A phase 1b/2, multicenter, adaptive, double-blind, randomized, placebo-controlled study to assess the safety, tolerability, immunogenicity, and pharmacodynamic effects of ACI-24.060 in subjects with prodromal Alzheimer’s disease and in adults with Down syndrome (ABATE)
- Trial ID
- 2022-500069-29-00
- Protocol
- ACI-24-AD-DS-2102
- Sponsor
- AC Immune S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of ACI-24.060 in subjects with prodromal **Alzheimer's disease** and in adults with Down syndrome. This is clinically relevant as it aims to ensure that the investigational product is safe for use in these populations, which is a critical step before further clinical development.
Secondary objectives include:
- Part 1: To assess the anti-amyloid β (Aβ) antibody response generated by ACI-24.060 in serum.
- Part 2: To assess the pharmacodynamic effect of ACI-24.060 on amyloid-related fluid biomarkers.
- Part 2: To assess the effect of ACI-24.060 on brain amyloid levels using PET scan.
These secondary objectives are important for understanding the immunogenicity and pharmacodynamic effects of ACI-24.060, which could provide insights into its potential efficacy in modifying disease pathology.
Participants
The clinical trial involves a total of **160 participants** diagnosed with **Alzheimer's disease**. The study population includes both male and female subjects, with an age range of 35 to 85 years. Participants were selected based on specific criteria, including a diagnosis of prodromal Alzheimer's disease or mild to moderate intellectual disability, as per the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classification. The trial includes individuals with a Clinical Dementia Rating (CDR)-Global Score of 0.5 and those with a PET scan at screening consistent with the presence of amyloid pathology. Participants are required to have a study partner who maintains regular contact and can provide reliable information. Lifestyle considerations such as the use of acetylcholinesterase inhibitors or memantine are noted, with participants either not taking any marketed treatment for Alzheimer's disease or receiving a stable dose for at least two months prior to baseline. The trial population includes vulnerable groups, such as individuals with Down syndrome, who meet specific cytogenetic and amyloid pathology criteria. Both male and female participants are required to adhere to effective contraceptive measures throughout the study duration.
Plans and Procedures
The clinical trial is a **phase 1b/2**, multicenter, adaptive, double-blind, randomized, placebo-controlled study designed to evaluate the safety, tolerability, immunogenicity, and pharmacodynamic effects of **ACI-24.060** in subjects with prodromal **Alzheimer's disease** and in adults with Down syndrome. The trial is expected to run from September 2022 to July 2026. Participants will be randomly assigned to receive either ACI-24.060 or a placebo, with the administration route being **intramuscular injection** for ACI-24.060. The study will include several key visits: an initial screening visit, multiple follow-up visits, and a final end-of-study visit. The screening visit will determine eligibility based on criteria such as age, diagnosis, and ability to provide informed consent. Follow-up visits will monitor safety and collect data on the primary and secondary endpoints, including adverse events, antibody response, and other clinical assessments. The end-of-study visit will conclude the participant's involvement and gather final data for analysis.
Participants are expected to be involved in the study for its entire duration unless specific conditions necessitate early termination. These conditions may include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The primary endpoints focus on safety and tolerability, assessed through adverse events, physical and neurological examinations, and various clinical evaluations. Secondary endpoints include the measurement of anti-Aβ antibody titers in serum. The trial's design ensures that neither the participants nor the investigators know which treatment the participants receive, maintaining the double-blind nature of the study. This methodology is crucial for minimizing bias and ensuring the reliability of the trial results.
Treatment
The clinical trial involves the administration of **ACI-24.060**, an investigational medication formulated as an **injection**. The active substance in ACI-24.060 is **PAL1-15 ACETATE**, a protein-based compound. This medication is administered via **intramuscular injection**. The primary objective of the study is to assess the safety, tolerability, and immunogenicity of ACI-24.060 in subjects with prodromal Alzheimer's disease and adults with Down syndrome. The dosing schedule and frequency of administration are determined by the study protocol, and participant compliance is monitored throughout the trial.
In addition to ACI-24.060, the study utilizes a **placebo** as a comparator treatment. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo does not contain any active substance and is administered in a manner consistent with the experimental treatment to ensure blinding.
Another auxiliary medication used in the trial is **[18F]PI-2620**, a **solution for injection** containing the active substance **IZAFLORTAUCIPIR (18F)**. This compound is administered **intravenously** and is used to support imaging studies within the trial. The administration schedule is aligned with the imaging requirements of the study, and compliance is monitored accordingly.
Additionally, **Neuraceq 300 MBq/mL solution for injection** is employed as an auxiliary treatment. This solution contains **FLORBETABEN (18F)** as the active substance and is also administered **intravenously**. Neuraceq is used to facilitate imaging procedures, and its administration is scheduled based on the imaging needs of the trial. Participant adherence to the dosing schedule is closely monitored to ensure the integrity of the imaging data.
Efficacy
Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints focus on safety and tolerability, which will be evaluated by monitoring adverse events, results from physical and neurological examinations, global assessments of tolerability, vital signs, brain MRI assessments, electrocardiograms (ECG), routine hematology and biochemistry evaluations in blood and urine, inflammatory markers in blood and cerebrospinal fluid (CSF), and suicidality as measured with the Columbia-Suicide Severity Rating Scale (C-SSRS).
The secondary endpoints will assess the pharmacodynamic effects, specifically the **immunogenicity** of the investigational product ACI-24.060. This will be measured by analyzing anti-Aβ antibody titers in serum, including parameters such as the geometric mean of antibody titers, change from baseline, responder rate, peak, and area under the curve (AUC). These assessments will provide insights into the antibody response generated by ACI-24.060 in subjects with prodromal Alzheimer's disease and adults with Down syndrome.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part 1 : Age ≥50 and ≤85 years at screening.
- Part 1 : Diagnosis of prodromal AD: MCI due to AD according to National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria.
- Part 1 : PET scan at screening consistent with the presence of amyloid pathology.
- Part 1 : Clinical Dementia Rating (CDR)-Global Score of 0.5.
- Part 1 : Subjects who in the opinion of the investigator are able to understand the details of the study and to provide written informed consent.
- Part 1 : Subjects either not taking any marketed treatment for AD or receiving a stable dose of an acetylcholinesterase inhibitor (ACHEI) and/or memantine for at least 2 months prior to screening.
- Part 1 : Subjects cared for by a reliable spouse, informant, or study partner to assure compliance, assist with clinical assessments, and report safety issues, and spouse, informant or study partner consents to serve in this role.
- Part 1 : Females who are either post-menopausal for at least 1 year and/or surgically sterilized, or females of childbearing potential or not post-menopausal must have a negative blood pregnancy test at screening and be willing to use highly effective methods of contraception from the screening visit until the end of their participation. Male participants in the trial with female partners of childbearing potential are required to use barrier methods of contraception (condoms with spermicide) in addition to contraceptive measures used by female partners during the whole study duration.
- Part 1 : Subjects and study partners must be sufficiently proficient in the official language(s) of the country they are living in and able to comply with all study procedures, including lumbar punctures.
- Part 2 : Age ≥35 and ≤50 years at screening (subjects with DS with age ≥35 and ≤39 years may be considered on the condition that there is prior evidence of amyloid results compatible with AD pathology at PET-scan and/or in biofluids).
- Part 2 : Male or female subjects with DS with a cytogenetic diagnosis being either trisomy 21 or complete unbalanced translocation of the chromosome 21.
- Part 2 : PET scan at screening consistent with the presence of amyloid pathology.
- Part 2 : Subjects, their legal representatives (if applicable) and/or their study partners, in the opinion of the investigator, are able to understand the details of the study and to provide written informed consent before starting any study-related activities.
- Part 2 : In the opinion of the investigator, subjects, their legal representatives (if applicable), and/or their study partners or informants are able to fully participate in the study, are sufficiently proficient in the official languages(s) of the country they are living in, and are capable of reliably completing study assessments.
- Part 2 : Females who are either post-menopausal for at least 1 year and/or surgically sterilized, or females of childbearing potential or not post-menopausal must have a negative blood pregnancy test at screening and be willing to use highly effective methods of contraception from the screening visit until the end of their participation. Male participants in the trial with female partners of childbearing potential are required to use barrier methods of contraception (condoms with spermicide) in addition to contraceptive measures used by female partners during the whole study duration.
- Part 2 : Mild to moderate intellectual disability as per Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classification.
- Part 2 : Subjects must have a study partner who has direct and regular contact, at least 10 hours per week, with the subject and who is able to provide reliable answers to questions related to the subject, according to the study investigator.
Exclusion Criteria
- Part 1 and Part 2 - Comorbidities: Any unstable and/or clinically significant medical condition likely to hamper the evaluation of safety and/or efficacy of the study treatment (e.g., moderate and/or severe untreated obstructive sleep apnea, clinically significant reduction in serum B12 or folate levels, stroke, or other cerebrovascular conditions), as per investigator’s judgement. A known history of vitamin D deficiency, unless treated with vitamin D replacement for at least 2 months prior to screening. Subjects considered to be at risk of, or exhibiting symptoms or signs suggestive of vitamin D deficiency should undergo testing for serum vitamin D at screening and be excluded if deficiency is detected. Local guidelines for vitamin D supplementation should be applied whenever possible.
- Part 1 and Part 2 - Comorbidities: Subjects considered to be unable to be compliant with study-related activities (eg, completion of any study exams and assessments, respect of visit schedule and/or treatment administration) and/or to have comorbidities preventing the completion of any study exams and assessments (eg, significant hearing or visual impairments or other disabilities) according to the investigator.
- Part 1 and Part 2 - Comorbidities: DSM-5 criteria for substance use disorders (with the exception of tobacco use disorder) currently met within the past 5 years.
- Part 1 and Part 2 - Comorbidities: History or presence of uncontrolled seizures. If history of seizures, they must be well controlled with no occurrence of seizures in the 2 years before study screening. The use of antiepileptic medications is permitted.
- Part 1 and Part 2 - Comorbidities: Clinically significant arrhythmias or other clinically significant abnormalities on ECG at screening.
- Part 1 and Part 2 - Comorbidities: Myocardial infarction within 1 year prior to baseline, unstable angina pectoris, or significant coronary artery disease.
- Part 1 and Part 2 - Comorbidities: Concomitant or history of clinically significant and/or unstable psychiatric or neurologic disorder other than those considered to be related to AD (e.g., head injury with loss of consciousness, symptomatic stroke, Parkinson’s disease, severe carotid occlusive disease, transient ischemic attacks [TIAs],, hemorrhagic and/or non-hemorrhagic stroke). Subjects with a history of major depressive disorder may be included if they have been free of major episodes for at least 1 year before screening.
- Part 1 and Part 2 - Comorbidities: History of meningitis or meningoencephalitis
- Part 1 and Part 2 - Comorbidities: History of moderate or severe traumatic brain injury.
- Part 1 and Part 2 - Comorbidities: History or presence of inflammatory neurological disorders including but not limited to neuromyelitis optica spectrum disorder (NMOSD).
- Part 1 and Part 2 - Comorbidities: History of cancer within the past 5 years other than treated squamous cell carcinoma, basal cell carcinoma and melanoma in-situ, in-situ prostate cancer, or in-situ breast cancer which have been fully removed and are considered cured.
- Part 1 and Part 2 - Comorbidities: History of chronic or recurrent infections judged to be clinically significant by the investigator and which would potentially hamper the evaluation of efficacy and safety assessments.
- Part 1 and Part 2 - Comorbidities: History or presence of immunological or autoimmune disorders including but not limited to myasthenia gravis, systemic lupus erythematosus, Sjogren syndrome, and sarcoidosis. For autoimmune thyroid disease refer to exclusion criterion No. 42.
- Part 1 and Part 2 - Comorbidities: History of severe allergic reaction (eg, anaphylaxis) including, but not limited to severe allergic reaction to previous vaccines, foods, and/or medications.
- Part 1 and Part 2 - Comorbidities: Clinically significant abnormal vital signs including sustained sitting blood pressure >160/90 mm Hg.
- Part 1 and Part 2 - Comorbidities: Significant risk of suicide, defined using the C-SSRS as the subject answering “yes” to suicidal ideation questions 4 or 5 or answering “yes” to suicidal behavior within the past 12 months.
- Part 1 and Part 2 - Comorbidities: Clinically significant infections or major surgical operation within 3 months prior to screening.
- Part 1 and Part 2 - Comorbidities: Planned surgery anticipated to occur during participation in the study must be reviewed and approved by the medical monitor at screening.
- Part 1 and Part 2 - Comorbidities: Subjects who have donated blood or blood products in the 30 days before screening or who plan to donate blood while participating in the study.
- Part 1 and Part 2 - Comorbidities: Subjects with clinically uncontrolled diabetes mellitus and/or with hemoglobin A1c levels of ≥8.0 %.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 09 Sept 2022 | 75 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Neuraceq 300 MBq/mL solution for injection | Other | SOLUTION FOR INJECTION | INTRAVENOUS | — | — | PRD6020031 |
[18F]PI-2620 | Other | SOLUTION FOR INJECTION | INTRAVENOUS | — | — | PRD8361304 |
ACI-24.060 | Test | INJECTION | INTRAMUSCULAR INJECTION | — | — | PRD9606229 |
Placebo | Placebo | N/A | — | — | — | N/A |