Impact of the Administration of Fludrocortisone in Very Premature Infants (MINIPREM)
Primary Purpose
Partial Mineralocorticoid Deficiency
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Oral Fludrocortisone (enteral)
Placebo Oral Tablet
Sponsored by
About this trial
This is an interventional treatment trial for Partial Mineralocorticoid Deficiency focused on measuring Neonatology, Endocrinology
Eligibility Criteria
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)
Sites / Locations
- Hôpital Robert Debré
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Fludrocortisone 10 µg tablets
placebo oral tablet
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
urinary sodium and potassium concentrations
plasma sodium and potassium concentrations
plasma renin concentrations
Number of blood tests
Neonatal complications
Patent ductus arteriosus (diagnosed by ultrasound)
Presence of intraventricular hemorrhage (diagnosed by ultrasound)
Oxygen inspired fraction (FiO2)
Blood pressure
urinary dosage of aldosterone and cortisol
urinary index (Aldosterone/Nau)
number of days of invasive and non invasive ventilation
weight newborns
Full Information
NCT ID
NCT03001089
First Posted
December 12, 2016
Last Updated
February 15, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT03001089
Brief Title
Impact of the Administration of Fludrocortisone in Very Premature Infants
Acronym
MINIPREM
Official Title
Impact of the Administration of Fludrocortisone on Fluid and Electrolyte Balance in Very Premature Infants: Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
June 1, 2017 (Actual)
Primary Completion Date
September 8, 2020 (Actual)
Study Completion Date
September 8, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Partial Mineralocorticoid Deficiency
Keywords
Neonatology, Endocrinology
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
66 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Fludrocortisone 10 µg tablets
Arm Type
Active Comparator
Arm Description
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.
Arm Title
placebo oral tablet
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Oral Fludrocortisone (enteral)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Intervention Description
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.
Primary Outcome Measure Information:
Title
Urinary sodium loss evaluated by the urinary ratio Na / creatinine
Description
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.
Time Frame
day 3 (when urinary sodium losses are at their highest in very premature infants)
Secondary Outcome Measure Information:
Title
Urinary sodium loss evaluated by the urinary ratio Na / creatinine
Description
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.
Time Frame
day1, day5, day8, day10 and day15
Title
urinary sodium and potassium concentrations
Time Frame
day1,day3, day5, day8, day10 and day15
Title
plasma sodium and potassium concentrations
Time Frame
day1, day3, day8 et day15
Title
plasma renin concentrations
Time Frame
day1, day3, day8 et day15
Title
Number of blood tests
Time Frame
day1,day3, day5, day8, day10 and day15
Title
Neonatal complications
Time Frame
up to 36 post-conceptional weeks (PCW)
Title
Patent ductus arteriosus (diagnosed by ultrasound)
Time Frame
Between day2 and day5 and between day7 and day15
Title
Presence of intraventricular hemorrhage (diagnosed by ultrasound)
Time Frame
between day2 and day5, and between day7 and day15, and at the age of 36 PCW
Title
Oxygen inspired fraction (FiO2)
Time Frame
At Day 28 and 36 PCW
Title
Blood pressure
Time Frame
From day1 to day8, at day10, at day15, at one month, three month, six month, twelve month and at 36 PCW
Title
urinary dosage of aldosterone and cortisol
Time Frame
At one month, three month, six month and twelve month.
Title
urinary index (Aldosterone/Nau)
Time Frame
day3, day8 and day15
Title
number of days of invasive and non invasive ventilation
Time Frame
At Day 28 and 36 PCW
Title
weight newborns
Time Frame
from day1 to day 8, at day 10 and day 15and at 36 PCW
10. Eligibility
Sex
All
Minimum Age & Unit of Time
26 Weeks
Maximum Age & Unit of Time
32 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Martinerie Laetitia, PHD
Organizational Affiliation
APHP
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Robert Debré
City
Paris
ZIP/Postal Code
75019
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Impact of the Administration of Fludrocortisone in Very Premature Infants
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