LITHIUM CARBONATE for TBR1-related neurocognitive disorder

Inclusion criteria

• {"criterion_text":"- Written informed consent from the patient, parent or legal representative\n- ≥ 6 years old at the time of consent\n- Proven pathogenic or probably pathogenic TBR1 variant (SNV confirmed by Sanger sequencing or CNV including only TBR1)\n- If applicable: Stable concomitant psychoactive medication regimen (dose and schedule) ≥2 months prior to lithium initiation\n- Affected individuals able to take tablet /capsules orally\n- Highly effective method of contraception in affected female individuals of childbearing age (Combined hormonal contraception, progestogen-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system or abstinence) during treatment and for at least 3 months after the final dose of lithium\n- 1 available parent/guardian able to attend all visits having acceptable reading skills\n- Highly effective method of contraception in affected men individuals of childbearing age (condom or abstinence) during the treatment and for at least 5 days after the final dose of lithium"}

Exclusion criteria

• {"criterion_text":"- Renal/liver insufficiency (disturbed liver function, abnormal creatinine clearance)\n- Parent/guardian incapable of expressing consent\n- Person not affiliated to a national health insurance scheme\n- Person subject to a court order\n- Cognitivo-behavioural therapy focused on ASD in 6 weeks previous to inclusion\n- Other genetic pathogenic variant associated to neurocognitive disorders\n- Any introduction of psychotropic molecules within 2 months prior to the trial, including neuroleptics, monoamine oxidase inhibitors, stimulants, antidepressants.\n- Concomitant use of Angiotensin-Converting Enzyme (ACE) inhibitor, angiotensin II receptor antagonists, Nonsteroidal anti-inflammatory drugs, diuretics.\n- Current lithium treatment\n- Severe behavioural disorder or refusal to take drug treatment not allowing for compliance with medication;\n- Impossibility to perform blood tests to check the lithiaemia when the patient is included.\n- Unbalanced thyroid or diabetic pathology\n- Participation in another therapeutic trial\n- Long QT/Brugada syndrome or familial antecedent of Brugada syndrome, cardiac insufficiency\n- Addison disease, dehydration, sodium restriction\n- Non-stabilized epileptic disease.\n- Patient with concomitant diseases for which the experimental treatment by lithium could alter the tolerance\n- Hypersensitivity to lactose, lithium or one of its excipients\n- Patient with a wheat allergy (other than celiac disease)\n- Pregnant or breastfeeding woman"}

Primary endpoints

• {"endpoint_text":"- Clinical response defined as an improvement at the end of the 24 months of lithium carbonate treatment in the Vineland II Adaptive Behaviour Scale (VABS-II) score ≥ standard error of the mean (SEM) of the VABS-II at baseline (end of the observational period).","definition_or_measurement_approach":"Measured using the Vineland II Adaptive Behaviour Scale (VABS-II); clinical response defined as improvement ≥ standard error of the mean (SEM) of the VABS-II at baseline (end of the observational period) after 24 months of lithium carbonate treatment."}

Secondary endpoints

• {"endpoint_text":"- 1. Incidence and severity of lithium related adverse events (AE) using the CTCAE V5.0.","definition_or_measurement_approach":"Safety assessed by incidence and severity of adverse events graded using CTCAE V5.0."}
• {"endpoint_text":"- 2. Improvement ≥ SEM of the VABS-II at baseline (end of the observational period), in socialization subscale and communication subscale standard scores of the VABS-II after 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Change in VABS-II socialization and communication standard scores; improvement defined as ≥ SEM of VABS-II at baseline."}
• {"endpoint_text":"- 3. Clinical response defined as an improvement ≥ SEM of the VABS-II at baseline (end of the observational period) after 6 months of treatment compared with untreated patients.","definition_or_measurement_approach":"VABS-II improvement ≥ SEM at 6 months compared between treated participants and untreated patients."}
• {"endpoint_text":"- 4. Change in score of QoL assessed by the Paediatric Quality of Life Inventory 4.0 (PedSQL) or the San Martin Quality of Life scale after 6, 12, 18 and 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Quality of life measured by PedSQL 4.0 or San Martin QoL scale at specified timepoints (6,12,18,24 months)."}
• {"endpoint_text":"- 5. Clinical response defined as an improvement ≥ SEM of the VABS-II at baseline (end of the observational period) at 12 and 18 months of lithium treatment.","definition_or_measurement_approach":"VABS-II improvement ≥ SEM at 12 and 18 months compared to baseline."}
• {"endpoint_text":"- 6. Evolution of number of seizures clinic or infra-clinic and/or brain activity as measured by EEG whenever appropriate after 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Seizure frequency/severity and EEG measures assessed where appropriate after 24 months of treatment."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 1. Difference in socialization subscale and communication subscale standard scores of the VABS-II after 6, 12 and 18 months of lithium carbonate treatment.","definition_or_measurement_approach":"Exploratory change in VABS-II subscale standard scores at 6,12,18 months."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 2. Difference in reasoning and inhibition abilities assessed the 3 reasoning tasks on tablet of increasing difficulty(measured by reaction Time and Error Rate analysis) after 6, 12, 18 and 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Reasoning/inhibition assessed by three tablet tasks; measured by reaction time and error rate analysis at multiple timepoints."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 3. Change in scores of Aberrant Behaviour Checklist (ABC) questionnaire in children and adults, of Child Behaviour Checklist (CBCL) scale in children, of Adult Behaviour Checklist (ABCL) scale in adults after 6, 12, 18 and 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Behavior assessed by ABC, CBCL (children) or ABCL (adults) at specified timepoints."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 4. Change in scores of Clinical Global Impression scale (CGI), after 6, 12, 18 and 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Clinical Global Impression (CGI) score changes at multiple timepoints."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 5. Change in scores of Wechsler Scale or Leiter-3 according to the investigator's assessment of the disability (WISC-V in children aged 6 to 16 years, WAIS-IV in children older than 16 years; Leiter 3 in patients aged 3 to 75 years with no language skills and moderate to severe ID) after 24 months of lithium carbonate treatment.","definition_or_measurement_approach":"Cognitive assessment using WISC-V, WAIS-IV or Leiter-3 as appropriate after 24 months."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 6. Change in scores of Pervasive Development Disorder in Mentally Retarded persons Scales (PDD-MRS) and Autism Diagnostic Observation Schedule (ADOS II) in children and adults after 12 and 24 months of lithium carbonate treatment","definition_or_measurement_approach":"PDD-MRS and ADOS II score changes at 12 and 24 months."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS : Saturation of empirical data obtained through individual interviews on parents’/caregivers’ expectations regarding the clinical trial.","definition_or_measurement_approach":"Qualitative saturation of interview data on parents'/caregivers' expectations."}
• {"endpoint_text":"- EXPLORATORY ENDPOINTS : Saturation of the empirical data obtained through individual interviews on parents’/caregivers’ perception of the treatment’s effectiveness particularly with regard to the expectations that were expressed","definition_or_measurement_approach":"Qualitative saturation of interviews on parents'/caregivers' perception of treatment effectiveness."}

Other endpoints

• {"endpoint_text":"- EXPLORATORY ENDPOINTS: 1. Difference in socialization subscale and communication subscale standard scores of the VABS-II after 6, 12 and 18 months of lithium carbonate treatment.\n- EXPLORATORY ENDPOINTS: 2. Difference in reasoning and inhibition abilities assessed the 3 reasoning tasks on tablet of increasing difficulty(measured by reaction Time and Error Rate analysis) after 6, 12, 18 and 24 months of lithium carbonate treatment.\n- EXPLORATORY ENDPOINTS: 3. Change in scores of Aberrant Behaviour Checklist (ABC) questionnaire in children and adults, of Child Behaviour Checklist (CBCL) scale in children, of Adult Behaviour Checklist (ABCL) scale in adults after 6, 12, 18 and 24 months of lithium carbonate treatment.\n- EXPLORATORY ENDPOINTS: 4. Change in scores of Clinical Global Impression scale (CGI), after 6, 12, 18 and 24 months of lithium carbonate treatment.\n- EXPLORATORY ENDPOINTS: 5. Change in scores of Wechsler Scale or Leiter-3 according to the investigator's assessment of the disability (WISC-V in children aged 6 to 16 years, WAIS-IV in children older than 16 years; Leiter 3 in patients aged 3 to 75 years with no language skills and moderate to severe ID) after 24 months of lithium carbonate treatment.\n- EXPLORATORY ENDPOINTS: 6. Change in scores of Pervasive Development Disorder in Mentally Retarded persons Scales (PDD-MRS) and Autism Diagnostic Observation Schedule (ADOS II) in children and adults after 12 and 24 months of lithium carbonate treatment\n- EXPLORATORY ENDPOINTS : Saturation of empirical data obtained through individual interviews on parents’/caregivers’ expectations regarding the clinical trial.\n- EXPLORATORY ENDPOINTS : Saturation of the empirical data obtained through individual interviews on parents’/caregivers’ perception of the treatment’s effectiveness particularly with regard to the expectations that were expressed","definition_or_measurement_approach":"Exploratory endpoints measured as described: VABS-II subscales, tablet-based reasoning tasks (reaction time and error rate), ABC/CBCL/ABCL questionnaires, CGI, Wechsler/Leiter cognitive scales, PDD-MRS and ADOS II, and qualitative interview saturation for parents/caregivers."}

France

Earliest CTIS Part Ii Submission Date

08-11-2024

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

549

Number Of Sites

7

Number Of Participants

12

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Dijon

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France