A pilot, multicentre, controlled, open-label study evaluating 24 months of lithium carbonate treatment in patients with TBR1-related neurocognitive disorder. ESALIT (Efficacy- Safety-Lithium-TBR1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Dijon

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

9 Sep 2025 → ongoing

Decision date (initial)

2024-12-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-513955-34-00

ClinicalTrials.gov

NCT06776848

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

After a 6 to 12 months observational period, evaluate the effect of 24 months of lithium carbonate treatment on adaptative behaviour in patients with TBR1-related neurocognitive disorder.

Secondary objectives 14

1. To evaluate in patients with TBR1-related neurocognitive disorder, and compared with data collected at the end of the 6 months observational period: 1. The safety of lithium carbonate,
2. To evaluate in patients with TBR1-related neurocognitive disorder, and compared with data collected at the end of the 6 months observational period: 2. The effect of 24 months of lithium carbonate treatment on social communication defect,
3. To evaluate in patients with TBR1-related neurocognitive disorder, and compared with data collected at the end of the 6 months observational period: 3. The effect of 6 months of lithium carbonate treatment on adaptative behaviour
4. To evaluate in patients with TBR1-related neurocognitive disorder, and compared with data collected at the end of the 6 months observational period: 4. The effects of 6, 12, 18 and 24 months of lithium carbonate treatment on quality of life (QoL)
5. To evaluate in patients with TBR1-related neurocognitive disorder, and compared with data collected at the end of the 6 months observational period: 5. The effects of 12 and 18 months of lithium carbonate treatment on adaptative behaviour
6. To evaluate in patients with TBR1-related neurocognitive disorder, and compared with data collected at the end of the 6 months observational period: 6. The effects of 24 months lithium carbonate treatment on frequency and severity of seizures clinic or infra-clinic
7. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY : 1. The effect of 6, 12 and 18 months of lithium carbonate treatment on social communication
8. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY : 2. The effect of 6, 12, 18 and 24 months of lithium carbonate treatment on reasoning and inhibition abilities
9. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY: 3. The effects of 6, 12, 18 and 24 months lithium carbonate treatment on behaviour
10. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY: 4. The effects of 6, 12, 18 and 24 months lithium carbonate treatment on Clinical Global state
11. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY: 5. The effects of 24 months lithium carbonate treatment on intellectual efficiency
12. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY: 6. The effects of 12 and 24 months lithium carbonate treatment on autistic spectrum disorder (ASD)
13. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY : To explore parent’s expectations regarding the clinical trial between M0 and M6
14. EXPLORATORY OBJECTIVES OF EFFECTIVE LITHIUM THERAPY : To explore parent’s perception of treatment’s effectiveness between end of the treatment and 3 months after

Conditions and MedDRA coding

Proven pathogenic or probably pathogenic TBR1 variant

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Written informed consent from the patient, parent or legal representative
2. ≥ 6 years old at the time of consent
3. Proven pathogenic or probably pathogenic TBR1 variant (SNV confirmed by Sanger sequencing or CNV including only TBR1)
4. If applicable: Stable concomitant psychoactive medication regimen (dose and schedule) ≥2 months prior to lithium initiation
5. Affected individuals able to take tablet /capsules orally
6. 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
7. 1 available parent/guardian able to attend all visits having acceptable reading skills
8. 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 20

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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).

Secondary endpoints 14

1. 1. Incidence and severity of lithium related adverse events (AE) using the CTCAE V5.0.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. EXPLORATORY ENDPOINTS: 4. Change in scores of Clinical Global Impression scale (CGI), after 6, 12, 18 and 24 months of lithium carbonate treatment.
11. 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.
12. 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
13. EXPLORATORY ENDPOINTS : Saturation of empirical data obtained through individual interviews on parents’/caregivers’ expectations regarding the clinical trial.
14. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Dijon

Sponsor organisation

Centre Hospitalier Universitaire De Dijon

Address

1 Boulevard Jeanne D Arc, Bp 77908 Bp 77908

City

Dijon

Postcode

21000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Chef de projets

Public contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Chef de projets

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications