Oral Glibenclamide in Preterm Infants With Hyperglycaemia (GALOP)

Study Overview
=================
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.

Official Title
-----------------
Oral Glibenclamide in Preterm Infants With Hyperglycaemia (GALOP)

Conditions
-----------------
Transient; Hypoglycemia, Neonatal, Preterm, Glibenclamide Adverse Reaction

Intervention / Treatment
-----------------
* Drug: Glibenclamide
* Biological: Pharmacokinetics study
* Biological: C-peptide proinsulin ratio
* Biological: Blood glucose on fluorinated tube
* Biological: Routine biological monitoring
* Biological: glycose holter monitor


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 34 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glibenclamide oral<br>Amglidia®: glibenclamide oral suspension 6 mg/ml administered by gastric tube after dilution to 1/6th in human milk | Drug: Glibenclamide<br>* Amglidia®: glibenclamide oral suspension 6 mg/ml administered by gastric tube after dilution to 1/6th in human milk<br>Biological: Pharmacokinetics study<br>* 0.2 ml blood sampling at 3 hours, 6 hours, 10 hours and 24 hours after the first administration and after 24 hours of blood glucose stabilization. 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<br>Biological: C-peptide proinsulin ratio<br>* blood sampling at before first administration and after 24 hours for measurement of C-peptide proinsulin ratio<br>Biological: Blood glucose on fluorinated tube<br>* 0.3 ml blood sampling at 3 hours, 6 hours, 10 hours and 24 hours after the first administration and after 24 hours of blood glucose stabilization.<br>Biological: Routine biological monitoring<br>* If there are not performed as part of standard care, biological monitoring of ALT, AST, complete blood count, hemostasis, urea, creatinine, blood ionogram 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.<br>Biological: glycose holter monitor<br>* glucose levels will be collected with a smarter continuous glucose monitoring system, placed on inclusion and until the end of treatment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood 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) | At 72 hours after the first administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall success of the treatment | Overall success of the treatment defined by continuation to the end of treatment without recourse to insulin. | 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 | 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 | 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 | 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 | At the end of treatment assessed up to 15 days | 
| Blood glucose profile on glibenclamide | Proportion of time spent in hypoglycemia (< 2.6 mmol/l) during the period of glibenclamide treatment | At the end of treatment assessed up to 15 days | 
| Duration of glibenclamide treatment | Duration of glibenclamide treatment. | At the end of treatment assessed up to 15 days | 
| Nutritional intakes and growth | Carbohydrate | At the end of treatment assessed up to 15 days | 
| Nutritional intakes and growth: | lipid | At the end of treatment assessed up to 15 days | 
| Nutritional intakes and growth: | protein | At the end of treatment assessed up to 15 days | 
| Nutritional intakes and growth: | mean caloric intake (kcal/kg/day) during treatment | At the end of treatment assessed up to 15 days | 
| Nutritional intakes and growth: | mean weight gain (g/kg/day) | At the end of treatment assessed up to 15 days | 
| Nutritional intakes and growth | Carbohydrate | At 36 week of amenorrhea corrected age | 
| Nutritional intakes and growth: | lipid | At 36 week of amenorrhea corrected age | 
| Nutritional intakes and growth: | protein | At 36 week of amenorrhea corrected age | 
| Nutritional intakes and growth: | mean caloric intake (kcal/kg/day) during treatment | At 36 week of amenorrhea corrected age | 
| Nutritional intakes and growth: | mean weight gain ((g/kg/day) | 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 | 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 | 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 | At 36 week of amenorrhea corrected age | 
| Number of adverse reactions on glibenclamide | evaluation of number of adverse reactions identified during the study | 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 | At 36 week of amenorrhea corrected age | 
| Mortality | Mortality will be assessed | At 36 week of amenorrhea corrected age | 
| Dose adjustment | Number of dose adjustments, to evaluate the easy of use | 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 | 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 | 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 | At day three of treatment | 
| Plasma concentrations of glibenclamide | Evaluated by the pharmacokinetics study | At 3 hours after the first administration | 
| Plasma concentrations of glibenclamide | Evaluated by the pharmacokinetics study | At 6 hours after the first administration | 
| Plasma concentrations of glibenclamide | Evaluated by the pharmacokinetics study | At 10 hours after the first administration | 
| Plasma concentrations of glibenclamide | Evaluated by the pharmacokinetics study | At 24 hours after the first administration | 
| Plasma concentrations of glibenclamide | Evaluated by the pharmacokinetics study | At 24 hours of blood glucose stabilization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
transient hypoglycemia, preterm, glibenclamide