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

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ClinicalTrials.gov Identifier: NCT03001089
Recruitment Status : Completed
First Posted : December 22, 2016
Last Update Posted : February 16, 2021
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.


Condition or disease Intervention/treatment Phase
Partial Mineralocorticoid Deficiency Drug: Oral Fludrocortisone (enteral) Drug: Placebo Oral Tablet Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Impact of the Administration of Fludrocortisone on Fluid and Electrolyte Balance in Very Premature Infants: Pilot Study
Actual Study Start Date : June 1, 2017
Actual Primary Completion Date : September 8, 2020
Actual Study Completion Date : September 8, 2020


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.




Primary Outcome Measures :
  1. Urinary sodium loss evaluated by the urinary ratio Na / creatinine [ Time Frame: day 3 (when urinary sodium losses are at their highest in very premature infants) ]
    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 :
  1. Urinary sodium loss evaluated by the urinary ratio Na / creatinine [ Time Frame: day1, day5, day8, day10 and day15 ]
    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.

  2. urinary sodium and potassium concentrations [ Time Frame: day1,day3, day5, day8, day10 and day15 ]
  3. plasma sodium and potassium concentrations [ Time Frame: day1, day3, day8 et day15 ]
  4. plasma renin concentrations [ Time Frame: day1, day3, day8 et day15 ]
  5. Number of blood tests [ Time Frame: day1,day3, day5, day8, day10 and day15 ]
  6. Neonatal complications [ Time Frame: up to 36 post-conceptional weeks (PCW) ]
  7. Patent ductus arteriosus (diagnosed by ultrasound) [ Time Frame: Between day2 and day5 and between day7 and day15 ]
  8. 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 ]
  9. Oxygen inspired fraction (FiO2) [ Time Frame: At Day 28 and 36 PCW ]
  10. 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 ]
  11. urinary dosage of aldosterone and cortisol [ Time Frame: At one month, three month, six month and twelve month. ]
  12. urinary index (Aldosterone/Nau) [ Time Frame: day3, day8 and day15 ]
  13. number of days of invasive and non invasive ventilation [ Time Frame: At Day 28 and 36 PCW ]
  14. weight newborns [ Time Frame: from day1 to day 8, at day 10 and day 15and at 36 PCW ]


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Ages Eligible for Study:   26 Weeks to 32 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03001089


Locations
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France
Hôpital Robert Debré
Paris, France, 75019
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Martinerie Laetitia, PHD APHP
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03001089    
Other Study ID Numbers: P150905
First Posted: December 22, 2016    Key Record Dates
Last Update Posted: February 16, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Neonatology
Endocrinology
Additional relevant MeSH terms:
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Hypoaldosteronism
Adrenal Insufficiency
Adrenal Gland Diseases
Endocrine System Diseases
Fludrocortisone
Anti-Inflammatory Agents