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

NCT05751525 | Recruiting

• 1 other identifier: 120925
• Study Type: observational
• Target: 21
• Locations: 4 countries
• Sites: 4

Brief 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. 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.

Conditions

Neurodevelopmental Disorders; Intellectual Disability; Development Delay; ADHD; Autism Spectrum Disorder; Epilepsy

Outcome Measures

Primary Outcomes (4)

• Number and type of neurodevelopmental and psychiatric disorders

  Measured by Development and Wellbeing Assessment (DAWBA)

  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.

  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.

  At or up to 2 years after recruitment

• IQ score

  Measured by Leiter-3 International Performance Scale

  Up to 3 years after recruitment

Secondary Outcomes (3)

• Major milestones

  At or up to 2 years after recruitment

• Communication difficulties

  Up to 3 years after recruitment

• Hyperactivity, emotional problems, conduct problems, peer relationships, prosocial behaviour.

  At or up to 2 years after recruitment

Study Arms (2)

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

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

Interventions

Sulfonylurea DRUG

Glibenlclamide / glyburide

Early SU treatment; Late SU treatment

Eligibility Criteria

• Age: 2 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• 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).

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Royal Devon and Exeter NHS Foundation Trust: lead
• University of Chicago: collaborator
• University of Bergen: collaborator
• University of Rome Tor Vergata: collaborator

Study Sites (4)

University of Chicago

Chicago, Illinois, 60637, United States

RECRUITING

University of Rome

Rome, Italy

RECRUITING

University of Bergen

Bergen, Norway

RECRUITING

University of Exeter

Exeter, United Kingdom

RECRUITING

Related Publications (15)

• 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.

  PMID: 15115830 BACKGROUND

• Pearson 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.

  PMID: 16885550 BACKGROUND

• Bowman 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.

  PMID: 29880308 BACKGROUND

• Flanagan 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.

  PMID: 16609879 BACKGROUND

• Gloyn 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.

  PMID: 16670688 BACKGROUND

• Svalastoga 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.

  PMID: 31932458 BACKGROUND

• Bowman 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.

  PMID: 27086753 BACKGROUND

• Landmeier 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.

  PMID: 27555491 BACKGROUND

• Clark 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.

  PMID: 20595581 BACKGROUND

• Mlynarski 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.

  PMID: 17982434 BACKGROUND

• Slingerland 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.

  PMID: 17047922 BACKGROUND

• Slingerland 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.

  PMID: 18307455 BACKGROUND

• Fendler 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.

  PMID: 23462667 BACKGROUND

• Shah 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.

  PMID: 22855734 BACKGROUND

• Beltrand 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.

  PMID: 26438614 BACKGROUND

MeSH Terms

Conditions

Neurodevelopmental Disorders; Intellectual Disability; Learning Disabilities; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Epilepsy

Interventions

Sulfonylurea Compounds

Condition Hierarchy (Ancestors)

Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Communication Disorders; Attention Deficit and Disruptive Behavior Disorders; Child Development Disorders, Pervasive; Brain Diseases; Central Nervous System Diseases

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Sulfones; Sulfur Compounds

Study Officials

• Prof Andrew Hattersley

  University of Exeter / Royal Devon University Healthcare Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr Pamela Bowman, MBBS MSc PhD

CONTACT

P.Bowman@exeter.ac.uk

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2023
• First Posted: March 2, 2023
• Study Start: July 1, 2016
• Primary Completion: August 1, 2025
• Study Completion: December 31, 2025
• Last Updated: June 13, 2024

Record last verified: 2024-06

Locations

IT (1); US (1); GB (1); NO (1)