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Salt Wasting, Hydro-sodium Balance and Fludrocortisone Requirement in Congenital Adrenal Hyperplasia (NaCAH)

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ClinicalTrials.gov Identifier: NCT03550261
Recruitment Status : Recruiting
First Posted : June 8, 2018
Last Update Posted : November 18, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Congenital adrenal hyperplasia (CAH) in its classic neonatal form with severe salt-wasting represents a challenge for pediatric endocrinologists in order to maintain sodium balance, especially as the physiopathology and optimal therapeutic management of this urinary salt loss remain poorly studied, particularly during the neonatal period.

The human kidney presents the characteristic of being immature at birth with a functional tubulopathy associating sodium wasting and difficulty to concentrate urine, in connection with a transient renal resistance to aldosterone action, which is exacerbated in case of CAH by insufficiency of aldosterone production.

The objective of project is therefore to study the secretion profiles of plasma and urinary steroids in neonates with classical salt-wasting form of CAH before treatment and under treatment with Fludrocortisone and Hydrocortisone during the first months of life, using an advanced technology: LC-MSMS (Liquid chromatography coupled with tandem mass spectrometry). The study of the existence of a correlation between plasma and urinary steroid profiles will also make it possible to subsequently consider simplified medical follow-up for these patients.

This project will lead to a better understanding of sodium handling and steroid secretion and excretion profiles in CAH neonates, in order to improve the therapeutic management of mineralocorticoid replacement in these patients.


Condition or disease
Congenital Adrenal Hyperplasia (CAH)

Detailed Description:

Congenital adrenal hyperplasia in its severe salt-wasting form is a challenge in order to maintain sodium balance. The pathophysiology of this impaired sodium balance is still poorly investigated as well as its therapeutic management, notably in the neonatal period. Consensus practice guidelines have been established for hydrocortisone replacement therapy, in order to maintain negative feedback on the pituitary-adrenal axis to prevent from virilization and excessive growth velocity. However, mineralocorticoid substitution and sodium supplementation is currently empirically adapted based on weight gain and renin levels. There is significant need for improvement of this essential part of CAH treatment. Particularly, CAH patients have higher risk of adverse cardio-vascular outcomes, which could relate to an excessive glucocorticoid and/or mineralocorticoid exposure in early infancy rather than to the genotype of the patient.

A clinical human study in classical CAH neonates, using Liquid Chromatography coupled to tandem Mass Spectrometry LC-MS/MS technology will assess prospectively plasma and urinary steroid profiling (precursors and substitute hormones, notably Fludrocortisone dosages) during the first six months of life, before and under treatment; and in correlation with genotype.

Thirty neonates (boys and girls) diagnosed with a severe form of CAH and followed in one of the 5 following French reference tertiary centers: Robert Debré Hospital, Paris; Necker Hospital, Paris; Bicetre Hospital, Le Kremlin-Bicetre; Trousseau Hospital, Paris; Lyon Hospital, , will be included in the study and will be followed for a period of six months. The duration of inclusion will be 24 months.

Genotyping will be processed for all children in Lyon.This project will lead to a better understanding of sodium handling and steroid secretion and excretion profiles in CAH neonates, in order to improve management of mineralocorticoid replacement.


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Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Salt Wasting, Hydro-sodium Balance and Fludrocortisone Requirement in Congenital Adrenal Hyperplasia
Actual Study Start Date : May 17, 2018
Estimated Primary Completion Date : December 10, 2020
Estimated Study Completion Date : December 10, 2020





Primary Outcome Measures :
  1. Plasma LC-MSMS dosages [ Time Frame: 48 hours ]
    Determine if a correlation exist between plasma and urinary steroid profile by LC-MSMS and genotype before treatment, and if there exist a correlation to the Fludrocortisone dose after 48h of treatment

  2. Urinary LC-MSMS dosages [ Time Frame: 48 hours ]
    Determine if a correlation exist between plasma and urinary steroid profile by LC-MSMS and genotype before treatment, and if there exist a correlation to the Fludrocortisone dose after 48h of treatment


Secondary Outcome Measures :
  1. Plasma LC-MSMS dosages [ Time Frame: day1, day2, 1 month, 3 months and 6 months ]
    Steroid profiles will be compared between urine and plasma to search for a correlation

  2. Urinary LC-MSMS dosages [ Time Frame: day1, day2, 1 month, 3 months and 6 months ]
    Steroid profiles will be compared between urine and plasma to search for a correlation


Biospecimen Retention:   Samples Without DNA

For blood samples, the biochemistry laboratory of each investigating centre will centrifuge all blood samples, collect the plasma and transfer it into a new tube on which the corresponding labels will be affixed.

The tubes will be frozen at -20° C in a freezer at a specific location where the tubes with the same identification number (blood and urine sample from the same child) will be grouped.

The urinary samples (H0, H48, M1, M3 and M6) collected on a gauze compress will arrive at the laboratory of each centre in tubes already labelled (sterile urine jar) and will be frozen directly at -20° C with the tubes.



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Ages Eligible for Study:   up to 15 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Newborns (boys and girls) diagnosed with a neonatal form of CAH and followed up in one of the following 5 French reference centres: Robert Debré Hospital, Paris; Necker Hospital, Paris; Bicêtre Hospital, Le Kremlin-Bicêtre; Trousseau Hospital, Paris; Femme-Mère-Enfant Hospital, Lyon.
Criteria

Inclusion Criteria:

  • Newborns with confirmation or strong suspicion of diagnosis of congenital adrenal hyperplasia:
  • Newborns with abnormal differentiation of the external genitalia, without palpable gonad at birth and high 17 OHP plasma level
  • Newborns diagnosed with antenatal CAH,
  • Newborns diagnosed at birth with CAH (due to parents at risk of transmission of the disease),
  • Newborns diagnosed by systematic screening for 17 OHP on the 3rd day of life (thus having a high dosage of 17 OHP), confirmed by a second sample.

For all these patients the diagnosis of CAH will have to be confirmed secondarily by molecular biology.

Exclusion Criteria:

  • Newborn with an anomaly of sexual differentiation from another origin,
  • Newborn already under treatment with Fludrocortisone and/or Hydrocortisone.

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): NCT03550261


Contacts
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Contact: Martinerie Laetitia, PHD 01 40 03 25 88 laetitia.martinerie@aphp.fr

Locations
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France
Hôpital Robert Debré Recruiting
Paris, France, 75019
Contact: MARTINERIE Laetitia, PHD    014003 2588    laetitia.martinerie@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Martinerie Naetitia, PHD APHP

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03550261     History of Changes
Other Study ID Numbers: NI17028J
First Posted: June 8, 2018    Key Record Dates
Last Update Posted: November 18, 2019
Last Verified: September 2019

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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:
CAH
Salt-wasting
LC-MSMS
plasma and urine steroid profile
Fludrocortisone
Additional relevant MeSH terms:
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Adrenal Hyperplasia, Congenital
Adrenogenital Syndrome
Wasting Syndrome
Adrenocortical Hyperfunction
Hyperplasia
Cachexia
Pathologic Processes
Emaciation
Weight Loss
Body Weight Changes
Body Weight
Signs and Symptoms
Metabolic Diseases
Nutrition Disorders
Disorders of Sex Development
Urogenital Abnormalities
Congenital Abnormalities
Genetic Diseases, Inborn
Steroid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Adrenal Gland Diseases
Endocrine System Diseases
Gonadal Disorders
Fludrocortisone
Anti-Inflammatory Agents