Efficacy and Safety of AEF0217 in Treating Behavioral and Cognitive Impairments in Adults and Adolescents with Down Syndrome: A Phase 2B Randomized Controlled Trial
- Trial ID
- 2025-521013-10-00
- Protocol
- AEF0217-201
- Sponsor
- Aelis Farma
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to identify the endpoints and doses of AEF0217 administered over 24 weeks that demonstrate an improvement in adaptive behaviours compared to a placebo in adults and older adolescents with Down syndrome. The investigation also evaluates the dynamics of these effects and the influence of age group, degree of disability, APOE4 genotype, and baseline plasma concentrations of AEA and 2-AG. The secondary objectives include:
- Identification of endpoints and doses for improvement in fluid cognition and crystallized cognition, including the influence of age, disability degree, genotype, and baseline plasma levels.
- Evaluation of changes in quality of life.
- Assessment of sleep quantity and quality.
- Evaluation of safety and tolerability of 24 weeks of treatment.
Participants
The sponsor did not provide the total number of participants. The study population consists of male and female patients with a clinical diagnosis of Down syndrome, confirmed via karyotyping. Participants must be between 16 and 32 years of age, possess a body mass index between 18.0 and 35 kg/m², and demonstrate independent mobility with sufficient vision and hearing. Eligibility is determined by an IQ score between 35 and 70 as measured by the Leiter-3, alongside specific language test scores. The study includes individuals with varying degrees of disability, specifically moderate or mild. A reliable caregiver must be present to provide information regarding adaptive behaviours. Medical stability is required, although controlled type 1 or 2 diabetes and stable hypothyroidism are permitted. The study also evaluates the influence of the APOE4 genotype and baseline plasma concentrations of AEA and 2-AG.
Plans and Procedures
This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial is designed to assess the efficacy, safety, and tolerability of AEF0217 in adults and older adolescents with Down syndrome. The study aims to identify optimal doses for treating behavioral and cognitive impairments by evaluating improvements in adaptive behaviors over a 24-week treatment period. The research methodology involves comparing the test substance, administered as an oral solution at doses of 0.2 mg or 0.6 mg, against a placebo. The clinical sequence begins with a screening visit to confirm eligibility through chromosomal analysis, intelligence quotient assessment, and vital sign monitoring. Following randomization, participants undergo a 24-week treatment phase. The trial includes assessments of various endpoints, such as changes in neuropsychological scores and safety laboratory parameters. A follow-up period extends through week 32, which serves as the end-of-study visit. Total participant involvement is expected to last approximately 32 weeks. Early termination of participation may occur based on investigator judgment regarding clinical safety or protocol non-compliance.
Treatment
The experimental treatment consists of 1-((3S,8S,9S,10R,13S,14S,17S)3-benzyloxy-10,13,17-trimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1Hcyclopenta[a]phenanthrene-17-yl)ethan-1-one} administered as an oral solution. This substance is provided in two distinct dosages: 0.2 mg and 0.6 mg, which are intended for oral use.
The placebo, identified as AEF0217 Placebo, is utilized as a comparator treatment within the study protocol.
Efficacy
The efficacy of AEF0217 in patients with Down syndrome will be evaluated using several parameters over a 24-week period. The primary endpoint is the change from baseline to the end of Week 24 in the normalized raw scores of the nine subdomains of the Vineland Adaptive Behavior Scales, Third Edition (VABS-3).
Secondary efficacy assessments include the following:
- Changes from baseline to the end of Week 24 in the fluid cognition composite change sensitive score of the NIH-Toolbox for ID (NIH-TCB for ID), as well as changes in the five individual scores of the tests used to measure this composite score.
- Changes from screening values to the end of Week 24 in the Verbal Comprehension Index (VCI) of the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V), including normalized scores for the two individual tests of vocabulary and similarities.
- Changes from baseline to the end of Week 24 in the total scores of the Pediatric Quality of Life Inventory (Peds-QL) scales, specifically the Generic Core scale, the Cognitive Functioning scale, and the Impact Family Questionnaire.
- Changes from baseline to the end of Week 24 in the summary scores for psychosocial health, physical health, parent HRQL, and family functioning.
- Changes from baseline to the end of Week 24 in the normalized mean scale scores of the domains within the Generic Core and Impact Family scales.
- Changes from baseline to the end of Week 24 in the sleep efficiency score of the Pittsburgh Sleep Quality Index (PSQI).
- Changes from baseline to the end of Week 24 and Week 32 in the total score and the five subscales of the Aberrant Behavior Checklist (ADAMS), which include maniac/hyperactive behavior, depressed mood, social avoidance, general anxiety, and compulsive behavior.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female.
- Age ≥16 to ≤32years.
- BMI ≥18.0 and ≤35 kg/m2
- Clinical diagnosis of Down syndrome (full trisomy 21 and translocations) documented by chromosomal analysis (karyotyping).
- Must be independently mobile and have sufficient vision and hearing to participate in the trial evaluations.
- IQ >35–70 measured with Leiter-3. Individuals with IQ from >35 to <40 must have adequate cognitive and behavioural abilities according to the judgment of the principal investigator.
- VCI of WISC-V language test score ≥ 4, based on mental age (estimated via IQ).
- Must be able to understand most of the time and to express if he/she does not understand to the extent that he/she can accept the trial procedures. Must not use other forms of communication, signs, symbol boards, or devices as his/her primary form of communication.
- Must have a parent or other reliable caregiver who agrees to accompany the participant to all clinic visits, provide information about the participant as required by the protocol, and ensure compliance with the medication schedule and protocol requirements
- The parent or caregiver must be a constant and reliable informant with sufficient contact with the participant to have detailed knowledge of the participant’s adaptive functioning to be able to answer accurately the questions asked by a neuropsychologist at the assessments.
- Vital signs, ECG , and safety laboratory3 parameters must be without clinically relevant abnormalities as per the judgement of the investigator, except for: - Stable type 1 or 2 diabetes provided the participant is monitored regularly prior to and during the trial to ensure adequate glucose control. - Hypothyroidism controlled by treatment so that the participant is euthyroid and T4 stable (range 77–155 nmol/L) for at least 6 weeks prior to randomization. Fluctuations in TSH up to a maximum of 10 mIU/L are allowed.
Exclusion Criteria
- Pregnant or nursing female.
- Participants with secondary psychiatric disorders including conduct disorders, attention deficit hyperactivity disorder, depressive disorders, anxiety disorders, and others that: 1) dominate the overall clinical condition according to the investigator’s assessment; and/or 2) are not stabilized by medical or behavioural treatments, a stabilized treatment being defined as a stable therapeutic regimen and dose for the 3 months prior to randomization; and/or 3) the type of pharmacological treatment is on the list of drugs that are prohibited.
- Symptoms of early dementia confirmed by the NTG-EDSD
- Substance use disorder as defined by the DSM-5.
- Current diagnosis of epilepsy.
- A history of intentional self-harm or suicide attempts brought on by suicidal thoughts. Suicidal ideation in the 12 months before screening, even if there was no suicide attempt or intentional self-harm. Assessed using 3 distinct questions about suicidal behaviour, suicidal ideation, and any self-harming actions.
- Treatment with 1st generation neuroleptic drugs currently or within 3 months prior to randomization and benzodiazepines currently or in the 4 weeks prior to baseline assessments.
- Intake of products containing EGCG (e.g., TEAVIGO, Mega Green Tea Capsules Life Extension, or Font-UP Grand Fontaine Laboratories) currently or during the last 4 weeks prior to the baseline assessments.
- Treatment with medications or very regular consumption of fruits (i.e., pomelo/grapefruit) or natural remedies (i.e., hypericum preparations) known to strongly or moderately induce or inhibit CYP3A4/5 P450 isozymes.
- Administration of an investigational medicinal product, including AEF0217, within the last 3 months prior to randomization.
- Mosaic Down syndrome or Down Syndrome Regression Disorder (DSRD).
- Active or clinically relevant conditions that could, in the investigator’s judgment, affect absorption, distribution, or metabolism of the trial medication (e.g., inflammatory bowel disease, gastric or duodenal ulcers or severe lactose intolerance); controlled celiac disease is allowed.
- Clinically relevant obstructive pulmonary disease or asthma that is untreated. Patients well-controlled by treatment (inhalation or oral) for at least 6 weeks prior to screening may be included if considered safe by the investigator
- Known severe obstructive sleep apnoea or if the investigator thinks that the person should be referred for a diagnosis/treatment of obstructive sleep apnoea.
- Recent (≤1 year) or ongoing haematologic or oncologic disorders (mild anaemia is allowed).
- History of active epilepsy, recurrent seizures, infantile spasms with ongoing neurological sequelae, severe head trauma, or central nervous system infections (e.g., meningitis). Participants with remote childhood febrile seizures or resolved infantile spasms without seizures for ≥10 years and without current anti-seizure treatment may be included after medical evaluation and medical monitor and /or sponsor confirmation.
- Clinically relevant unstable gastrointestinal, renal, hepatic, endocrine (including metabolic syndrome), or cardiovascular system disease as per the investigator’s judgement.
- Any prevailing psychiatric disorder diagnosed using the DSM-5 that dominates a person's overall clinical condition outside of Down syndrome. If symptoms consistent with a diagnosis of psychiatric illness are detected during the screening assessment (NPI-Q) and considered as dominating, the investigator may request a psychiatric evaluation. If necessary, a consultant psychiatrist will be responsible for the final diagnosis, as this is not the investigator’s responsibility.
- Known hypersensitivity to AEF0217 or fructose intolerance.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 27 Oct 2025 | 80 |
 Italy | Recruiting | 27 Oct 2025 | 58 |
 Spain | Recruiting | 27 Oct 2025 | 50 |
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 |
|---|---|---|---|---|---|---|
AEF0217 Placebo | Placebo | N/A | — | — | — | N/A |