Proven Pathogenic or Probably Pathogenic TBR1 VariantPhase 1/2ESALITNCT06776848
A Study Evaluating 24 Months of Lithium Carbonate Treatment in Patients With TBR1-related Neurocognitive Disorder
A Phase 1/2 study testing Observation phase, Lithium treatment and biological monitoring in people with Proven Pathogenic or Probably Pathogenic TBR1 Variant, run by Centre Hospitalier Universitaire Dijon at 1 site in France.
Trial summary
TBR1 is a human gene encoding a brain-specific transcription factor, principally expressed in the excitatory neurons of the neocortex. It regulates development of axonal projection and expression of numerous genes involved in autism spectrum disorders (ASD) and intellectual disability (ID). Read more about this study
- Who is it for?
- Ages 6 years and older
- Conditions the study is for
- Proven Pathogenic or Probably Pathogenic TBR1 Variant
- What is being tested?
- Observation phase, Lithium treatment and biological monitoring
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteFrance
- Study dates
- 12 Sep 2025to 12 Sep 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Written informed consent from the patient, parent or legal representative
- ≥6 years old at the time of consent
- Proven pathogenic or probably pathogenic TBR1 variant (SNV confirmed by Sanger sequencing or CNV including only TBR1)
- If applicable: Stable concomitant psychoactive medication regimen (dose and schedule) ≥2 months prior to lithium initiation
- Affected individuals able to take tablet /capsules orally
- 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
- 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
- 1 available parent/guardian able to attend all visits having acceptable reading skills
Who cannot join
- Criteria related to associated pathologies leading to particular risks:
- Renal/liver insufficiency (disturbed liver function, abnormal creatinine clearance)
- Unbalanced thyroid or diabetic pathology
- Long QT/Brugada syndrome or familial antecedent of Brugada syndrome, cardiac insufficiency
- Addison disease, dehydration, sodium restriction
- Non-stabilized epileptic disease.
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- Criteria related to contra-indication to treatment:
- Patient with concomitant diseases for which the experimental treatment by lithium could alter the tolerance
- Hypersensitivity to lactose, lithium or one of its excipients
- Patient with a wheat allergy (other than celiac disease)
- Pregnant or breastfeeding woman
- Criteria related to treatments/procedures:
- Parent/guardian incapable of expressing consent
- Person not affiliated to a national health insurance scheme
- Person subject to a court order
- Cognitivo-behavioural therapy focused on ASD in 6 weeks previous to inclusion
- Other genetic pathogenic variant associated to neurocognitive disorders
- Any introduction of psychotropic molecules within 2 months prior to the trial, including neuroleptics, monoamine oxidase inhibitors, stimulants, antidepressants.
- Concomitant use of Angiotensin-Converting Enzyme (ACE) inhibitor, angiotensin II receptor antagonists, Nonsteroidal anti-inflammatory drugs, diuretics.
- Current lithium treatment
- Severe behavioural disorder or refusal to take drug treatment not allowing for compliance with medication;
- Impossibility to perform blood tests to check the lithiaemia when the patient is included.
- Participation in another therapeutic trial
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site, 1 recruiting
- Recruiting
CHU Dijon Bourgogne
Dijon, 21000
Sophie NAMBOT, 0380295313 ext. +33, sophie.nambot@chu-dijon.fr
About this study
Official title: A Pilot, Multicentre, Controlled, Open-label Study Evaluating 24 Months of Lithium Carbonate Treatment in Patients With TBR1-related Neurocognitive Disorder
TBR1 is a human gene encoding a brain-specific transcription factor, principally expressed in the excitatory neurons of the neocortex. It regulates development of axonal projection and expression of numerous genes involved in autism spectrum disorders (ASD) and intellectual disability (ID). Recent progress in detection and analysis of rare variants allowed to identify group of genes with strong statistical evidence for association with ASD risk, of which TBR1. Numerous studies on mice showed that TBR1 heterozygous mice display autistic traits as deficiencies in social interaction, in cognitive flexibility, and in associative memory. Functional analyses on human cell lines have demonstrated that de novo truncating variants in TBR1 identified in patients with sporadic ASD disrupt transcriptional repression activity, localization, homodimerization of TBR1 product.
In 2019, only 12 single nucleotide variants (SNVs) and few copy number variations (CNVs) involving TBR1 have been reported in the literature and clinical descriptions were poor. To provide details on the phenotype linked to TBR1 mutations, we and others gathered 25 new individuals with de novo TBR1 SNV and CNV, complemented by a review of individuals previously reported in the literature. On 38 individuals, all presented developmental delay (DD)/ID, ranging from mild to severe, and 76% of them presented autistic traits. Additional behaviour disorders were observed in 85% of individuals, mainly attention deficit and aggressive behaviour. However, the natural history of patients with TBR1 variations is not well known.
Read more
Development of RNA-Seq allowed a better understanding of its transcription factor role and revealed that Tbr1 promotes expression of layer 6 markers as Wnt7b. In heterozygous and homozygous TBR1 mutant mice, Fazel Darbandi et al (1), observed that Wnt7b expression is reduced in cortical layer 6 and that neurons have reduced excitatory and inhibitory synaptic density. They showed that lithium chloride and lithium carbonate, WNT-signalling agonists, rescue the dendritic spines, the synaptic and the axonal defects in Tbr1layer5, Tbr1layer6 and Tbr1 constitutive (Tbr1+/-) mutant mice. They also observed an improvement of social interactions in mice after treatment by lithium. These results suggest an important and novel biological mechanism underlying ASD that may have implications for the treatment of patients with TBR1 variants.
Moreover, lithium treatment has already been evaluated in patients with neurocognitive disorders not linked to TBR1 showing an improvement in the adaptative behaviour and cognition function.
As of today, only symptomatic treatments are available. As lithium increase neuronal activity in mice, and may thus improve the symptoms of this disorder, we propose a clinical trial to study the security and efficacy of lithium carbonate targeting the patients with TBR1-related disorders, with specific and adapted endpoints. Lithium carbonate treatment will be administered after an observation period of 6 to 12 months, allowing to ascertain the stability of neurocognitive abnormalities.
- Being tested
- Observation phase, Lithium treatment, biological monitoring
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Observation phaseOther
Start of the observation phase for all patients for a period of 6 months. Group B: continuation of the observation phase for a further 6 months
Lithium treatmentDrug
The daily dose of lithium will be increased until the target lithiaemia is reached, while monitoring tolerance and possible adverse effects.
biological monitoringBiological
The blood level of lithium will be monitored by regular blood tests
- every 4 days until a targeted blood level is obtained
| Study group | Role | What they receive |
|---|---|---|
| Groupe A | Experimental | Not described Receives: Other: Observation phase; Drug: Lithium treatment; Biological: biological monitoring |
| Groupe B | Experimental | Not described Receives: Other: Observation phase; Drug: Lithium treatment; Biological: biological monitoring |
What is being measured
The primary outcome is the main question the study is designed to answer.
improvement in the Vineland II Adaptive Behaviour Scale (VABS-II) score ≥ standard error of the mean of the VABS-II
Measured: at the end of the 24 months of lithium carbonate treatment compared to baseline (end of the observational period)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jan 2025
- Study start12 Sep 2025
- Primary completion12 Sep 2027 (estimated)
- Study completion12 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Proven Pathogenic or Probably Pathogenic TBR1 VariantStudies of the same condition, open and under way.
- More trials run by Centre Hospitalier Universitaire DijonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier Universitaire Dijon
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06776848
- Sponsor's protocol ID
- NAMBOT PHRCN 2021
- Acronym
- ESALIT
- Status last verified
- May 2026
- First submitted
- 10 Jan 2025
- Last updated
- 22 May 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot, Multicentre, Controlled, Open-label Study Evaluating 24 Months of Lithium Carbonate Treatment in Patients With TBR1-related Neurocognitive Disorder
- ClinicalTrials.gov ID
- NCT06776848
- Acronym / sponsor ID
- ESALIT / NAMBOT PHRCN 2021
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Centre Hospitalier Universitaire DijonUniversity, hospital or other
- Study start
- 12 Sep 2025 (actual)
- Primary completion
- 12 Sep 2027 (estimated)
- Study completion
- 12 Sep 2027 (estimated)
- First posted
- 15 Jan 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
TBR1 is a human gene encoding a brain-specific transcription factor, principally expressed in the excitatory neurons of the neocortex. It regulates development of axonal projection and expression of numerous genes involved in autism spectrum disorders (ASD) and intellectual disability (ID). Recent progress in detection and analysis of rare variants allowed to identify group of genes with strong statistical evidence for association with ASD risk, of which TBR1. Numerous studies on mice showed that TBR1 heterozygous mice display autistic traits as deficiencies in social interaction, in cognitive flexibility, and in associative memory. Functional analyses on human cell lines have demonstrated that de novo truncating variants in TBR1 identified in patients with sporadic ASD disrupt transcriptional repression activity, localization, homodimerization of TBR1 product.
In 2019, only 12 single nucleotide variants (SNVs) and few copy number variations (CNVs) involving TBR1 have been reported in the literature and clinical descriptions were poor. To provide details on the phenotype linked to TBR1 mutations, we and others gathered 25 new individuals with de novo TBR1 SNV and CNV, complemented by a review of individuals previously reported in the literature. On 38 individuals, all presented developmental delay (DD)/ID, ranging from mild to severe, and 76% of them presented autistic traits. Additional behaviour disorders were observed in 85% of individuals, mainly attention deficit and aggressive behaviour. However, the natural history of patients with TBR1 variations is not well known.
Development of RNA-Seq allowed a better understanding of its transcription factor role and revealed that Tbr1 promotes expression of layer 6 markers as Wnt7b. In heterozygous and homozygous TBR1 mutant mice, Fazel Darbandi et al (1), observed that Wnt7b expression is reduced in cortical layer 6 and that neurons have reduced excitatory and inhibitory synaptic density. They showed that lithium chloride and lithium carbonate, WNT-signalling agonists, rescue the dendritic spines, the synaptic and the axonal defects in Tbr1layer5, Tbr1layer6 and Tbr1 constitutive (Tbr1+/-) mutant mice. They also observed an improvement of social interactions in mice after treatment by lithium. These results suggest an important and novel biological mechanism underlying ASD that may have implications for the treatment of patients with TBR1 variants.
Moreover, lithium treatment has already been evaluated in patients with neurocognitive disorders not linked to TBR1 showing an improvement in the adaptative behaviour and cognition function.
As of today, only symptomatic treatments are available. As lithium increase neuronal activity in mice, and may thus improve the symptoms of this disorder, we propose a clinical trial to study the security and efficacy of lithium carbonate targeting the patients with TBR1-related disorders, with specific and adapted endpoints. Lithium carbonate treatment will be administered after an observation period of 6 to 12 months, allowing to ascertain the stability of neurocognitive abnormalities.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Groupe A | Experimental | Other: Observation phase, Drug: Lithium treatment, Biological: biological monitoring |
| Groupe B | Experimental | Other: Observation phase, Drug: Lithium treatment, Biological: biological monitoring |
Who may qualify
- Ages
- 6 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- Written informed consent from the patient, parent or legal representative
- ≥6 years old at the time of consent
- Proven pathogenic or probably pathogenic TBR1 variant (SNV confirmed by Sanger sequencing or CNV including only TBR1)
- If applicable: Stable concomitant psychoactive medication regimen (dose and schedule) ≥2 months prior to lithium initiation
- Affected individuals able to take tablet /capsules orally
Key exclusion criteria (23 listed)
- Renal/liver insufficiency (disturbed liver function, abnormal creatinine clearance)
- Unbalanced thyroid or diabetic pathology
- Long QT/Brugada syndrome or familial antecedent of Brugada syndrome, cardiac insufficiency
- Addison disease, dehydration, sodium restriction
- Non-stabilized epileptic disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Observation phaseStart of the observation phase for all patients for a period of 6 months. Group B: continuation of the observation phase for a further 6 months | Other | Groupe A, Groupe B |
| Lithium treatmentThe daily dose of lithium will be increased until the target lithiaemia is reached, while monitoring tolerance and possible adverse effects. | Drug | Groupe A, Groupe B |
| biological monitoringThe blood level of lithium will be monitored by regular blood tests - every 4 days until a targeted blood level is obtained | Biological | Groupe A, Groupe B |
Primary outcome
improvement in the Vineland II Adaptive Behaviour Scale (VABS-II) score ≥ standard error of the mean of the VABS-II
Time frame: at the end of the 24 months of lithium carbonate treatment compared to baseline (end of the observational period)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 May 2026.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Observation phase, Lithium treatment and biological monitoring in people with Proven Pathogenic or Probably Pathogenic TBR1 Variant, run by Centre Hospitalier Universitaire Dijon at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 22 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sophie NAMBOT (0380295313 ext. +33, sophie.nambot@chu-dijon.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
improvement in the Vineland II Adaptive Behaviour Scale (VABS-II) score ≥ standard error of the mean of the VABS-II (time frame: at the end of the 24 months of lithium carbonate treatment compared to baseline (end of the observational period)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 May 2026.