Glibenclamide Adverse Reaction, Preterm, Transient; Hypoglycemia, Neonatal
Conditions
Keywords
transient hypoglycemia, preterm, glibenclamide
Brief summary
The purpose of this study is to confirm hypothesis that Glibenclamide can be administered orally and is an alternative to insulin therapy in treating transient hyperglycemia of premature newborns.
Detailed description
Transient hyperglycemia of premature newborns results from an overall decrease in insulin sensitivity, which is responsible at the beta cell level for abnormalities of intragranular cleavage of proinsulin into insulin, leading to reduced active insulin secretion. Intravenous administration of exogenous insulin can be used to combat insulin resistance and lower blood glucose, but it is difficult to manage in premature newborns and is associated with a substantial risk of hypoglycemia. Glibenclamide, which stimulates endogenous insulin secretion and can be administered orally, might be an alternative to insulin therapy in treating transient hyperglycemia of premature newborns.
Interventions
DRUGGlibenclamide
Amglidia®: glibenclamide oral suspension 6 mg/ml administered by gastric tube after dilution to 1/6th in human milk
BIOLOGICALPharmacokinetics study
* For the first 10 patients during the test phase, four 0.2 ml samples will be taken at H3, H6, H10, and H24 (+/- 1 hour) after the first dose; an additional sample will be taken for patients whose blood sugar levels stabilize beyond 24 hours, after 6 hours of stable blood sugar levels (4-10 mmol/l); * For subsequent patients included during phase II: * 1 sample of 0.2 ml within the first 24 hours of treatment, during a care assessment. * 1 sample of 0.2 ml within the first 24 hours of treatment, during a care assessment * 1 sample of 0.2 ml per day at each daily check-up as part of care during the treatment period. * In centers that are unable to perform the samples and the appropriate techniques for centralizing these PK points, these samples will not be taken. PK parameters of glibenclamide will be determined using nonlinear analysis: area under the plasma concentration time curve (AUC), absorption constant, apparent clearance and volume of distribution.
BIOLOGICALC-peptide proinsulin ratio
blood sampling at before first administration and after 24 hours for measurement of C-peptide proinsulin ratio if it is impossible to collect both volumes, the C-peptide collection will be prioritized
BIOLOGICALRoutine biological monitoring
If there are not performed as part of standard care, biological monitoring of ALT, AST, complete blood count, hemostasis, urea, creatinine, blood ionogram, total bilirubin and conjugated bilirubin will be done before first administration at the following time frame : 48 hours after the first administration than each days during treatment period, and 48 hours after the end of treatment. Transaminases and hemostasis will be done only in case of clinical indication before the first administration.
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 34 Weeks
Healthy volunteers
No
Inclusion criteria
* Newborn less than 34 week of amenorrhea corrected age * Birth weight \< 1500 g * Birth term \< 32 week of amenorrhea * Hyperglycemia ≥ 10 mmol/l in 2 measurements, 3 hours apart after potential reduction of glucose intakes following each department's protocol * Secure venous access point (umbilical venous catheter or epicutaneo-cava catheter) * Enteral feeding considered before inclusion or already established * Consent obtained from persons holding parental authority * Beneficiary of social security
Exclusion criteria
* Contraindication to enteral feeding (at the discretion of the clinician responsible for the child) * Contraindication to glibenclamide according to current SPC * Foetal growth restriction (FGR) birth weight \< 3rd percentile (AUDIPOG definition) * Severe birth defect, including cardiac malformation associated with a risk of myocardial ischemia * Severe sepsis requiring mechanical ventilation or haemodynamic support * Severe renal dysfunction (serum creatinine \> 120 µmol/l) * Severe hepatocellular failure (V factor less than the standard laboratory range for the age) and/or severe cholestasis (\> 50 µmol/L) * Hyperglycemia associated with an error in administering glucose infusion * Profound hypophosphoremia (\< 1 mmol/l) * Hypersensitivity to glibenclamide or other sulphonylureas or sulphonamides, or one of the excipients * Patient with continuous insulin IV administration * Patient treated with miconazole
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood glucose control | At 72 hours after the first administration | The primary evaluation criteria is 72 hours blood glucose control on glibenclamide treatment (success of the treatment). This is defined as the non-use of insulin and absence of severe hypoglycemia (\< 1.5 mmol/l) or persistent moderate hypoglycemia (\< 2.6 mmol/l in 2 successive measurements (dextro) at an interval of more than 3 hours) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall success of the treatment | At 36 week of amenorrhea corrected age | Overall success of the treatment defined by continuation to the end of treatment without recourse to insulin. |
| Blood glucose profile on glibenclamide | At the end of treatment assessed up to 15 days | Time between the start of glibenclamide treatment and the 1st blood glucose \< 10 mmol/l |
| Duration of glibenclamide treatment | At the end of treatment assessed up to 15 days | Duration of glibenclamide treatment. |
| Nutritional intakes and growth | At the end of treatment assessed up to 15 days | Carbohydrate |
| Nutritional intakes and growth: | At the end of treatment assessed up to 15 days | lipid |
| Number of children with episode of hypoglycemia | At 72 hours after first administration | Number of children with at least one episode of moderate (blood glucose \< 2.6 mmol/l) or severe (\< 1.5 mmol/l) hypoglycemia |
| Type of adverse reactions on glibenclamide | At 36 week of amenorrhea corrected age | evaluation of the type of adverse reactions identified during the study |
| Number of adverse reactions on glibenclamide | At 36 week of amenorrhea corrected age | evaluation of number of adverse reactions identified during the study |
| Number of participants with co-morbidity | At 36 week of amenorrhea corrected age | Neonatal morbidity assessed at 36 WA corrected age: intraventricular haemorrhage, periventricular leukomalacia, retinopathy of premature newborns, haemodynamic disorders, ulcerative necrotising enterocolitis |
| Mortality | At 36 week of amenorrhea corrected age | Mortality will be assessed |
| Dose adjustment | At the end of treatment assessed up to 15 days | Number of dose adjustments, to evaluate the easy of use |
| ease of use by caregivers | At day one of treatment | Assessment scores by visual-analogue scale for ease of use by caregivers; 0 as the lowest score, 10 as the highest score |
| Plasma concentrations of glibenclamide | At 3 hours after the first administration | Evaluated by the pharmacokinetics study |
Countries
France
Contacts
STUDY_DIRECTORJacques BELTRAND, Pr
Assistance Publique - Hôpitaux de Paris
STUDY_DIRECTORMichel POLAK
Assistance Publique - Hôpitaux de Paris
STUDY_DIRECTORDelphine MITANCHEZ
CHRU de Tours
Outcome results
None listed