Neonatal Diabetes Secondary to Mutation in the Potassium Channel Clinical Trial
Official title:
Tolerance and Acceptability of Glibentek in Patients With Neonatale Diabetes Secondary to Mutations in K+-ATP Channels
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.
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.
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