Oral glibenclamide in hyperglycaemia of the premature infant
Coordinating investigator :
Pr Elsa KERMORVANT, Service de Pédiatrie et Réanimation néonatales, Hôpital Necker – Enfants Malades, Paris
Scientific Director :
Pr Jacques BELTRAND et Pr Michel POLAK, Service d’Endocrinologie, Gynécologie et Diabétologie pédiatriques, Hôpital Necker – Enfants Malades, Paris
Pr Delphine MITANCHEZ, Service de médecine néonatale, Hôpital Bretonneau, Tours, France
Sponsor : Assistance Publique – Hôpitaux de Paris
Scientific justification :
Transient hyperglycaemia in premature infants results from an overall reduction in insulin sensitivity, with abnormal intragranular cleavage of proinsulin into insulin in the beta cell, leading to reduced secretion of active insulin. Intravenous administration of exogenous insulin can counteract insulin resistance and lower blood glucose levels, but it is difficult to use in premature infants and is associated with a significant risk of hypoglycaemia. Glibenclamide, which stimulates endogenous insulin secretion and can be administered enterally, could be an alternative to insulin therapy for the treatment of transient hyperglycaemia in premature infants.
Primary objective and primary endpoint
Primary objective :
To assess the 72-hour efficacy of an enteral suspension of glibenclamide in controlling transient hyperglycaemia in premature infants weighing less than 1500 g.
Primary Endpoint : 72 hours glycaemic control on glibenclamide treatment (success of the treatment). This is defined as the non-use of insulin and absence of severe hypoglycaemia (< 1.5 mmol/l) or persistent moderate hypoglycaemia (< 2.6 mmol/l in 2 successive capillary measurements at an interval of more than 3 hours).
Secondary objectives and enpoints :
Secondary objectives :
- To assess the overall efficacy of a suspension of glibenclamide in controlling hyperglycaemia;
- To assess the glycaemic profile under glibenclamide (time to glycaemic control, time spent in glycaemic target range);
- To assess caloric intake and early neonatal growth in premature infants treated with glibenclamide;
- To assess the safety and tolerability of glibenclamide;
- To assess the ease of use of glibenclamide;
- To evaluate the pharmacokinetics of enteral glibenclamide.
Secondary endpoints:
Efficacy :
- Overall success of the treatment defined by continuation to the end of treatment without insulin use.
- Glycaemic profile under glibenclamide :
- Time between the start of glibenclamide treatment and the 1st blood glucose < 10 mmol/l
- Time between the start of glibenclamide treatment and the 1st blood glucose < 8 mmol/l
- Proportion of time spent within the target blood glucose range (≥ 4 and < 10 mmol/l) during the period of glibenclamide treatment
- Proportion of time spent above the target level (≥ 10 mmol/l) during the period of glibenclamide treatment
- Proportion of time spent in hypoglycaemia (< 2.6 mmol/l) during the period of glibenclamide treatment.
- Duration of glibenclamide treatment.
- Nutritional intakes and growth:
- Carbohydrate, lipid, protein, mean caloric intake (kcal/kg/day) during treatment
- Mean weight gain (g/kg/day) during treatment and at 36 weeks post-menstrual age.
Tolerance and safety :
- Number of children with at least one episode of moderate (blood glucose < 2.6 mmol/l) or severe (< 1.5 mmol/l) hypoglycaemia within the first 72 hours of treatment and for the duration of treatment
- Number and type of adverse reactions to glibenclamide:
- Enteropathy, intestinal intolerance, necrotising enterocolitis;
- Liver abnormalities, increased creatinine levels or abnormal blood counts;
- And any other side effect.
- Neonatal morbidity assessed at 36 weeks post-menstrual age: intraventricular haemorrhage, periventricular leukomalacia, retinopathy of premature newborns, haemodynamic disorders, necrotising enterocolitis
- Mortality at 36 weeks post-menstrual age.
Ease of use :
- Number of dose adjustments;
- Ease of use assessment score by caregivers.
Pharmacocinétique :
- Concentrations plasmatiques de glibenclamide.
Design of the study:
Phase II, multicentre, non-comparative, dose-escalation therapeutic trial. The aim is to provide an initial assessment of the treatment’s efficacy and safety in premature infants.
Catégory :
Cat 2 : phase 2
Population of study participants :
Premature infants with transient hyperglycaemia
Inclusion Criteria (Test Phase / Phase II)
- Newborn less than 34 weeks post-mentrual age
- Birth weight < 1500 g
- Gestational age < 32 weeks
- Hyperglycaemia ≥ 10 mmol/l on 2 measurements taken at least 3 hours apart after eventual reduction of glucose intakes following each unit’s protocol (if not consecutive, within a maximum interval of 9 hours)
- Secure venous access point (umbilical venous catheter or epicutaneo-cava catheter)
- Enteral feeding considered or already started prior to enrolment
- Consent obtained from legal guardians
- Beneficiary of social security
Exclusion Criteria (Phase test/Phase II):
- Contraindication to enteral feeding (at the discretion of the clinician responsible for the child)
- Small for gestational age: 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 (if assessment indicated: V factor less than the standard laboratory range for the age) and/or severe cholestasis (conjugated bilirubin > 50 μmol/L)
- Hyperglycaemia 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
Investigational medicinal product(s):
Amglidia®: glibenclamide oral suspension 6 mg/ml. It will be administered via the gastric tube after dilution to 1/6th in human milk (human milk circuit identical to that of the study site).
1st dose of 0.2 mg/kg; subsequent doses administered every 3 or 6 hours at a dosage adapted according to capillary glycaemia monitored every 3 hours. Once blood glucose levels have returned to normal (4-6 mmol/l for 48 hours without glibenclamide), repeat dose only if blood glucose levels rise again above 8 mmol/l. As is usual with insulin treatment, treatment should last 3 to 15 days, rarely more than a week.
On the other hand, if no blood glucose < 10 mmol/l 18 hours after the first dose of treatment or if blood glucose > 20 mmol/l in the first 6 hours after treatment, stop glibenclamide and switch to insulin.
Comparator treatment : NA
Interventions added for the study :
- 4 to 5 blood samples of 0.2 ml for pharmacokinetic study;
- Blood sampling (3 samples for a maximum total volume of 2 ml): CBC, urea, creatinine, transaminases, haemostasis if not done as part of routine care;
- Blood glucose on fluoride tube at the time of pharmacokinetic sampling.
Expected benefits for the participants and for society
The expected benefits of glibenclamide oral suspension for patients and healthcare teams are related to its mode of action and the reduction of the burden and difficulties associated with insulin management:
- Stimulation of endogenous insulin secretion ;
- Increased peripheral and hepatic sensitivity to insulin, by increasing portal insulin concentration (which inhibits endogenous glucose production more effectively than exogenous insulin);
- Reduced risks associated with intravenous route (infections);
- Reduced logistical burden associated with insulin administration (training of nursing staff, maintenance of a central or peripheral route);
- Reduced nursing workload associated with insulin preparation (extemporaneous preparation time, including saturation of tubing) and monitoring of insulin infusions.
Risks and burdens added by the study :
For the premature infants in the study, the foreseeable risks are as follows:
- difficulties in balancing blood glucose levels and inadequate control, necessitating a rapid switch to insulin;
- digestive disorders: intestinal intolerance, enteropathy (however, the low osmolarity of the glibenclamide suspension and its dilution in human milk limits this risk).
The study is classified as Risk D by the sponsor (phase II study with a high level of monitoring in a vulnerable population).
Practical implementation :
Test phase: inclusion is planned in 3 stages with :
- 2 infants of gestational age ≥ 28 weeks’ gestation, then
- 3 infants of gestational age ≥ 26 weeks’ gestation, then
- 5 infants with no minimum gestational age criteria
Phase II: the second part of the study (including 35 patients) is a multicentre, non-comparative phase II therapeutic trial. The aim is to provide an initial assessment of the efficacy of the treatment and its safety in premature infants.
In practice, for each patient included (Phase test/Phase II):
T0 (when blood glucose ≥ 10 mmol/l on 2 occasions): inclusion visit; start of glibenclamide treatment;
During treatment: blood glucose monitoring every 3 h; evaluation of safety and tolerability (H12, H24 then daily); evaluation of ease of use; pharmacokinetic study;
48 hours after the end of treatment: assessment of clinical and biological tolerance;
36 SA AC: end-of-research visit.
Number of participants included :
45 (including test phase: 10)
Number of centres : 6
Duration of the study :
- inclusion period: 42 months
- duration of participation (treatment 3 to 15 days + follow-up): up to 36 SA corrected age, i.e. a maximum of 3 months
- total duration: 45 months