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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

10 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-03-20

Study Completion Date

2019-07-22

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.

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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.

Conditions

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Neonatal Diabetes Secondary to Mutation in the Potassium Channel

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Patients with neonatal diabetes

Group Type EXPERIMENTAL

Glibenclamide

Intervention Type DRUG

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.

Interventions

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Glibenclamide

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.

Intervention Type DRUG

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

Minimum Eligible Age

1 Month

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Michel Polak, MD, PhD

Role: STUDY_DIRECTOR

Hopital Universitaire Necker Enfants Malades, Assistance publique - hôpitaux de Paris, Faculté de medicine Paris Descartes, Université Sorbonne Paris cité