Impact of Sulphonylureas on Neurodevelopmental Outcomes in KCNJ11-related Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome (iDEND)

June 11, 2024 updated by: Royal Devon and Exeter NHS Foundation Trust

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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:

  1. To identify and recruit the largest international cohort of individuals with V59M mutations reported to date.
  2. To characterise the neurodevelopmental phenotype in these patients using standardised validated questionnaires and assessments.
  3. 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 Type

Observational

Enrollment (Estimated)

21

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Rome, Italy
        • Recruiting
        • University of Rome
        • Contact:
          • Fabrizio Barbetti
  • Norway
      • Bergen, Norway
        • Recruiting
        • University of Bergen
        • Contact:
          • Pernille Svalastoga
  • United Kingdom
      • Exeter, United Kingdom
        • Recruiting
        • University of Exeter
        • Contact:
          • Pamela Bowman
  • United States
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • University of Chicago
        • Contact:
          • Maria Salguero Bermonth

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 50 years (Child, Adult)

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

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).

Description

Inclusion Criteria:

  • Current age ≥2 years
  • Heterozygous for a V59M mutation in the KCNJ11 gene
  • Successfully transferred to oral sulphonylurea therapy
  • Willing to participate

Exclusion Criteria:

  • Never able to transfer to oral sulphonylurea therapy
  • Unwilling to participate

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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.
Drug: Sulfonylurea
Glibenlclamide / glyburide
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.
Drug: Sulfonylurea
Glibenlclamide / glyburide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
At or up to 2 years after recruitment
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.
At or up to 2 years after recruitment
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.
At or up to 2 years after recruitment
IQ score
Time Frame: Up to 3 years after recruitment
Measured by Leiter-3 International Performance Scale
Up to 3 years after recruitment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major milestones
Time Frame: At or up to 2 years after recruitment
Measured by parent report / review of clinical records
At or up to 2 years after recruitment
Communication difficulties
Time Frame: Up to 3 years after recruitment
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.
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
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.
At or up to 2 years after recruitment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Royal Devon and Exeter NHS Foundation Trust

Collaborators

University of Chicago
University of Bergen
University of Rome Tor Vergata

Investigators

  • Principal Investigator: Prof Andrew Hattersley, University of Exeter / Royal Devon University Healthcare Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2016

Primary Completion (Estimated)

August 1, 2025

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

January 25, 2023

First Submitted That Met QC Criteria

February 20, 2023

First Posted (Actual)

March 2, 2023

Study Record Updates

Last Update Posted (Actual)

June 13, 2024

Last Update Submitted That Met QC Criteria

June 11, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 120925

Drug and device information, study documents

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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