AEF0217 for improving daily living and thinking in Down syndrome

A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicentre, Phase 2b Trial to Assess the Efficacy, Safety and Tolerability of AEF0217 for 24 Weeks in Adults and Older Adolescents With Down Syndrome.

This trial will test whether daily AEF0217 helps adolescents and adults with Down syndrome improve daily living skills, thinking, sleep, and quality of life.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 188 (estimated)
• Ages: 16 Years to 32 Years
• Sex: All
• Sponsor: Aelis Farma (Industry-sponsored)
• Locations: 10 sites (Bordeaux and 9 other locations)
• Trial ID: NCT07334912 on ClinicalTrials.gov

What this trial studies

This is a randomized, double-blind, placebo-controlled, parallel-group Phase 2b trial comparing three doses of AEF0217 to placebo in about 188 participants with Down syndrome across clinical centers in Spain, France, and Italy. Participants aged 16–32 will take study medication daily for 24 weeks with regular clinic and phone visits for safety and efficacy assessments, and a follow-up visit at week 32; those completing treatment may be invited into a 12-month open-label extension. Primary outcome measures focus on adaptive behaviors (daily life activities), with secondary measures including fluid and crystallized cognition, quality of life, and sleep efficiency; blood and urine samples will monitor safety and drug/endocannabinoid levels. The trial is designed to detect dose-related benefits while closely monitoring adverse events in a controlled, multicenter setting.

Who should consider this trial

Good fit: Ideal participants are independently mobile adolescents and adults aged 16–32 with a documented chromosomal diagnosis of Down syndrome, a BMI between 18 and 35 kg/m2, adequate vision and hearing, and ability to comply with study visits and contraception requirements.

Not a fit: Patients outside the age or BMI ranges, those unable to attend study visits or comply with procedures, pregnant individuals, or those with medical conditions that contraindicate trial participation are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, AEF0217 could improve daily functioning, cognitive performance, sleep, and overall quality of life for adolescents and adults with Down syndrome.

How similar studies have performed: Early-phase work has explored AEF0217 or related compounds for tolerability, but using AEF0217 to improve adaptive behavior and cognition in Down syndrome is a novel application and efficacy remains unproven.

Eligibility criteria

Inclusion Criteria:

* 1\. Male and female. For males: Throughout the trial and until the end of the trial, male participants should refrain from donating sperm and, if sexually active, use double-barrier contraceptive methods (i.e., male condoms and spermicide), or the female partner must use the same highly effective contraceptive methods as female trial participants .

For females: Female participants of childbearing potential, defined as having a menstrual cycle that is confirmed prior to enrolment, must use highly effective contraception throughout the trial and until 3 months after the last dose of the trial intervention, be sexually abstinent, or have a vasectomized partner.

* 2\. Age ≥16 to ≤32years.
* 3\. BMI ≥18.0 and ≤35 kg/m2.
* 4\. Clinical diagnosis of Down syndrome (full trisomy 21 or translocations) documented by chromosomal analysis (karyotyping).
* 5\. Must be independently mobile and have sufficient vision and hearing to participate in the trial evaluations.
* 6\. 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.
* 7\. VCI of WISC-V language test score \>4, based on mental age (estimated via IQ).
* 8.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.
* 9\. 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
* 10.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.
* 11\. 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.
* 12\. a. Assent by the participant and consent by the legally authorized representative(s) on behalf of the participant or b. Consent by the participant in situations where consent rather than assent can be provided by the participant.
* 13\. Informed consent by the participant's caregiver to take on the obligations of the caregiver in this trial.

Exclusion Criteria:

* 1\. Pregnant or nursing female. Down syndrome
* 2\. Mosaic Down syndrome or Down Syndrome Regression Disorder (DSRD). Medical history and clinical status
* 3\. 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.
* 4\. 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.
* 5\. Known severe obstructive sleep apnoea or if the investigator thinks that the person should be referred for a diagnosis/treatment of obstructive sleep apnoea.
* 6\. Recent (≤1 year) or ongoing haematologic or oncologic disorders (mild anaemia is allowed).
* 7\. History of infantile spasms/convulsions/epilepsy, severe head trauma or central nervous system infections (e.g., meningitis), except for isolated events of febrile seizures more than 8 years ago.
* 8\. Clinically relevant unstable gastrointestinal, renal, hepatic, endocrine (including metabolic syndrome), or cardiovascular system disease as per the investigator's judgement.
* 9\. 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.
* 10\. 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.
* 11\. Symptoms of early dementia confirmed by the NTG-EDSD.
* 12\. Substance use disorder as defined by the DSM-5.
* 13\. Positive urine test for alcohol and drugs of abuse at screening and prior to first dosing.
* 14\. Current diagnosis of epilepsy.
* 15\. 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.
* 16\. Known hypersensitivity to AEF0217 or fructose intolerance.
* 17\. Clinically significant illness, such as active infections, within 2 weeks prior to randomization, according to the investigator's judgment.
* 18\. Any current life-threatening disease.
* 19\. Any additional clinically significant concomitant disease, condition, or screening result that, in the investigator's opinion, could endanger the participant's safety, interfere with trial conduct and related procedures, or influence how the trial results are interpreted.
* 20\. 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.
* 21\. 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.
* 22\. 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..
* 23\. Administration of an investigational medicinal product, including AEF0217, within the last 3 months prior to randomization.

Where this trial is running

Bordeaux and 9 other locations

• CHU de Bordeaux — Bordeaux, France (Not_yet_recruiting)
• Genetics department, Hospices Civils de Lyon — Lyon, France (Not_yet_recruiting)
• Service Génétique Médicale, CHU de Montpellier — Montpellier, France (Recruiting)
• Genetics department, Institut Jérôme Lejeune — Paris, France (Recruiting)
• Service de Génétique, Chromosomique et Moléculaire, Chu de Saint Etienne — Saint-Etienne, France (Recruiting)
• IRCCS Istituto Delle Scienze Neurologiche, Azienda Unita Sanitaria Locale Di Bologna — Bologna, Italy (Recruiting)
• Centro di Medicina dell'Invecchiamento, Policlinico Universitario Agostino Gemelli IRCCS — Roma, Italy (Recruiting)
• UOR of Neurofarmacology and Translational Neurosciences, Associazione Oasi Maria S.S.Onlus — Troina, Italy (Recruiting)
• Integrative Pharmacology and Systems Neurosciences, Hospital del Mar Research Institute — Barcelona, Spain (Recruiting)
• Servicio de Medicina Interna, Hospital Universitario De La Princesa — Madrid, Spain (Not_yet_recruiting)

Study contacts

• Principal investigator: Rafael DE LA TORRE FORNELL, PharmD, PhD — Hospital del Mar Research Institute
• Study coordinator: Stéphanie Monlezun, Ph. D

Conditions Down Syndrome; Trisomy 21; adaptative behaviour; cognitive impairments