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

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Diabetes Secondary to Mutation in the Potassium Channel
• Intervention / Treatment: Drug: Glibenclamide

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 7501
    • Hôpital Universitaire Necker Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Patients with neonatal diabetes

Drug: 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Michel Polak, MD, PhD, Hopital Universitaire Necker Enfants Malades, Assistance publique - hôpitaux de Paris, Faculté de medicine Paris Descartes, Université Sorbonne Paris cité

Publications and helpful links

General Publications

• Busiah K, Drunat S, Vaivre-Douret L, Bonnefond A, Simon A, Flechtner I, Gerard B, Pouvreau N, Elie C, Nimri R, De Vries L, Tubiana-Rufi N, Metz C, Bertrand AM, Nivot-Adamiak S, de Kerdanet M, Stuckens C, Jennane F, Souchon PF, Le Tallec C, Desiree C, Pereira S, Dechaume A, Robert JJ, Phillip M, Scharfmann R, Czernichow P, Froguel P, Vaxillaire M, Polak M, Cave H; French NDM study group. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected]. Lancet Diabetes Endocrinol. 2013 Nov;1(3):199-207. doi: 10.1016/S2213-8587(13)70059-7. Epub 2013 Sep 6. Erratum In: Lancet Diabetes Endocrinol. 2013 Nov;1(3):e14.
• Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT; Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006 Aug 3;355(5):467-77. doi: 10.1056/NEJMoa061759.
• Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006 Aug 3;355(5):456-66. doi: 10.1056/NEJMoa055068.
• Beltrand J, Baptiste A, Busiah K, Bouazza N, Godot C, Boucheron A, Djerada Z, Gozalo C, Berdugo M, Treluyer JM, Elie C, Polak M; GLID-KIR study group. Glibenclamide oral suspension: Suitable and effective in patients with neonatal diabetes. Pediatr Diabetes. 2019 May;20(3):246-254. doi: 10.1111/pedi.12823. Epub 2019 Feb 21.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2015
• Primary Completion (Actual): March 4, 2016
• Study Completion (Actual): July 22, 2019

Study Registration Dates

• First Submitted: February 24, 2015
• First Submitted That Met QC Criteria: March 2, 2015
• First Posted (Estimate): March 3, 2015

Study Record Updates

• Last Update Posted (Actual): August 30, 2019
• Last Update Submitted That Met QC Criteria: August 29, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Acceptability; Phase 3; Neonatal diabetes
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Neoplasms; Endocrine System Diseases; Neoplastic Processes; Diabetes Mellitus; Neoplasm Metastasis; Infant, Newborn, Diseases; Hypoglycemic Agents; Physiological Effects of Drugs; Glyburide
• Other Study ID Numbers: 2014-003436-39