Neurodevelopmental DisordersiDENDNCT05751525
Impact of Sulphonylureas on Neurodevelopmental Outcomes in KCNJ11-related Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome
An observational study of Neurodevelopmental Disorders and Intellectual Disability, run by Royal Devon and Exeter NHS Foundation Trust at 4 sites in 4 countries.
Trial summary
The goal of this observational study is to learn about the impact of the diabetes drug glibenclamide (glyburide) on neurodevelopment in individuals with iDEND (developmental delay, epilepsy and neonatal diabetes) due to the V59M mutation in the KCNJ11 gene. Read more about this study
- Who is it for?
- Ages 2 to 50 years
- Conditions the study is for
- Neurodevelopmental Disorders, Intellectual Disability, Development Delay
- What is being tested?
- Sulfonylurea
- How many people
- 21 participants
- Where
- 4 sitesin 4 countries
- Study dates
- 1 Jul 2016to 31 Dec 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
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 2 to 50 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: Participating centres will recruit and assess participants meeting study eligibility criteria (University of Exeter, UK, University of Chicago, USA, University of Bergen, Norway and University of Rome, Italy). Participants will be allocated to the early treatment or late treatment group depending on age at initiation of SU therapy, in a ratio of 1:2 (early:late).
Who may be able to join
- Current age ≥2 years
- Heterozygous for a V59M mutation in the KCNJ11 gene
- Successfully transferred to oral sulphonylurea therapy
- Willing to participate
Who cannot join
- Never able to transfer to oral sulphonylurea therapy
- Unwilling to participate
Trial locations and contacts
4 sites in 4 countries.
Dr Pamela Bowman, MBBS MSc PhD contact
4 sites in 4 countries
United States1 site, 1 recruiting
- Recruiting
University of Chicago
Chicago, Illinois, 60637
Maria Salguero Bermonth
Norway1 site, 1 recruiting
- Recruiting
University of Bergen
Bergen
Pernille Svalastoga
United Kingdom1 site, 1 recruiting
- Recruiting
University of Exeter
Exeter
Pamela Bowman
About this study
Official title: Impact of Timing of Initiation of Sulphonylurea Therapy on Neurodevelopmental Outcomes in Individuals With Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome Due to the V59M Mutation in the KCNJ11 Gene
The goal of this observational study is to learn about the impact of the diabetes drug glibenclamide (glyburide) on neurodevelopment in individuals with iDEND (developmental delay, epilepsy and neonatal diabetes) due to the V59M mutation in the KCNJ11 gene. The main question it aims to answer is whether initiating sulphonylurea (SU) therapy in the first year of life results in better neurodevelopmental outcomes in affected individuals, in comparison to starting therapy later than 12 months of age.
Participants will undergo a neurodevelopmental assessment comprising parental and teacher completion of standardised questionnaires, and where possible face to face neuropsychological testing.
Researchers will compare the outcomes of these standardised tests in the individuals who started SU therapy <12 months of age in comparison to those who started >12 months of age.
Read the detailed description
Background:
The role of the KATP channel in the pancreas The KATP channel is made up of 4 pore-forming Kir6.2 subunits (encoded by the KCNJ11 gene) and 4 regulatory SUR1 subunits (encoded by the ABCC8 gene). In the pancreas, the KATP channel plays a central role in glucose-stimulated insulin secretion.
KATP channel mutations cause neonatal diabetes that can be treated with oral sulphonylureas Neonatal diabetes is defined as diabetes occurring in the first 6 months of life; it has an incidence of approximately 1 in 200,000 live births. Neonatal diabetes is due to a monogenic defect, and mutations in the KCNJ11 and ABCC8 genes are the commonest cause. These are important to diagnose as over 90% of patients can switch from insulin treatment to an oral sulphonylurea with a resulting improvement in glycaemic control which is maintained long-term.
Central Nervous System features occur in patients with neonatal diabetes due to KATP mutations.
Around 20% of patients with mutations in the KCNJ11 gene have an overt severe neurological phenotype. This is consistent with the expression of the KATP channel in the brain. There is a phenotype/genotype relationship e.g. most patients with the V59M mutation have the intermediate DEND syndrome (iDEND - Developmental delay, Epilepsy and Neonatal Diabetes), with moderate developmental delay and substantial intellectual disability. DEND syndrome is characterised by severe developmental delay and epilepsy diagnosed within the first 12 months of life. People with iDEND syndrome also show hyperactivity, impulsivity, inattention and impaired visuomotor performance. Autism (comprising impaired language and social interaction and restricted/repetitive behaviours), ADHD and anxiety disorders have been reported in individuals with the V59M mutation. Mouse models with V59M mutations have replicated the hyperactive phenotype seen in humans. These finding suggests a possible role for the KATP channel in neurodevelopment.
Previous research suggests earlier initiation of treatment results in more favourable CNS outcomes After switching from insulin to oral sulphonylureas, some patients with a V59M mutation have a clear but incomplete improvement in neurological / cognitive function suggesting that the KATP channel in the CNS responds in part to sulphonylureas. Sulphonylurea therapy is also associated with changes in brain perfusion patterns, in particular improved cerebellar perfusion. The timing of initiation of sulphonylurea therapy appears to be important; one study showed an inverse correlation between age of initiation of treatment with sulphonylureas and performance in the visual-motor integration test (a neuromotor coordination task) in patients with V59M/A mutations. Another prospective study showed improved neurological and psychomotor function in a group of patients with a mixture of KATP channel mutations (only one of which was V59M); this improvement was greater in the younger patients.
The reason for greater neurological improvements in younger patients may relate to greater neuroplasticity in the brain in the first 12 months of life; if this is the case then it is crucial to make a genetic diagnosis of KATP channel neonatal diabetes early and transfer patients as soon as possible to sulphonylurea therapy.
Despite its clinical importance, to date there has been no formal study of whether age of first treatment with a sulphonylurea affects neurodevelopmental outcomes in patients with V59M mutations.
Aim:
To establish whether early treatment with sulphonylureas improves neurodevelopmental outcomes in patients with the V59M mutation in the KCNJ11 gene.
Objectives:
- To identify and recruit the largest international cohort of individuals with V59M mutations reported to date.
- To characterise the neurodevelopmental phenotype in these patients using standardised validated questionnaires and assessments.
- To compare outcomes in those who started treatment with SU in the first 12 months of life vs those who started treatment later than 12 months.
Methods:
Data collection form will be completed by clinicians / researchers using parent/carer report and / or review of notes +/- clinical observation. The study procedure for each participant is as follows:
- Standard medical, perinatal and social history including major milestones
- Developmental Assessment (see below)
- Development and Wellbeing Assessment (DAWBA) to establish ICD-10/DSM-IV / V psychiatric diagnoses and Strengths and Difficulties Questionnaire (SDQ) to provide a quantitative measure of psychiatric morbidity in five key areas (hyperactivity, emotional, conduct problems, peer relationships, prosocial behaviour) and overall impact. The DAWBA and SDQ are standardised, validated questionnaires given to informants (usually parents and teachers) and patients themselves if aged 11 years or over and able to complete them. These can be completed online, and normative data derived from large population surveys is available.
- Leiter-3 International Performance Scale Cognitive battery where neither the examiner nor the child is required to speak, and the child is not required to read or write either. As the test is nonverbal, it is especially suitable for children and adolescents who are cognitively delayed, disadvantaged, nonverbal or non-English speaking, speech or hearing impaired, motor impaired, have a diagnosis of ADHD or autism. Provides IQ scores and scaled scores for its subtests.
- CCC-2 (Children's Communication Checklist) - parental questionnaire used to identify communication problems in children aged 4-16.
Data analysis:
Patients will be divided into 2 groups based on starting SU treatment (1) >12 months and (2) <12 months. Where possible scores on the above tests will be converted to SD scores using normative population data. Results from the 2 groups will be compared using non-parametric statistical methods to establish whether, for the same mutation, the age at which treatment is initiated impacts on the degree of developmental delay, psychopathology and impact.
- Conditions
- Neurodevelopmental Disorders, Intellectual Disability, Development Delay, ADHD, Autism Spectrum Disorder, Epilepsy
- Being tested
- Sulfonylurea
- Medical subject headings
- Neurodevelopmental Disorders, Intellectual Disability, Learning Disabilities, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SulfonylureaDrug
Glibenlclamide / glyburide
| Study group | Role | What they receive |
|---|---|---|
| Early SU treatment | Patients with permanent neonatal diabetes (PNDM) due to the V59M mutation in the KCNJ11 gene who commenced sulfonylurea therapy in the first twelve months of life. Receives: Drug: Sulfonylurea | |
| Late SU treatment | Patients with permanent neonatal diabetes (PNDM) due to the V59M mutation in the KCNJ11 gene who commenced sulfonylurea older than the age of twelve months. Receives: Drug: Sulfonylurea |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number and type of neurodevelopmental and psychiatric disorders
Measured by Development and Wellbeing Assessment (DAWBA)
Measured: At or up to 2 years after recruitment
Level of difficulty due to neurodevelopmental and psychiatric morbidity
Measured by Strengths and Difficulties Questionnaire (SDQ) total difficulties score. Scores range from 0-40 with higher scores indicating greater difficulties. Scores will be converted to Z-scores using normative population data for the purposes of analysis.
Measured: At or up to 2 years after recruitment
Impact on daily life
Measured by SDQ impact score. Scores range from 0-10 for parent and self-report and 0-6 for teacher report, with higher scores indicating greater difficulties. Scores will be converted to Z-scores using normative population data for the purposes of analysis.
Measured: At or up to 2 years after recruitment
IQ score
Measured by Leiter-3 International Performance Scale
Measured: Up to 3 years after recruitment
Secondary outcomes (3)
Major milestones
Measured by parent report / review of clinical records
Measured: At or up to 2 years after recruitment
Communication difficulties
Measured by the Children's Communication Checklist 2 (CCC-2) questionnaire, consisting of 70 items scored by parents / caregivers. Lower scores indicate more communication difficulties.
Measured: Up to 3 years after recruitment
Hyperactivity, emotional problems, conduct problems, peer relationships, prosocial behaviour.
Measured by SDQ subsections. Scores range from 0-10 for each subsection with higher scores indicating greater difficulties, except prosocial score where lower scores indicate greater difficulties. Scores will be converted to Z-scores using normative population data for the purposes of analysis.
Measured: At or up to 2 years after recruitment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2023
- Study start1 Jul 2016
- Primary completion1 Aug 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Neurodevelopmental DisordersStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Case-control
- Time perspective
- Retrospective
- Enrolment
- 21 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Royal Devon and Exeter NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- University of Chicago, University of Bergen, University of Rome Tor Vergata
- Responsible party
- Sponsor
- Investigators
- Prof Andrew Hattersley, Principal investigator, University of Exeter / Royal Devon University Healthcare Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05751525
- Sponsor's protocol ID
- 120925
- Acronym
- iDEND
- Status last verified
- Jun 2024
- First submitted
- 25 Jan 2023
- Last updated
- 13 Jun 2024
- Results posted
- No
- Data monitoring committee
- No
Publications
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004 Apr 29;350(18):1838-49. doi: 10.1056/NEJMoa032922.
PubMed 15115830Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT; Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006 Aug 3;355(5):467-77. doi: 10.1056/NEJMoa061759.
PubMed 16885550Bowman P, Sulen A, Barbetti F, Beltrand J, Svalastoga P, Codner E, Tessmann EH, Juliusson PB, Skrivarhaug T, Pearson ER, Flanagan SE, Babiker T, Thomas NJ, Shepherd MH, Ellard S, Klimes I, Szopa M, Polak M, Iafusco D, Hattersley AT, Njolstad PR; Neonatal Diabetes International Collaborative Group. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study. Lancet Diabetes Endocrinol. 2018 Aug;6(8):637-646. doi: 10.1016/S2213-8587(18)30106-2. Epub 2018 Jun 4.
PubMed 29880308Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia. 2006 Jun;49(6):1190-7. doi: 10.1007/s00125-006-0246-z. Epub 2006 Apr 12.
PubMed 16609879Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanne-Chantelot C, Nivot S, Coutant R, Ellard S, Hattersley AT, Robert JJ. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur J Hum Genet. 2006 Jul;14(7):824-30. doi: 10.1038/sj.ejhg.5201629. Epub 2006 May 3.
PubMed 16670688Svalastoga P, Sulen A, Fehn JR, Aukland SM, Irgens H, Sirnes E, Fevang SKE, Valen E, Elgen IB, Njolstad PR. Intellectual Disability in KATP Channel Neonatal Diabetes. Diabetes Care. 2020 Mar;43(3):526-533. doi: 10.2337/dc19-1013. Epub 2020 Jan 13.
PubMed 31932458Bowman P, Broadbridge E, Knight BA, Pettit L, Flanagan SE, Reville M, Tonks J, Shepherd MH, Ford TJ, Hattersley AT. Psychiatric morbidity in children with KCNJ11 neonatal diabetes. Diabet Med. 2016 Oct;33(10):1387-91. doi: 10.1111/dme.13135. Epub 2016 May 21.
PubMed 27086753Landmeier KA, Lanning M, Carmody D, Greeley SAW, Msall ME. ADHD, learning difficulties and sleep disturbances associated with KCNJ11-related neonatal diabetes. Pediatr Diabetes. 2017 Nov;18(7):518-523. doi: 10.1111/pedi.12428. Epub 2016 Aug 24.
PubMed 27555491Clark RH, McTaggart JS, Webster R, Mannikko R, Iberl M, Sim XL, Rorsman P, Glitsch M, Beeson D, Ashcroft FM. Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin. Science. 2010 Jul 23;329(5990):458-61. doi: 10.1126/science.1186146. Epub 2010 Jul 1.
PubMed 20595581Mlynarski W, Tarasov AI, Gach A, Girard CA, Pietrzak I, Zubcevic L, Kusmierek J, Klupa T, Malecki MT, Ashcroft FM. Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11. Nat Clin Pract Neurol. 2007 Nov;3(11):640-5. doi: 10.1038/ncpneuro0640.
PubMed 17982434Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ. Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia. 2006 Nov;49(11):2559-63. doi: 10.1007/s00125-006-0407-0. Epub 2006 Sep 19.
PubMed 17047922Slingerland AS, Hurkx W, Noordam K, Flanagan SE, Jukema JW, Meiners LC, Bruining GJ, Hattersley AT, Hadders-Algra M. Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation. Diabet Med. 2008 Mar;25(3):277-81. doi: 10.1111/j.1464-5491.2007.02373.x.
PubMed 18307455Fendler W, Pietrzak I, Brereton MF, Lahmann C, Gadzicki M, Bienkiewicz M, Drozdz I, Borowiec M, Malecki MT, Ashcroft FM, Mlynarski WM. Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion. Diabetes Care. 2013 Aug;36(8):2311-6. doi: 10.2337/dc12-2166. Epub 2013 Mar 5.
PubMed 23462667Shah RP, Spruyt K, Kragie BC, Greeley SA, Msall ME. Visuomotor performance in KCNJ11-related neonatal diabetes is impaired in children with DEND-associated mutations and may be improved by early treatment with sulfonylureas. Diabetes Care. 2012 Oct;35(10):2086-8. doi: 10.2337/dc11-2225. Epub 2012 Aug 1.
PubMed 22855734Beltrand J, Elie C, Busiah K, Fournier E, Boddaert N, Bahi-Buisson N, Vera M, Bui-Quoc E, Ingster-Moati I, Berdugo M, Simon A, Gozalo C, Djerada Z, Flechtner I, Treluyer JM, Scharfmann R, Cave H, Vaivre-Douret L, Polak M; GlidKir Study Group. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care. 2015 Nov;38(11):2033-41. doi: 10.2337/dc15-0837. Epub 2015 Oct 5.
PubMed 26438614
Study at a glance
From the registry record, last updated by the sponsor on 13 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Timing of Initiation of Sulphonylurea Therapy on Neurodevelopmental Outcomes in Individuals With Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome Due to the V59M Mutation in the KCNJ11 Gene
- ClinicalTrials.gov ID
- NCT05751525
- Acronym / sponsor ID
- iDEND / 120925
- Conditions
- Neurodevelopmental Disorders, Intellectual Disability, Development Delay, ADHD, Autism Spectrum Disorder, Epilepsy
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 21 participants (estimated)
- Lead sponsor
- Royal Devon and Exeter NHS Foundation TrustUniversity, hospital or other
- Collaborators
- University of Chicago, University of Bergen, University of Rome Tor Vergata
- Study start
- 1 Jul 2016 (actual)
- Primary completion
- 1 Aug 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 2 Mar 2023 (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.
The goal of this observational study is to learn about the impact of the diabetes drug glibenclamide (glyburide) on neurodevelopment in individuals with iDEND (developmental delay, epilepsy and neonatal diabetes) due to the V59M mutation in the KCNJ11 gene. The main question it aims to answer is whether initiating sulphonylurea (SU) therapy in the first year of life results in better neurodevelopmental outcomes in affected individuals, in comparison to starting therapy later than 12 months of age.
Participants will undergo a neurodevelopmental assessment comprising parental and teacher completion of standardised questionnaires, and where possible face to face neuropsychological testing.
Researchers will compare the outcomes of these standardised tests in the individuals who started SU therapy <12 months of age in comparison to those who started >12 months of age.
Detailed description
Background:
The role of the KATP channel in the pancreas The KATP channel is made up of 4 pore-forming Kir6.2 subunits (encoded by the KCNJ11 gene) and 4 regulatory SUR1 subunits (encoded by the ABCC8 gene). In the pancreas, the KATP channel plays a central role in glucose-stimulated insulin secretion.
KATP channel mutations cause neonatal diabetes that can be treated with oral sulphonylureas Neonatal diabetes is defined as diabetes occurring in the first 6 months of life; it has an incidence of approximately 1 in 200,000 live births. Neonatal diabetes is due to a monogenic defect, and mutations in the KCNJ11 and ABCC8 genes are the commonest cause. These are important to diagnose as over 90% of patients can switch from insulin treatment to an oral sulphonylurea with a resulting improvement in glycaemic control which is maintained long-term.
Central Nervous System features occur in patients with neonatal diabetes due to KATP mutations.
Around 20% of patients with mutations in the KCNJ11 gene have an overt severe neurological phenotype. This is consistent with the expression of the KATP channel in the brain. There is a phenotype/genotype relationship e.g. most patients with the V59M mutation have the intermediate DEND syndrome (iDEND - Developmental delay, Epilepsy and Neonatal Diabetes), with moderate developmental delay and substantial intellectual disability. DEND syndrome is characterised by severe developmental delay and epilepsy diagnosed within the first 12 months of life. People with iDEND syndrome also show hyperactivity, impulsivity, inattention and impaired visuomotor performance. Autism (comprising impaired language and social interaction and restricted/repetitive behaviours), ADHD and anxiety disorders have been reported in individuals with the V59M mutation. Mouse models with V59M mutations have replicated the hyperactive phenotype seen in humans. These finding suggests a possible role for the KATP channel in neurodevelopment.
Previous research suggests earlier initiation of treatment results in more favourable CNS outcomes After switching from insulin to oral sulphonylureas, some patients with a V59M mutation have a clear but incomplete improvement in neurological / cognitive function suggesting that the KATP channel in the CNS responds in part to sulphonylureas. Sulphonylurea therapy is also associated with changes in brain perfusion patterns, in particular improved cerebellar perfusion. The timing of initiation of sulphonylurea therapy appears to be important; one study showed an inverse correlation between age of initiation of treatment with sulphonylureas and performance in the visual-motor integration test (a neuromotor coordination task) in patients with V59M/A mutations. Another prospective study showed improved neurological and psychomotor function in a group of patients with a mixture of KATP channel mutations (only one of which was V59M); this improvement was greater in the younger patients.
The reason for greater neurological improvements in younger patients may relate to greater neuroplasticity in the brain in the first 12 months of life; if this is the case then it is crucial to make a genetic diagnosis of KATP channel neonatal diabetes early and transfer patients as soon as possible to sulphonylurea therapy.
Despite its clinical importance, to date there has been no formal study of whether age of first treatment with a sulphonylurea affects neurodevelopmental outcomes in patients with V59M mutations.
Aim:
To establish whether early treatment with sulphonylureas improves neurodevelopmental outcomes in patients with the V59M mutation in the KCNJ11 gene.
Objectives:
- To identify and recruit the largest international cohort of individuals with V59M mutations reported to date.
- To characterise the neurodevelopmental phenotype in these patients using standardised validated questionnaires and assessments.
- To compare outcomes in those who started treatment with SU in the first 12 months of life vs those who started treatment later than 12 months.
Methods:
Data collection form will be completed by clinicians / researchers using parent/carer report and / or review of notes +/- clinical observation. The study procedure for each participant is as follows:
- Standard medical, perinatal and social history including major milestones
- Developmental Assessment (see below)
- Development and Wellbeing Assessment (DAWBA) to establish ICD-10/DSM-IV / V psychiatric diagnoses and Strengths and Difficulties Questionnaire (SDQ) to provide a quantitative measure of psychiatric morbidity in five key areas (hyperactivity, emotional, conduct problems, peer relationships, prosocial behaviour) and overall impact. The DAWBA and SDQ are standardised, validated questionnaires given to informants (usually parents and teachers) and patients themselves if aged 11 years or over and able to complete them. These can be completed online, and normative data derived from large population surveys is available.
- Leiter-3 International Performance Scale Cognitive battery where neither the examiner nor the child is required to speak, and the child is not required to read or write either. As the test is nonverbal, it is especially suitable for children and adolescents who are cognitively delayed, disadvantaged, nonverbal or non-English speaking, speech or hearing impaired, motor impaired, have a diagnosis of ADHD or autism. Provides IQ scores and scaled scores for its subtests.
- CCC-2 (Children's Communication Checklist) - parental questionnaire used to identify communication problems in children aged 4-16.
Data analysis:
Patients will be divided into 2 groups based on starting SU treatment (1) >12 months and (2) <12 months. Where possible scores on the above tests will be converted to SD scores using normative population data. Results from the 2 groups will be compared using non-parametric statistical methods to establish whether, for the same mutation, the age at which treatment is initiated impacts on the degree of developmental delay, psychopathology and impact.
Study design
- Observational model
- Case-control
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Early SU treatment | – | Drug: SulfonylureaPatients with permanent neonatal diabetes (PNDM) due to the V59M mutation in the KCNJ11 gene who commenced sulfonylurea therapy in the first twelve months of life. |
| Late SU treatment | – | Drug: SulfonylureaPatients with permanent neonatal diabetes (PNDM) due to the V59M mutation in the KCNJ11 gene who commenced sulfonylurea older than the age of twelve months. |
Who may qualify
- Ages
- 2 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- Participating centres will recruit and assess participants meeting study eligibility criteria (University of Exeter, UK, University of Chicago, USA, University of Bergen, Norway and University of Rome, Italy). Participants will be allocated to the early treatment or late treatment group depending on age at initiation of SU therapy, in a ratio of 1:2 (early:late).
Key inclusion criteria (4 listed)
- Current age ≥2 years
- Heterozygous for a V59M mutation in the KCNJ11 gene
- Successfully transferred to oral sulphonylurea therapy
- Willing to participate
Key exclusion criteria (2 listed)
- Never able to transfer to oral sulphonylurea therapy
- Unwilling to participate
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 |
|---|---|---|
| SulfonylureaGlibenlclamide / glyburide | Drug | Early SU treatment, Late SU treatment |
Primary outcome
Number and type of neurodevelopmental and psychiatric disorders
Time frame: At or up to 2 years after recruitment
Measured by Development and Wellbeing Assessment (DAWBA)
Level of difficulty due to neurodevelopmental and psychiatric morbidity
Time frame: At or up to 2 years after recruitment
Measured by Strengths and Difficulties Questionnaire (SDQ) total difficulties score. Scores range from 0-40 with higher scores indicating greater difficulties. Scores will be converted to Z-scores using normative population data for the purposes of analysis.
Impact on daily life
Time frame: At or up to 2 years after recruitment
Measured by SDQ impact score. Scores range from 0-10 for parent and self-report and 0-6 for teacher report, with higher scores indicating greater difficulties. Scores will be converted to Z-scores using normative population data for the purposes of analysis.
IQ score
Time frame: Up to 3 years after recruitment
Measured by Leiter-3 International Performance Scale
3 secondary outcomes
Major milestones
Time frame: At or up to 2 years after recruitment
Communication difficulties
Time frame: Up to 3 years after recruitment
Hyperactivity, emotional problems, conduct problems, peer relationships, prosocial behaviour.
Time frame: At or up to 2 years after recruitment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jun 2024.
- Background: PubMed 15115830Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004 Apr 29;350(18):1838-49. doi: 10.1056/NEJMoa032922.
- Background: PubMed 16885550Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT; Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006 Aug 3;355(5):467-77. doi: 10.1056/NEJMoa061759.
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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. This study is not recruiting at the moment.
Dr Pamela Bowman, MBBS MSc PhD contact
Prof Andrew Hattersley principal investigator
University of Exeter / Royal Devon University Healthcare Trust
4 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Neurodevelopmental Disorders and Intellectual Disability, run by Royal Devon and Exeter NHS Foundation Trust at 4 sites in 4 countries.
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 4 inclusion and 2 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: status not confirmed, as of the sponsor's last update on 13 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Italy, Norway, United Kingdom. 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.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Dr Pamela Bowman, MBBS MSc PhD (P.Bowman@exeter.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number and type of neurodevelopmental and psychiatric disorders (time frame: At or up to 2 years after recruitment). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05751525, which also lists 15 linked publications.
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 13 Jun 2024.