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Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes (SuResponsKIR)

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ClinicalTrials.gov Identifier: NCT02624817
Recruitment Status : Completed
First Posted : December 8, 2015
Last Update Posted : October 3, 2017
Sponsor:
Collaborators:
University of Bergen
University of Exeter
Royal Devon and Exeter NHS Foundation Trust
Institut National de la Santé Et de la Recherche Médicale, France
Hôpital Necker-Enfants Malades
University of Rome Tor Vergata
Information provided by (Responsible Party):
Haukeland University Hospital

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

Condition or disease Intervention/treatment Phase
Permanent Neonatal Diabetes Mellitus Drug: Sulfonylurea Phase 4

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 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Long-term Sulfonylurea Response and Glucose Control After Switching From Insulin in Children With Diabetes Due to KCNJ11 (KIR6.2) Mutations
Actual Study Start Date : December 2015
Actual Primary Completion Date : August 2016
Actual Study Completion Date : August 2016


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 glucagon have been tested.
Drug: Sulfonylurea
See Arm description.
Other Name: Glibenclamide and other forms of sulfonylureas




Primary Outcome Measures :
  1. Sulfonylurea efficacy [ Time Frame: Within 13 years from intervention ]
    Insulin requirement with or without sulfonylurea treatment during the intervention

  2. Metabolic control [ Time Frame: Within 13 years from intervention ]
    Change in HbA1c levels during the intervention


Secondary Outcome Measures :
  1. All cause mortality [ Time Frame: Within 13 years from intervention ]
    Death of all causes

  2. Incidence of hypoglycemia [ Time Frame: Within 13 years from intervention ]
    Episodes per year of severe hypoglycemia (ISPAD definitions)

  3. Incidence of ketoacidosis [ Time Frame: Within 13 years from intervention ]
    Episodes per year of severe ketoacidosis (ISPAD definitions)

  4. Development of diarrhea [ Time Frame: Within 13 years from intervention ]
    Chronic diarrhea with no clear cause

  5. Development of discoloured teeth [ Time Frame: Within 13 years from intervention ]
    Discoloured teeth with no clear cause

  6. Insulin secretory response to intravenous glucose [ Time Frame: Within 13 years from intervention ]
    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

  7. Insulin secretory response to oral glucose [ Time Frame: Within 13 years from intervention ]
    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

  8. Sulfonylurea dose [ Time Frame: Within 13 years from intervention ]
    Change in sulfonylurea dose (per kg and day, and absolute dose per day) from start of intervention and up till end of study

  9. Insulin secretory response to a glucagon test [ Time Frame: Within 13 years from intervention ]
    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



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Ages Eligible for Study:   9 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02624817


Locations
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Norway
Haukeland University Hospital
Bergen, Norway, 5021
Sponsors and Collaborators
Haukeland University Hospital
University of Bergen
University of Exeter
Royal Devon and Exeter NHS Foundation Trust
Institut National de la Santé Et de la Recherche Médicale, France
Hôpital Necker-Enfants Malades
University of Rome Tor Vergata
Investigators
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Study Director: Pål R Njølstad, MD PhD Haukeland University Hospital

Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Haukeland University Hospital
ClinicalTrials.gov Identifier: NCT02624817     History of Changes
Other Study ID Numbers: 167.06
First Posted: December 8, 2015    Key Record Dates
Last Update Posted: October 3, 2017
Last Verified: September 2017

Additional relevant MeSH terms:
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Diabetes Mellitus
Infant, Newborn, Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glyburide
Hypoglycemic Agents
Physiological Effects of Drugs