cog13
• Change from baseline to Week 48, 72, & 96 in ADCS-ADL-MCI
• Change from baseline to Week 48, 72, & 96 in ADCOMS
Secondary Efficacy Estimands:
Treatment policy estimands will be used to assess the secondary efficacy objectives. For each objective, all observed values collected, for each of the below secondary endpoints, will be used regardless of whether or not the participant interrupted study intervention, permanently discontinued study intervention, or took a prohibited medication. The ratio of slopes will be used as the summary measure for the first 5 endpoints listed and the difference in means will be used as the summary measure for the 6th to 11th endpoints.
Pharmacokinetic Endpoints:
Serum PK concentrations of AL002 and relevant PK parameters
CSF PK concentrations of AL002 (when available)
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 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) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MMSE, RBANS, ADAS-Cog13,and ADCS-ADL-MCI tests performed prior to study drug administration,and any stressful procedures.ADCOMS is a composite measurement of all.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 |
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| 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.8.5 | 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 |
| Australia |
| Canada |
| New Zealand |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Argentina |
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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
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| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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