Glibentek in Patients With Neonatal Diabetes Secondary to Mutations in K+-ATP Channels
Condition: Neonatal Diabetes Secondary to Mutation in the Potassium Channel
MeSH terms: Neoplasm Metastasis; Infant, Newborn, Diseases; Diabetes Mellitus
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): Glibenclamide
Intervention type(s): Drug
Intervention description(s): 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 MeSH terms: Glyburide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acceptability; Phase 3; Neonatal diabetes