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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
35
Amglidia®: glibenclamide oral suspension 6 mg/ml administered by gastric tube after dilution to 1/6th in human milk
* 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.
Hopital Necker - Enfants malades
Paris, France
RECRUITINGBlood glucose control
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)
Time frame: At 72 hours after the first administration
Overall success of the treatment
Overall success of the treatment defined by continuation to the end of treatment without recourse to insulin.
Time frame: At 36 week of amenorrhea corrected age
Blood glucose profile on glibenclamide
Time between the start of glibenclamide treatment and the 1st blood glucose \< 10 mmol/l
Time frame: At the end of treatment assessed up to 15 days
Blood glucose profile on glibenclamide
Time between the start of glibenclamide treatment and the 1st blood glucose \< 8 mmol/l
Time frame: At the end of treatment assessed up to 15 days
Blood glucose profile on glibenclamide
Proportion of time spent within the target blood glucose range (≥ 4 and \< 10 mmol/l) during the period of glibenclamide treatment
Time frame: At the end of treatment assessed up to 15 days
Blood glucose profile on glibenclamide
Proportion of time spent above the target level (≥ 10 mmol/l) during the period of glibenclamide treatment
Time frame: At the end of treatment assessed up to 15 days
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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
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.
Blood glucose profile on glibenclamide
Proportion of time spent in hypoglycemia (\< 2.6 mmol/l) during the period of glibenclamide treatment
Time frame: At the end of treatment assessed up to 15 days
Duration of glibenclamide treatment
Duration of glibenclamide treatment.
Time frame: At the end of treatment assessed up to 15 days
Nutritional intakes and growth
Carbohydrate
Time frame: At the end of treatment assessed up to 15 days
Nutritional intakes and growth:
lipid
Time frame: At the end of treatment assessed up to 15 days
Nutritional intakes and growth:
protein
Time frame: At the end of treatment assessed up to 15 days
Nutritional intakes and growth:
mean caloric intake (kcal/kg/day) during treatment
Time frame: At the end of treatment assessed up to 15 days
Nutritional intakes and growth:
mean weight gain (g/kg/day)
Time frame: At the end of treatment assessed up to 15 days
Nutritional intakes and growth
Carbohydrate
Time frame: At 36 week of amenorrhea corrected age
Nutritional intakes and growth:
lipid
Time frame: At 36 week of amenorrhea corrected age
Nutritional intakes and growth:
protein
Time frame: At 36 week of amenorrhea corrected age
Nutritional intakes and growth:
mean caloric intake (kcal/kg/day) during treatment
Time frame: At 36 week of amenorrhea corrected age
Nutritional intakes and growth:
mean weight gain ((g/kg/day)
Time frame: At 36 week of amenorrhea corrected age
Number of children with episode of hypoglycemia
Number of children with at least one episode of moderate (blood glucose \< 2.6 mmol/l) or severe (\< 1.5 mmol/l) hypoglycemia
Time frame: At 72 hours after first administration
Number of children with episode of hypoglycemia
Number of children with at least one episode of moderate (blood glucose \< 2.6 mmol/l) or severe (\< 1.5 mmol/l) hypoglycemia
Time frame: At the end of treatment assessed up to 15 days
Type of adverse reactions on glibenclamide
evaluation of the type of adverse reactions identified during the study
Time frame: At 36 week of amenorrhea corrected age
Number of adverse reactions on glibenclamide
evaluation of number of adverse reactions identified during the study
Time frame: At 36 week of amenorrhea corrected age
Number of participants with co-morbidity
Neonatal morbidity assessed at 36 WA corrected age: intraventricular haemorrhage, periventricular leukomalacia, retinopathy of premature newborns, haemodynamic disorders, ulcerative necrotising enterocolitis
Time frame: At 36 week of amenorrhea corrected age
Mortality
Mortality will be assessed
Time frame: At 36 week of amenorrhea corrected age
Dose adjustment
Number of dose adjustments, to evaluate the easy of use
Time frame: At the end of treatment assessed up to 15 days
ease of use by caregivers
Assessment scores by visual-analogue scale for ease of use by caregivers; 0 as the lowest score, 10 as the highest score
Time frame: At day one of treatment
ease of use by caregivers
Assessment scores by visual-analogue scale for ease of use by caregivers; 0 as the lowest score, 10 as the highest score
Time frame: At day two of treatment
ease of use by caregivers
Assessment scores by visual-analogue scale for ease of use by caregivers; 0 as the lowest score, 10 as the highest score
Time frame: At day three of treatment
Plasma concentrations of glibenclamide
Evaluated by the pharmacokinetics study
Time frame: At 3 hours after the first administration
Plasma concentrations of glibenclamide
Evaluated by the pharmacokinetics study
Time frame: At 6 hours after the first administration
Plasma concentrations of glibenclamide
Evaluated by the pharmacokinetics study
Time frame: At 10 hours after the first administration
Plasma concentrations of glibenclamide
Evaluated by the pharmacokinetics study
Time frame: At 24 hours after the first administration
Plasma concentrations of glibenclamide
Evaluated by the pharmacokinetics study
Time frame: At 24 hours of blood glucose stabilization