Glibentek in Patients With Neonatal Diabetes Secondary to Mutations in K+-ATP Channels

Study Overview
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Brief Summary
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The understanding of the molecular mechanisms of neonatal diabetes has deeply changed the therapy of patients carrying mutations in the K-ATP channel. Indeed, those patients are not treated anymore by insulin injections but by glibenclamide an oral anti-diabetic drug widely used in type 2 diabetes. Anyway, its galenic form (pills of 5 mg) is not suitable for children and difficult to administrate to infants or young children. The purpose of this study is to determine if a new galenic form of this durg is more suitable and as efficient as pills in children with neonatal diabetes.

Detailed Description
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Neonatal diabetes mellitus (NDM), characterized by hyperglycaemia requiring exogenous insulin therapy, is a rare condition that appears during the first months of life with an estimated incidence of 1 in 12000 newborns. We recently published that in our large cohort, the origin of the disease is an heterozygous activating mutation of the coding sequence of KCNJ11 or ABCC8 genes in 42% of patients. These genes encode for the Kir 6.2 subunit (KCNJ11 gene) and for the SUR1 subunit (ABCC8 gene) of the ATP-sensitive K+ channel (KATP) whom function in the beta cell is to induce a membrane depolarization triggering the exocytosis of insulin-containing granules. The understanding of the molecular substrate of the disease has deeply changed the therapy, allowing the switch from insulin injections to an oral medication with sulfonylureas. Indeed, these drugs specifically bind to SUR1 subunit increasing the closing ability of the KATP by an ATP-independent mechanisms stimulating insulin secretion. Together with others we demonstrated that these drugs were efficient in replacement of subcutaneous injected insulin in children or adults with a Kir6.2 or a SUR1 activating mutation allowing an excellent metabolic control of the disease without the side effects of insulin (hypoglycemia). Anyway, in most countries, glibenclamide has not been approved for use in children by heath authorities in france and its use is then only temporary tolerated in this specific indication. Furthermore its galenic form (pills) is not suitable for children and especially for infants. The dosage is too high for most infants and young children or children wih neurologic defects (frequently associated to this kind of neonatal diabetes) can't swallow pills. Chewing the pill can't be an alternative as sulfamides are known induce alterations of tooth enamel color. Most patients parents have to crush the pills and dilute the powder in water before administrating it to their child. Such process doesn't follow recommendations of administration of and medicine contradiction. It can also alter the drug cinetic.as glibenclamide is not completely soluble in water. After our successful clinical trial, we decided then to be a part in the development of a galenice form suitable for children. The AMMtek company has created a new galenic dedicated to pediatric patients. This new oral solution has been demonstrated to be safe and effective in a phase 1 study. Its pediatric investigation plan has been validated in july 2013 by the European medicine agency. The French drug and food agency (ANSM) has asked for a tolerance and acceptability study before giving its approval for use in children and infants with neonatal diabetes. The aim of this study is then to determine the tolerance and acceptability of an oral solution of glibenclamide (Glinbentek) developed and dedicated to pediatric patients with neonatal diabetes secondary to mutation in potassium channels.

Official Title
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Tolerance and Acceptability of Glibentek in Patients With Neonatale Diabetes Secondary to Mutations in K+-ATP Channels

Conditions
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Neonatal Diabetes Secondary to Mutation in the Potassium Channel

Intervention / Treatment
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* Drug: Glibenclamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age below 18 years Neonatal diabetes secondary to documented mutation in one of the 2 sub units of potassium channels Patients already treated by glibenclamide pills Signed consent Exclusion Criteria: Families unable to fill in the questionnaries Patients unable to answer to the visual hedonic squale Patients unable to take the oral solution Known allergy to sulfonylureas or to other antidiabetic or antibiotic sulfamides Insulin therapy associated to glibenclamide Miconazole therapy Porphyria Breast feeding Severe renal failure (creatinine clearance below 30 ml/mn) Liver failure (prothombine time below 70) Not affiliated to the health care system

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with neonatal diabetes<br>Patients with neonatal diabetes | Drug: Glibenclamide<br>* Glibenclamide pills will be administrated during one month at the previously used dosage. During the first month of the study we wwil record pharmacokinetic data, number of hypoglycaemia and the administration problems associated to this galenic form. At the end of the first month of enrolment, patients will be given oral solution of glibenclamide for the 4 remaining months. Pharmacocinetic data, number of hypoglycaemia and parents and children feeling about pratictability of administration will be then recorded.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability of an oral solution of glibenclamide (Hedonic visual scale) | Hedonic visual scale | 2 months after the change from pills to oral solution. | 
| Acceptability of an oral solution of glibenclamide (Hedonic visual scale) | Hedonic visual scale | 3 months after the change from pills to oral solution. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance of an oral solution of glibenclamide (Self administrated questionnaries) | Self administrated questionnaries, liver and renal biology | 2 months after the change from pills to oral solution. | 
| Tolerance of an oral solution of glibenclamide (Self administrated questionnaries) | Self administrated questionnaries, liver and renal biology | 3 months after the change from pills to oral solution. | 
| Recording pharmaceutical data on pills and oral solution of glibenclamide (Blood drug dosage) | Blood drug dosage | At inclusion | 
| Recording pharmaceutical data on pills and oral solution of glibenclamide (Blood drug dosage) | Blood drug dosage | 2 months after the switch from pills to oral solution | 
| No alteration in metabolic control of the disease | HbA1C at month 3, fructosamine at month 2 and 3, self record of hypoglycaemia during month 1, 2 and 3, glycemia before and after meals during 2 consecutive days at introduction of oral solution and during 2 meals at month 2 and month 3 | During the first month of administration | 
| No alteration in metabolic control of the disease | HbA1C at month 3, fructosamine at month 2 and 3, self record of hypoglycaemia during month 1, 2 and 3, glycemia before and after meals during 2 consecutive days at introduction of oral solution and during 2 meals at month 2 and month 3 | 2 months after the change from pills to oral solution | 
| No alteration in metabolic control of the disease | HbA1C at month 3, fructosamine at month 2 and 3, self record of hypoglycaemia during month 1, 2 and 3, glycemia before and after meals during 2 consecutive days at introduction of oral solution and during 2 meals at month 2 and month 3 | 3 months after the change from pills to oral solution | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acceptability, Phase 3, Neonatal diabetes