Impact of the Administration of Fludrocortisone in Very Premature Infants (MINIPREM)

Impact of the Administration of Fludrocortisone on Fluid and Electrolyte Balance in Very Premature Infants: Pilot Study

Water and electrolytic homeostasis is remarkably controlled by the mineralocorticoid pathway (renin-angiotensin-aldosterone system acting on the renal tubule). However, the neonatal period in humans is characterized by a reduced ability of the kidney to ensure normal functions of urine concentration and maintenance of sodium and water balance. This renal functional immaturity, is associated in the very premature infants (VPT) (born <32 weeks of amenorrhea (SA)) to an immaturity of the adrenal responsible for a default of aldosterone biosynthesis . This relative aldosterone deficiency induces difficulties for VPT to adapt to extra-uterine life when maintaining a positive sodium balance is essential for postnatal growth. The improvement of perinatal care (antenatal corticosteroids maturation, ventilation techniques and use of surfactant) have increased the survival of these children . Nevertheless, extreme prematurity (less than 32 weeks), which concerns nearly 2% of live births in France, remains associated with neurodevelopmental sequelae in nearly 40% of children at 5 years .

Secondary hydroelectrolytic disorders with transient mineralocorticoid adrenal insufficiency is probably one of the factors responsible of these neurological deleterious outcomes as well as the occurrence of other complications (bronchopulmonary dysplasia, enterocolitis necrotizing) of extreme prematurity. Indeed, aside from the administration of antenatal steroids to induce maturation, the prevention of postnatal dehydration reduces the risk of intracranial hemorrhage in that population. However, high fluid intake are associated with an increased incidence of patent ductus arteriosus, of bronchopulmonary dysplasia and necrotizing enterocolitis. This necessitates the evaluation of preventive measures to avoid such fluid and electrolyte imbalances by a pharmacological approach based on mineralocorticoid administration in very premature infants, due to the relative aldosterone deficiency identified in this population.

Study Overview

• Status: Completed
• Conditions: Partial Mineralocorticoid Deficiency
• Intervention / Treatment: Drug: Oral Fludrocortisone (enteral); Drug: Placebo Oral Tablet

Detailed Description

Extreme prematurity affects about 2% of births per year in France and is subject to a significant morbidity and mortality. It is likely that the fluid and electrolyte imbalances associated with mineralocorticoid adrenal insufficiency transient observed in this population of vulnerable newborns contribute to the occurrence of complications that will influence the prognosis medium and long term these children. The expected impact of our pilot study is a direct benefit to the patient, with reduced kidney soda losses from the 3rd day of life and throughout the first week of life (assessed by a non-invasive method: urine collection to compress and measurement of urinary Na / creatinine). This physiological approach (substitution of the deficient hormone) allow better control of sodium and water balance. This could limit a number of common complications of extreme prematurity, occurring in the first weeks of life, such as patent ductus arteriosus, intra-ventricular hemorrhage and bronchopulmonary dysplasia.

The administration of glucocorticoids during the postnatal period (with action both glucocorticoid and mineralocorticoid) enables a reduction in the incidence of bronchopulmonary dysplasia severe. However, such treatment is associated with an increased incidence of neurodevelopmental effects related to activation of the glucocorticoid pathway. Using a specific mineralocorticoid agonist should preserve the beneficial effects without the adverse effects observed. The results of this pilot study will in a second time to consider a clinical trial Phase III national or international evaluating the significant reduction of these complications after substitution by Fludrocortisone the first week of life in the great premature. These results should have a major medical and economic impact. Indeed, neonatal morbidity indicators (intraventricular hemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia and enterocolitis necrotizing) are associated with the subsequent development of neurodevelopmental sequelae (cerebral palsy and / or cognitive impairment) at the age of two and five years.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75019
    • Hôpital Robert Debré

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Very premature newborns defined by a gestational age <32 and ≥ 26 gestational weeks
• Eutrophic: birth weight between the 10th and 90th percentile of the French reference curves
• Absence of malformations or chromosomal abnormality identified
• Lack of adrenal, pituitary or gonadal diseases diagnosed prior birth
• Lack of participation in another research protocol
• "Inborn": born and hospitalized in the four neonatology departments participating in the study
• Informed consent of the holders of parental authority

Exclusion criteria:

• Maternal treatment prior to pregnancy: systemic or inhaled corticosteroids, hormone therapy for adrenal or pituitary insufficiency, antihypertensive treatment (calcium channel blockers, beta blockers, angiotensin)
• Lack or incomplete treatment of antenatal glucocorticoids (betamethasone)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fludrocortisone 10 µg tablets; Oral Fludrocortisone (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.	Drug: Oral Fludrocortisone (enteral); Oral Fludrocortisone (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.
Placebo Comparator: placebo oral tablet; Oral placebo (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.	Drug: Placebo Oral Tablet; oral placebo (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary sodium loss evaluated by the urinary ratio Na / creatinine	Measurement of Na / urinary creatinine ratio at day 3 (evaluating the efficacity of Fludrocortisone action on the kidney by lowering sodium losses, that are very high in very premature infants) by collection of a urinary spot collected on a gauze compress, placed in the diaper of the newborn.	day 3 (when urinary sodium losses are at their highest in very premature infants)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary sodium loss evaluated by the urinary ratio Na / creatinine	Measurement of Na / urinary creatinine ratio at day 1, 5, 8, 10 and 15 (evaluating the efficacity of Fludrocortisone action on the kidney by lowering sodium losses, that are very high in very premature infants) by collection of a urinary spot collected on a gauze compress, placed in the diaper of the newborn.	day1, day5, day8, day10 and day15
urinary sodium and potassium concentrations		day1,day3, day5, day8, day10 and day15
plasma sodium and potassium concentrations		day1, day3, day8 et day15
plasma renin concentrations		day1, day3, day8 et day15
Number of blood tests		day1,day3, day5, day8, day10 and day15
Neonatal complications		up to 36 post-conceptional weeks (PCW)
Patent ductus arteriosus (diagnosed by ultrasound)		Between day2 and day5 and between day7 and day15
Presence of intraventricular hemorrhage (diagnosed by ultrasound)		between day2 and day5, and between day7 and day15, and at the age of 36 PCW
Oxygen inspired fraction (FiO2)		At Day 28 and 36 PCW
Blood pressure		From day1 to day8, at day10, at day15, at one month, three month, six month, twelve month and at 36 PCW
urinary dosage of aldosterone and cortisol		At one month, three month, six month and twelve month.
urinary index (Aldosterone/Nau)		day3, day8 and day15
number of days of invasive and non invasive ventilation		At Day 28 and 36 PCW
weight newborns		from day1 to day 8, at day 10 and day 15and at 36 PCW

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Martinerie Laetitia, PHD, APHP

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): September 8, 2020
• Study Completion (Actual): September 8, 2020

Study Registration Dates

• First Submitted: December 12, 2016
• First Submitted That Met QC Criteria: December 20, 2016
• First Posted (Estimate): December 22, 2016

Study Record Updates

• Last Update Posted (Actual): February 16, 2021
• Last Update Submitted That Met QC Criteria: February 15, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Endocrinology; Neonatology
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency; Hypoaldosteronism; Anti-Inflammatory Agents; Fludrocortisone
• Other Study ID Numbers: P150905

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No