Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR) (SuResponsSUR)

Long-term Sulfonylurea Response and Glucose Control After Switching From Insulin in Children With Diabetes Due to ABCC8 (SUR1) Mutations

The purpose of this study is to investigate long term response of sulfonylurea and glucose control in children with diabetes due to mutations in ABCC8 that have been switched from insulin injections to sulfonylurea tablets.

Study Overview

• Status: Unknown
• Conditions: Permanent Neonatal Diabetes Mellitus
• Intervention / Treatment: Drug: Sulfonylurea

Detailed Description

Neonatal diabetes mellitus is a rare, monogenic form of diabetes occurring during the first 6-9 months of life characterized by hyperglycemia requiring exogenous insulin therapy. The estimated incidence is 1 per 12000 newborns. Although homozygous or compound heterozygous mutations in the genes IPF1 or GCK were the first genetic causes of this disease to be identified, activating mutations in the KIR6.2 and sulfonylurea receptor 1 (SUR1) subunits of the pancreatic ATP-sensitive K+ channel, coded for by the genes KCNJ11 and ABCC8, have recently been identified as the major causes of both transient and permanent neonatal diabetes. In the normal pancreatic beta-cell, metabolism results in increased cellular ATP, which binds to KIR6.2. The potassium channel subsequently closes and hence depolarizes the membrane initiating insulin release via increased calcium entry. Conversely, increased cellular ADP acts on SUR1 to open the channel and prevent insulin release. Activating mutations in these channels reduces sensitivity to the inhibitory actions of ATP and increases sensitivity to the stimulatory actions of ADP. This causes the ATP-sensitive K+ channel to remain open, even in the presence of glucose, therefore preventing insulin release. Sulfonylureas act by an ATP-independent mechanism to close these channels even when mutations are present. Sulfonylureas result in insulin release and were therefore immediately considered and showed to be a potential treatment option in neonatal diabetes caused by mutations in these channels. The effective replacement of insulin treatment by high-dose sulfonylureas has been shown to be successful in 90% of patients with Kir6.2 mutations and 85% of patients with SUR1 mutations resulting in improved glycemic control.

This dramatic effect of sulfonylurea is now standard, world-wide treatment in neonatal diabetes due to a mutation in either KCNJ11 or ABCC8. There is, however, far no information on long-term use of sulfonylurea in patients with KCNJ11 or ABCC8 mutations. The investigators have therefore initiated an international, multicenter, prospective study aiming to include some 75 patients aged from 9 years with a genetic diagnosis of diabetes due to a ABCC8 gene mutation identified by sequencing in Bergen, Norway; Exeter, U.K.; Paris, France or Rome, Italy. Most patients were referred based on membership in the International Society of Pediatric and Adolescent Diabetes. All of the patients attempted transfer from treatment with insulin to a sufficient dose of sulfonylureas. No other selection criteria were applied, and all patients were included when there was outcome data following the attempted transfer. The observation period was at least 9 years after commencing sulfonylureas in all patients. The study is conducted in accordance with the Declaration of Helsinki and informed consent has been obtained from all participating patients, with parental consent given on behalf of children.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Åsta N Sulen; Phone Number: 004748214508; Email: asta.sulen@student.uib.no
• Study Contact Backup: Name: Pernille Svalastoga, MD; Phone Number: 004798443631; Email: pernille.svalastoga@helse-bergen.no

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Recruiting
    • Haukeland University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 93 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Permanent diabetes due to a mutation in ABCC8 (SUR1)
• Patients successfully transferred from insulin to sulfonylurea
• Transferred to sulfonylurea treatment before November 1, 2006 (ie 9 years off insulin)
• Willing and able to provide informed consent (parents if younger than 16 years of age)

Exclusion Criteria:

• Permanent diabetes not due to a mutation in ABCC8 (SUR1)
• Patients not successfully transferred from insulin to sulfonylurea
• Transferred to sulfonylurea treatment after November 1, 2006 (ie les than 9 years off insulin)
• Not willing or able to provide informed consent (parents if younger than 16 years of age)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Drug, Sulfonylurea; Sulfonylurea tablets (glibenclamide, other forms of sulfonylureas) were administered at the time of intervention (before November 1, 2006). The patients have been prospectively followed up. Sulfonylurea dose, insulin requirement, death of all causes, episodes of severe hypoglycemia, ketoacidosis, development of discoloured teeth and diarrhea have been recorded. For a small number of subjects, increment of insulin and C-peptide after either an oral or intravenous glucose load and/or response to intravenous glucagon have been tested.

Drug: Sulfonylurea; See Arm description.; Other Names: Glibenclamide and other forms of sulfonylureas

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sulfonylurea efficacy	Insulin requirement with or without sulfonylurea treatment during the intervention	Within 13 years from intervention
Metabolic control	Change in HbA1c levels during the intervention	Within 13 years from intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality	Death of all causes	Within 13 years from intervention
Incidence of hypoglycemia	Episodes per year of severe hypoglycemia (ISPAD definitions)	Within 13 years from intervention
Incidence of ketoacidosis	Episodes per year of severe ketoacidosis (ISPAD definitions)	Within 13 years from intervention
Development of diarrhea	Chronic diarrhea with no clear cause	Within 13 years from intervention
Development of discoloured teeth	Discoloured teeth with no clear cause	Within 13 years from intervention
Insulin secretory response to intravenous glucose	Change in increment of insulin and C-peptide after a standard intravenous glucose tolerance test tested at start of intervention and retested at end of the study	Within 13 years from intervention
Insulin secretory response to oral glucose	Change in increment of insulin and C-peptide after a standard oral glucose tolerance test tested at start of intervention and retested at end of the study	Within 13 years from intervention
Sulfonylurea dose	Change in sulfonylurea dose (per kg and day, and absolute dose per day) from start of intervention and up till end of study	Within 13 years from intervention
Insulin secretory response to a glucagon test	Change in increment of C-peptide and glucose after a standard glucagon test tested at start of intervention and retested at end of the study	Within 13 years from intervention

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; University of Bergen; University of Rome Tor Vergata; University of Exeter; Hôpital Necker-Enfants Malades; Royal Devon and Exeter NHS Foundation Trust
• Investigators: Study Director: Pål Rasmus Njølstad, MD, PhD, Haukeland University Hospital

Publications and helpful links

General Publications

• 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.
• Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006 Aug 3;355(5):456-66. doi: 10.1056/NEJMoa055068.
• 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. Erratum In: N Engl J Med. 2004 Sep 30;351(14):1470.
• Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes. 2004 Oct;53(10):2713-8. doi: 10.2337/diabetes.53.10.2713.
• Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT; Neonatal Diabetes International Collaborative Group. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care. 2008 Feb;31(2):204-9. doi: 10.2337/dc07-1785. Epub 2007 Nov 19.
• Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997 Jan;15(1):106-10. doi: 10.1038/ng0197-106.
• Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001 May 24;344(21):1588-92. doi: 10.1056/NEJM200105243442104. No abstract available.
• Bowman P, Mathews F, Barbetti F, Shepherd MH, Sanchez J, Piccini B, Beltrand J, Letourneau-Freiberg LR, Polak M, Greeley SAW, Rawlins E, Babiker T, Thomas NJ, De Franco E, Ellard S, Flanagan SE, Hattersley AT; Neonatal Diabetes International Collaborative Group. Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes. Diabetes Care. 2021 Jan;44(1):35-42. doi: 10.2337/dc20-1520. Epub 2020 Nov 12.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2019
• Primary Completion (Anticipated): February 1, 2020
• Study Completion (Anticipated): February 1, 2020

Study Registration Dates

• First Submitted: December 4, 2015
• First Submitted That Met QC Criteria: December 7, 2015
• First Posted (Estimate): December 8, 2015

Study Record Updates

• Last Update Posted (Actual): February 12, 2020
• Last Update Submitted That Met QC Criteria: February 10, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Glyburide
• Other Study ID Numbers: 167.06b

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No