Clinical trial NCT02624830: Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
Official title: Long-term Sulfonylurea Response and Glucose Control After Switching From Insulin in Children With Diabetes Due to ABCC8 (SUR1) Mutations
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Permanent Neonatal Diabetes Mellitus
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: University of Bergen
name: University of Exeter
name: Royal Devon and Exeter NHS Foundation Trust
name: Institut National de la Santé Et de la Recherche Médicale, France
name: Hôpital Necker-Enfants Malades
name: University of Rome Tor Vergata
First posted: 2015-12-08
Enrollment: 30
Sex: ALL
Minimum age (years): 9
Maximum age (years): 95
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Sulfonylurea efficacy
timeFrame: Within 13 years from intervention
measure: Metabolic control
timeFrame: Within 13 years from intervention
Secondary outcomes:
measure: All cause mortality
timeFrame: Within 13 years from intervention
measure: Incidence of hypoglycemia
timeFrame: Within 13 years from intervention
measure: Incidence of ketoacidosis
timeFrame: Within 13 years from intervention
measure: Development of diarrhea
timeFrame: Within 13 years from intervention
measure: Development of discoloured teeth
timeFrame: Within 13 years from intervention
measure: Insulin secretory response to intravenous glucose
timeFrame: Within 13 years from intervention
measure: Insulin secretory response to oral glucose
timeFrame: Within 13 years from intervention
measure: Sulfonylurea dose
timeFrame: Within 13 years from intervention
measure: Insulin secretory response to a glucagon test
timeFrame: Within 13 years from intervention
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
Study officials:
affiliation: Haukeland University Hospital
name: Pål Rasmus Njølstad, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.