Evaluation of Lithium Carbonate in TBR1-Related Neurocognitive Disorder: A 24-Month Multicenter, Open-Label, Controlled Pilot Study

The primary objective of this study is to evaluate the effect of 24 months of **lithium carbonate** treatment on adaptive behavior in patients with TBR1-related neurocognitive disorder, following a 6 to 12 months observational period. This is clinically relevant as it aims to determine the potential therapeutic benefits of lithium carbonate in improving adaptive behavior, which is a critical aspect of daily functioning in individuals with this disorder.

Secondary objectives include evaluating the following in patients with TBR1-related neurocognitive disorder, compared with data collected at the end of the 6 months observational period:

• The safety of lithium carbonate.
• The effect of 24 months of lithium carbonate treatment on social communication defects.
• The effect of 6 months of lithium carbonate treatment on adaptive behavior.
• The effects of 6, 12, 18, and 24 months of lithium carbonate treatment on quality of life (QoL).
• The effects of 12 and 18 months of lithium carbonate treatment on adaptive behavior.
• The effects of 24 months of lithium carbonate treatment on the frequency and severity of clinical or infra-clinical seizures.

The clinical trial involves participants diagnosed with a **TBR1-related neurocognitive disorder**, characterized by a proven pathogenic or probably pathogenic TBR1 variant. The study population includes both male and female subjects, with an age range starting from 6 years old, as specified in the inclusion criteria. The trial targets a vulnerable population, requiring written informed consent from the patient, parent, or legal representative. Participants must be able to take tablets or capsules orally and, if applicable, maintain a stable psychoactive medication regimen for at least two months prior to the initiation of lithium treatment. Additionally, affected individuals of childbearing age must use a highly effective method of contraception during the treatment period and for a specified duration afterward. The sponsor has not provided the total number of participants involved in the study. The selection process ensures that participants meet specific health and lifestyle criteria, including the ability to attend all visits with a parent or guardian possessing acceptable reading skills.

The clinical trial is designed as a **controlled**, open-label study to evaluate the efficacy and safety of **lithium carbonate** treatment in patients with a TBR1-related neurocognitive disorder. The trial will span a total duration of 24 months, following an initial observational period of 6 to 12 months. Participants will be administered lithium carbonate either in capsule or tablet form, with the primary objective being to assess improvements in adaptive behavior as measured by the Vineland II Adaptive Behaviour Scale (VABS-II). The study will also monitor secondary endpoints, including the incidence and severity of adverse events, changes in quality of life, and various behavioral and cognitive assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic confirmation of a TBR1 variant, and the ability to take oral medication. Follow-up visits will occur at regular intervals throughout the treatment period to assess clinical response, monitor safety, and adjust treatment as necessary. The end-of-study visit will conclude the trial, evaluating the overall impact of the treatment on the participants' condition.

The expected length of participant involvement is approximately 30 to 36 months, including the observational period. Conditions that may lead to early termination from the study include significant adverse reactions to the treatment, non-compliance with study protocols, or withdrawal of consent by the participant or their legal representative. The trial aims to provide valuable insights into the potential benefits of lithium carbonate for individuals with this specific neurocognitive disorder, contributing to the broader understanding of treatment options for rare genetic conditions.

The clinical trial involves the administration of **lithium carbonate** as the experimental medication. The first formulation of lithium carbonate is provided in the form of a **capsule**. This pharmaceutical form is produced by CHUDIJON and is identified by the product name "carbonate de lithium." The active substance, lithium carbonate, is of chemical origin and is administered via the **oral route**. The frequency of administration is determined by the study protocol, and participant compliance is monitored throughout the trial. The capsule form is not a pediatric formulation and is designated as an orphan drug under the number EU/3/22/2632.

The second formulation of lithium carbonate used in the trial is a **tablet**, specifically "TERALITHE 250 mg, comprimé sécable," manufactured by LABORATOIRES DELBERT. This tablet is also administered orally and contains the same active substance, lithium carbonate, of chemical origin. The tablet form is similarly not a pediatric formulation and holds the same orphan drug designation as the capsule. The administration schedule and dosage are aligned with the study's objectives, and adherence to the dosing regimen is closely monitored to ensure participant compliance.

In addition to the experimental treatments, the study may involve the use of standard-of-care therapies or comparator treatments as deemed necessary by the study protocol. These non-experimental treatments are not specified in the provided data but are integral to the comprehensive evaluation of the experimental medication's efficacy and safety. The trial is designed to assess the impact of lithium carbonate on adaptive behavior in patients with TBR1-related neurocognitive disorder over a 24-month treatment period following an initial observational phase.

Efficacy in this clinical trial will be assessed through a series of primary, secondary, and exploratory endpoints. The primary endpoint is the clinical response, defined as an improvement in the Vineland II Adaptive Behaviour Scale (VABS-II) score by at least the standard error of the mean (SEM) at the end of 24 months of **lithium carbonate** treatment, compared to baseline scores at the end of the observational period. Secondary endpoints include the incidence and severity of lithium-related adverse events using the CTCAE V5.0, improvement in the socialization and communication subscales of the VABS-II, and changes in the Quality of Life (QoL) as assessed by the Paediatric Quality of Life Inventory 4.0 (PedSQL) or the San Martin Quality of Life scale at various timepoints (6, 12, 18, and 24 months). Additionally, the evolution of seizure frequency and brain activity as measured by EEG will be evaluated after 24 months of treatment.

Exploratory endpoints will further assess differences in VABS-II subscale scores, reasoning and inhibition abilities, and changes in scores from various behavioral and cognitive scales, including the Aberrant Behaviour Checklist (ABC), Child Behaviour Checklist (CBCL), Adult Behaviour Checklist (ABCL), Clinical Global Impression scale (CGI), Wechsler Scale or Leiter-3, Pervasive Development Disorder in Mentally Retarded persons Scales (PDD-MRS), and Autism Diagnostic Observation Schedule (ADOS II). These assessments will be conducted at multiple intervals throughout the 24-month treatment period. The efficacy parameters will be measured using validated scales and instruments, ensuring a comprehensive evaluation of the treatment's impact on patients with TBR1-related neurocognitive disorder.