Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes

Permanent Neonatal Diabetes Mellitus Clinical Trial

— SuResponsKIR  

Official title:

Long-term Sulfonylurea Response and Glucose Control After Switching From Insulin in Children With Diabetes Due to KCNJ11 (KIR6.2) Mutations

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02624817
• Other study ID #: 167.06
• Status: Completed
• Phase: Phase 4
• First received: December 4, 2015
• Last updated: September 29, 2017
• Start date: December 2015
• Est. completion date: August 2016

Study information

• Verified date: September 2017
• Source: Haukeland University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 KCNJ11 that have been switched from insulin injections to sulfonylurea tablets.

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 KCNJ11 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 9 Years and older

Eligibility

Inclusion Criteria:

• Permanent diabetes due to a mutation in KCNJ11 (KIR6.2)

• 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 KCNJ11 (KIR6.2)

• Patients not successfully transferred from insulin to sulfonylurea

• Transferred to sulfonylurea treatment after November 1, 2006 (ie less than 9 years off insulin)

• Not willing or able to provide informed consent (parents if younger than 16 years of age)

Related Conditions & MeSH terms

• Diabetes Mellitus
• Infant, Newborn, Diseases
• Permanent Neonatal Diabetes Mellitus

Intervention

Drug:
• Sulfonylurea
See Arm description.

Locations

Country	Name	City	State
Norway	Haukeland University Hospital	Bergen

Sponsors (7)

Lead Sponsor	Collaborator
Haukeland University Hospital	Hôpital Necker-Enfants Malades, Institut National de la Santé Et de la Recherche Médicale, France, Royal Devon and Exeter NHS Foundation Trust, University of Bergen, University of Exeter, University of Rome Tor Vergata

Country where clinical trial is conducted

Norway, 

References & Publications (7)

Babenko AP, Polak M, Cavé 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. — View 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, Njølst — View Citation

Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug 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. — View Citation

Pearson ER, Flechtner I, Njølstad 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, Søvik O, Polak M, Hattersley AT; Neonatal Diabetes International Collabo — View 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. — View 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, Søvik O, Njølstad PR. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient chara — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sulfonylurea efficacy	Insulin requirement with or without sulfonylurea treatment during the intervention	Within 13 years from intervention
Primary	Metabolic control	Change in HbA1c levels during the intervention	Within 13 years from intervention
Secondary	All cause mortality	Death of all causes	Within 13 years from intervention
Secondary	Incidence of hypoglycemia	Episodes per year of severe hypoglycemia (ISPAD definitions)	Within 13 years from intervention
Secondary	Incidence of ketoacidosis	Episodes per year of severe ketoacidosis (ISPAD definitions)	Within 13 years from intervention
Secondary	Development of diarrhea	Chronic diarrhea with no clear cause	Within 13 years from intervention
Secondary	Development of discoloured teeth	Discoloured teeth with no clear cause	Within 13 years from intervention
Secondary	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
Secondary	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
Secondary	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
Secondary	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