<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03001089</url>
  </required_header>
  <id_info>
    <org_study_id>P150905</org_study_id>
    <nct_id>NCT03001089</nct_id>
  </id_info>
  <brief_title>Impact of the Administration of Fludrocortisone in Very Premature Infants</brief_title>
  <acronym>MINIPREM</acronym>
  <official_title>Impact of the Administration of Fludrocortisone on Fluid and Electrolyte Balance in Very Premature Infants: Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Water and electrolytic homeostasis is remarkably controlled by the mineralocorticoid pathway&#xD;
      (renin-angiotensin-aldosterone system acting on the renal tubule). However, the neonatal&#xD;
      period in humans is characterized by a reduced ability of the kidney to ensure normal&#xD;
      functions of urine concentration and maintenance of sodium and water balance. This renal&#xD;
      functional immaturity, is associated in the very premature infants (VPT) (born &lt;32 weeks of&#xD;
      amenorrhea (SA)) to an immaturity of the adrenal responsible for a default of aldosterone&#xD;
      biosynthesis . This relative aldosterone deficiency induces difficulties for VPT to adapt to&#xD;
      extra-uterine life when maintaining a positive sodium balance is essential for postnatal&#xD;
      growth. The improvement of perinatal care (antenatal corticosteroids maturation, ventilation&#xD;
      techniques and use of surfactant) have increased the survival of these children .&#xD;
      Nevertheless, extreme prematurity (less than 32 weeks), which concerns nearly 2% of live&#xD;
      births in France, remains associated with neurodevelopmental sequelae in nearly 40% of&#xD;
      children at 5 years .&#xD;
&#xD;
      Secondary hydroelectrolytic disorders with transient mineralocorticoid adrenal insufficiency&#xD;
      is probably one of the factors responsible of these neurological deleterious outcomes as well&#xD;
      as the occurrence of other complications (bronchopulmonary dysplasia, enterocolitis&#xD;
      necrotizing) of extreme prematurity. Indeed, aside from the administration of antenatal&#xD;
      steroids to induce maturation, the prevention of postnatal dehydration reduces the risk of&#xD;
      intracranial hemorrhage in that population. However, high fluid intake are associated with an&#xD;
      increased incidence of patent ductus arteriosus, of bronchopulmonary dysplasia and&#xD;
      necrotizing enterocolitis. This necessitates the evaluation of preventive measures to avoid&#xD;
      such fluid and electrolyte imbalances by a pharmacological approach based on&#xD;
      mineralocorticoid administration in very premature infants, due to the relative aldosterone&#xD;
      deficiency identified in this population.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Extreme prematurity affects about 2% of births per year in France and is subject to a&#xD;
      significant morbidity and mortality. It is likely that the fluid and electrolyte imbalances&#xD;
      associated with mineralocorticoid adrenal insufficiency transient observed in this population&#xD;
      of vulnerable newborns contribute to the occurrence of complications that will influence the&#xD;
      prognosis medium and long term these children. The expected impact of our pilot study is a&#xD;
      direct benefit to the patient, with reduced kidney soda losses from the 3rd day of life and&#xD;
      throughout the first week of life (assessed by a non-invasive method: urine collection to&#xD;
      compress and measurement of urinary Na / creatinine). This physiological approach&#xD;
      (substitution of the deficient hormone) allow better control of sodium and water balance.&#xD;
      This could limit a number of common complications of extreme prematurity, occurring in the&#xD;
      first weeks of life, such as patent ductus arteriosus, intra-ventricular hemorrhage and&#xD;
      bronchopulmonary dysplasia.&#xD;
&#xD;
      The administration of glucocorticoids during the postnatal period (with action both&#xD;
      glucocorticoid and mineralocorticoid) enables a reduction in the incidence of&#xD;
      bronchopulmonary dysplasia severe. However, such treatment is associated with an increased&#xD;
      incidence of neurodevelopmental effects related to activation of the glucocorticoid pathway.&#xD;
      Using a specific mineralocorticoid agonist should preserve the beneficial effects without the&#xD;
      adverse effects observed. The results of this pilot study will in a second time to consider a&#xD;
      clinical trial Phase III national or international evaluating the significant reduction of&#xD;
      these complications after substitution by Fludrocortisone the first week of life in the great&#xD;
      premature. These results should have a major medical and economic impact. Indeed, neonatal&#xD;
      morbidity indicators (intraventricular hemorrhage, patent ductus arteriosus, bronchopulmonary&#xD;
      dysplasia and enterocolitis necrotizing) are associated with the subsequent development of&#xD;
      neurodevelopmental sequelae (cerebral palsy and / or cognitive impairment) at the age of two&#xD;
      and five years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2017</start_date>
  <completion_date type="Actual">September 8, 2020</completion_date>
  <primary_completion_date type="Actual">September 8, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Urinary sodium loss evaluated by the urinary ratio Na / creatinine</measure>
    <time_frame>day 3 (when urinary sodium losses are at their highest in very premature infants)</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urinary sodium loss evaluated by the urinary ratio Na / creatinine</measure>
    <time_frame>day1, day5, day8, day10 and day15</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urinary sodium and potassium concentrations</measure>
    <time_frame>day1,day3, day5, day8, day10 and day15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>plasma sodium and potassium concentrations</measure>
    <time_frame>day1, day3, day8 et day15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>plasma renin concentrations</measure>
    <time_frame>day1, day3, day8 et day15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of blood tests</measure>
    <time_frame>day1,day3, day5, day8, day10 and day15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal complications</measure>
    <time_frame>up to 36 post-conceptional weeks (PCW)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patent ductus arteriosus (diagnosed by ultrasound)</measure>
    <time_frame>Between day2 and day5 and between day7 and day15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of intraventricular hemorrhage (diagnosed by ultrasound)</measure>
    <time_frame>between day2 and day5, and between day7 and day15, and at the age of 36 PCW</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen inspired fraction (FiO2)</measure>
    <time_frame>At Day 28 and 36 PCW</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>From day1 to day8, at day10, at day15, at one month, three month, six month, twelve month and at 36 PCW</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urinary dosage of aldosterone and cortisol</measure>
    <time_frame>At one month, three month, six month and twelve month.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urinary index (Aldosterone/Nau)</measure>
    <time_frame>day3, day8 and day15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of days of invasive and non invasive ventilation</measure>
    <time_frame>At Day 28 and 36 PCW</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>weight newborns</measure>
    <time_frame>from day1 to day 8, at day 10 and day 15and at 36 PCW</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">66</enrollment>
  <condition>Partial Mineralocorticoid Deficiency</condition>
  <arm_group>
    <arm_group_label>Fludrocortisone 10 µg tablets</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo oral tablet</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oral Fludrocortisone (enteral)</intervention_name>
    <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.</description>
    <arm_group_label>Fludrocortisone 10 µg tablets</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <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.</description>
    <arm_group_label>placebo oral tablet</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Very premature newborns defined by a gestational age &lt;32 and ≥ 26 gestational weeks&#xD;
&#xD;
          -  Eutrophic: birth weight between the 10th and 90th percentile of the French reference&#xD;
             curves&#xD;
&#xD;
          -  Absence of malformations or chromosomal abnormality identified&#xD;
&#xD;
          -  Lack of adrenal, pituitary or gonadal diseases diagnosed prior birth&#xD;
&#xD;
          -  Lack of participation in another research protocol&#xD;
&#xD;
          -  &quot;Inborn&quot;: born and hospitalized in the four neonatology departments participating in&#xD;
             the study&#xD;
&#xD;
          -  Informed consent of the holders of parental authority&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Maternal treatment prior to pregnancy: systemic or inhaled corticosteroids, hormone&#xD;
             therapy for adrenal or pituitary insufficiency, antihypertensive treatment (calcium&#xD;
             channel blockers, beta blockers, angiotensin)&#xD;
&#xD;
          -  Lack or incomplete treatment of antenatal glucocorticoids (betamethasone)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>26 Weeks</minimum_age>
    <maximum_age>32 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Martinerie Laetitia, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>APHP</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hôpital Robert Debré</name>
      <address>
        <city>Paris</city>
        <zip>75019</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 12, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 22, 2016</study_first_posted>
  <last_update_submitted>February 15, 2021</last_update_submitted>
  <last_update_submitted_qc>February 15, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Neonatology</keyword>
  <keyword>Endocrinology</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypoaldosteronism</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fludrocortisone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03001089
org study id: P150905
nct id: NCT03001089
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: 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)
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.
measure: Urinary sodium loss evaluated by the urinary ratio Na / creatinine
time frame: day1, day5, day8, day10 and day15
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.
measure: urinary sodium and potassium concentrations
time frame: day1,day3, day5, day8, day10 and day15
measure: plasma sodium and potassium concentrations
time frame: day1, day3, day8 et day15
measure: plasma renin concentrations
time frame: day1, day3, day8 et day15
measure: Number of blood tests
time frame: day1,day3, day5, day8, day10 and day15
measure: Neonatal complications
time frame: up to 36 post-conceptional weeks (PCW)
measure: Patent ductus arteriosus (diagnosed by ultrasound)
time frame: Between day2 and day5 and between day7 and day15
measure: 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
measure: Oxygen inspired fraction (FiO2)
time frame: At Day 28 and 36 PCW
measure: 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
measure: urinary dosage of aldosterone and cortisol
time frame: At one month, three month, six month and twelve month.
measure: urinary index (Aldosterone/Nau)
time frame: day3, day8 and day15
measure: number of days of invasive and non invasive ventilation
time frame: At Day 28 and 36 PCW
measure: weight newborns
time frame: from day1 to day 8, at day 10 and day 15and at 36 PCW
arm group label: Fludrocortisone 10 µg tablets
arm group type: Active Comparator
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 group label: placebo oral tablet
arm group type: Placebo Comparator
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: Oral Fludrocortisone (enteral)
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 group label: Fludrocortisone 10 µg tablets
intervention type: Drug
intervention name: Placebo Oral Tablet
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.
arm group label: placebo oral tablet
criteria: 
gender: All
minimum age: 26 Weeks
maximum age: 32 Weeks
healthy volunteers: No
last name: Martinerie Laetitia, PHD
role: Principal Investigator
affiliation: APHP
facility: 
country: France
responsible party type: Sponsor
mesh term: Hypoaldosteronism
mesh term: Fludrocortisone
sharing ipd: No