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Hair Cortisol and Cushing's Disease (HAIRCUSH)

Primary Purpose

Cushing Disease

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Patient group
Remission control group
Bilateral surrenalectomy control group
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Cushing Disease focused on measuring UFC, LNSC, Hair cortisol, medical treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

In the three groups:

  • Age > 18
  • Cushing's disease medical history: histology confirming an ACTH staining adenoma, or ACTH-dependant Cushing syndrome with MRI confirmation of pituitary adenoma, or pituitary secretion of ACTH confirmed with petrosal sinus gradient
  • Written informed consent
  • Hair length ≥ 3 cm

In patient group:

  • Persistent CD diagnosed on usual criteria in expert centers including overt hypercortisolism with at least 2 UFC > 1.5 N prior to the start of medical treatment
  • Previous treatment with pasireotide, cabergoline, metyrapone, ketoconazole (alone or in association) AND hypercortisolism considered as controlled for at least 3 months based on 2 normal UFC.

In remission control group:

o Patients cured of CD and having recovered a normal pituitary function for at least 12 months following pituitary surgery (normal UFC associated to: cortisol suppression following dexamethasone suppression test, or normal LNSC, or midnight serum cortisol < 200 nmol/L)

In bilateral surrenalectomy control group:

o Patients with previous CD, treated with bilateral adrenalectomy and receiving weight adjusted doses of hydrocortisone for at least 6 months. Last daily dose of Hydrocortisone should be administered no later than 5 pm.

Exclusion Criteria:

In the three groups:

  • Renal Failure (Cl < 30 mL/min)
  • Non-compliant patients
  • Hair length < 3 cm
  • Severe depression and psychosis
  • Drug addiction and active alcoholism
  • Myocardial infarction or cerebrovascular accident < 3 months
  • Intense physical activity (marathon runner)
  • Night-shifters
  • Obesity with BMI > 35 kg/m2
  • Type 1 diabetes
  • Type 2 diabetes with HbA1C > 9 %

In patient group:

  • Patients receiving mifepristone and/or mitotane
  • Patients treated with anticortisolic agents during the titration process
  • Patients requiring additional hydrocortisone supplementation or exogenous corticosteroids
  • Pituitary radiotherapy < 5 years

Sites / Locations

  • Service d'Endocrinologie - CHU Caen
  • Service d'endocrinologie - HCL
  • Service d'Endocrinologie, Diabète et Maladies Métaboliques - APHM
  • CIC d'Endocrinologie, Maladies Métaboliques et Nutrition - CHU de Nantes
  • Service d'Endocrinologie - APHP Cochin
  • Service d'Endocrinologie et des Maladies de la Reproduction - APHP Bicêtre
  • Service d'endocirnologie, diabète, nutrition, Hôpital Haut Lévêque - CHU de Bordeaux

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Active Comparator

Arm Label

Patient group

Remission control group

Bilateral surrenalectomy control group

Arm Description

Outcomes

Primary Outcome Measures

Evaluate cortisol chronic tissue impregnation
Hypercortisolism will be controlled using 3 cm scalp hair sample in which Hair Cortisol will be measured in patients with Cushing Disease (CD) receiving a medical treatment.

Secondary Outcome Measures

Evaluate Hair Cortisol (Hcort) measure for Cushing Disease control
Compare Hair Cortisol to UFC (Urinary Free Cortisol), LNSC (late night salivary cortisol) and SC (salivary cortisone) in patients with CD receiving a medical treatment.
Compare cortisol tissue impregnation thanks to Hair Cortisol measurements in patients with CD receiving a medical treatment and patients control
Compare the results of Hair Cortisol measurements in patients with CD receiving a medical treatment and patients treated with weight-adjusted hydrocortisone replacement doses after bilateral adrenalectomy
Compare cortisol tissue impregnation thanks to Hair Cortisol measurements in patients cured from CD and patient with bilateral adrenalectomy
Compare the results of Hair Cortisol measurements in patients cured from CD and patients with bilateral adrenalectomy
Evaluate Hair Cortisol intra-individual variability
Evaluate the dosage of within-patient variability of Hair Cortisol for patients with CD receiving a medical treatment and control groups : patients cured from CD and patients with bilateral adrenalectomy
Evaluate UFC intra-individual variability
Assess the within-patient variability of UFC in patients with CD receiving a medical treatment
Satisfaction assessed by Cushing's QOL
Correlate a quality of life assessment with the results of Hair Cortisol, UFC and LNSC thanks to QOL questionnaire : cushing's QOL.
Evaluate LNSC intra-individual variability
Evaluate the dosage of within-patient variability of LNSC in patients with CD receiving a medical treatment
Evaluate SC intra-individual variability
Evaluate the dosage of within-patient variability of SC in patients with CD receiving a medical treatment

Full Information

First Posted
September 4, 2019
Last Updated
July 17, 2023
Sponsor
University Hospital, Bordeaux
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1. Study Identification

Unique Protocol Identification Number
NCT04201444
Brief Title
Hair Cortisol and Cushing's Disease
Acronym
HAIRCUSH
Official Title
Usefulness of Hair Cortisol/Cortisone Concentrations for the Monitoring of Medical Treatment in Patients With Cushing's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
March 10, 2021 (Actual)
Primary Completion Date
June 10, 2022 (Actual)
Study Completion Date
June 10, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux

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
The biochemical tools usable to assess the control of hypercortisolism in patients with Cushing's disease receiving medical treatments are debatable. The aim of the study is to compare the results of the measurement of cortisol and cortisone using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in scalp hair (so called "Hair Cortisol") to that of 24h urinary free cortisol (UFC) and late night salivary cortisol (LNSC) for the monitoring of medical therapy in patients with Cushing's disease (CD).
Detailed Description
Selective surgical removal of the pituitary corticotroph adenoma is the ideal treatment of Cushing's disease. However, surgery may not be feasible or is unsuccessful in roughly 25% of patients. In addition, a recurrence of the disease is observed after a transient remission in 15 to 25% of patients. Several therapeutic alternatives are available, amongst which medical treatment is commonly used. Drugs that are available in France to control hypercortisolism target the pituitary adenoma secretion (pasireotide and cabergoline) or inhibit adrenal steroidogenesis (ketoconazole and metyrapone). Usual criteria to monitor the treatment and titrate the drug dosage include evaluation of relevant clinical endpoints and measurement of UFC. However, limitations of UFC for this purpose, include difficulties in obtaining a complete 24 urine collection and the fact that UFC assess only short-term cortisol in a disease characterized by high variability over time in the intensity of hypercortisolism. Elsewhere, a mild to moderate hypercortisolism may persist despite a normal UFC. Several groups, including ours, have shown that LNSC is useful tool to diagnose overt and mild hypercortisolism and may be more sensitive than UFC to diagnose mild hypercortisolism. Despite being more convenient to collect than 24h urine, LNSC also suffers from only measuring time-point cortisol. Rare studies have examined whether LNSC could be an adequate biomarker for monitoring response to medical therapy in patients with CD and its usefulness to monitor drug treatment in CD is yet unknown (one study comparing UFC to LNSC in CD patients treated with pasireotide-LAR has been presented but is not yet published). Accordingly, the 2015 guidelines of the endocrine society recommend future research to accurately monitor patients for their response to medical therapy to guide dose optimization. More recently, the measurement of salivary cortisone in 3 saliva samples (SCx3) drawn at approximately 8 hours intervals and starting at 7-8 am have been shown to be a reliable estimate of cortisol production over 24h in normal subjects. Whether this parameter could be used as a substitute of UFC in patients treated with anticortisolic drugs remains unstudied. Hair cortisol concentration is a non-invasive way to measure cortisol exposure over much longer periods of time (weeks and months) than previously possible with samples of blood, saliva or urine. Several studies have shown that measurement of cortisol in a single scalp hair sample has a diagnostic accuracy for CS similar to currently used first-line tests and may also be used to identify overtreatment in patients receiving hydrocortisone replacement for adrenal insufficiency. To date, no data is available concerning hair Cortisol measurement in comparison with other usual biological tools in patients with CD receiving a medical treatment. Since 2016, the departments of endocrine biology and clinical endocrinology of Bordeaux university hospital (CHU) have developed the measurement of cortisol and cortisone in scalp hair using LC-MS/MS and have established normative values using several cohorts of control patients. The purpose of the study is to take advantage of the ability of hair cortisol to measure long-term cortisol exposure to assess the response to medical therapy in patients with CD. More specifically, the working hypothesis is that some patients with a normal UFC may still suffer from an occult mild hypercortisolism that will be identified only by hair cortisol. To study this hypothesis, the investigators will compare the results of hair cortisol to that multiple measurement of UFC, LNSC and SCx3 during a three-month period in patients with CD already treated with medical treatments and considered as "controlled" on the basis of previous UFC measurements.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cushing Disease
Keywords
UFC, LNSC, Hair cortisol, medical treatment

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
51 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patient group
Arm Type
Experimental
Arm Title
Remission control group
Arm Type
Active Comparator
Arm Title
Bilateral surrenalectomy control group
Arm Type
Active Comparator
Intervention Type
Diagnostic Test
Intervention Name(s)
Patient group
Intervention Description
Patients with Cushing Disease (CD) receiving a medical treatment: n = 30 Plasmatic cortisol UFC Urine biocollection Salive biocollection
Intervention Type
Diagnostic Test
Intervention Name(s)
Remission control group
Intervention Description
Patients in remission of CD and having recovered a normal pituitary function for at least 12 months following pituitary surgery (normal UFC associated to: cortisol suppression following dexamethasone suppression test, or normal LNSC, or midnight serum cortisol < 200 nmol/L) n = 15 Plasmatic cortisol UFC Urine biocollection Salive biocollection Haircortisol
Intervention Type
Diagnostic Test
Intervention Name(s)
Bilateral surrenalectomy control group
Intervention Description
Patients with previous CD, treated with bilateral adrenalectomy and receiving weight adjusted doses of hydrocortisone for at least 6 months. Last daily dose of Hydrocortisone should be administered no later than 5 pm. n = 15 Plasmatic cortisol UFC Urine biocollection Salive biocollection Haircortisol
Primary Outcome Measure Information:
Title
Evaluate cortisol chronic tissue impregnation
Description
Hypercortisolism will be controlled using 3 cm scalp hair sample in which Hair Cortisol will be measured in patients with Cushing Disease (CD) receiving a medical treatment.
Time Frame
3 months after inclusion day
Secondary Outcome Measure Information:
Title
Evaluate Hair Cortisol (Hcort) measure for Cushing Disease control
Description
Compare Hair Cortisol to UFC (Urinary Free Cortisol), LNSC (late night salivary cortisol) and SC (salivary cortisone) in patients with CD receiving a medical treatment.
Time Frame
3 months after inclusion day
Title
Compare cortisol tissue impregnation thanks to Hair Cortisol measurements in patients with CD receiving a medical treatment and patients control
Description
Compare the results of Hair Cortisol measurements in patients with CD receiving a medical treatment and patients treated with weight-adjusted hydrocortisone replacement doses after bilateral adrenalectomy
Time Frame
3 months after inclusion day
Title
Compare cortisol tissue impregnation thanks to Hair Cortisol measurements in patients cured from CD and patient with bilateral adrenalectomy
Description
Compare the results of Hair Cortisol measurements in patients cured from CD and patients with bilateral adrenalectomy
Time Frame
3 months after inclusion day
Title
Evaluate Hair Cortisol intra-individual variability
Description
Evaluate the dosage of within-patient variability of Hair Cortisol for patients with CD receiving a medical treatment and control groups : patients cured from CD and patients with bilateral adrenalectomy
Time Frame
At day 0 and day 90
Title
Evaluate UFC intra-individual variability
Description
Assess the within-patient variability of UFC in patients with CD receiving a medical treatment
Time Frame
3 months after inclusion day
Title
Satisfaction assessed by Cushing's QOL
Description
Correlate a quality of life assessment with the results of Hair Cortisol, UFC and LNSC thanks to QOL questionnaire : cushing's QOL.
Time Frame
3 months after inclusion day
Title
Evaluate LNSC intra-individual variability
Description
Evaluate the dosage of within-patient variability of LNSC in patients with CD receiving a medical treatment
Time Frame
3 months after inclusion day
Title
Evaluate SC intra-individual variability
Description
Evaluate the dosage of within-patient variability of SC in patients with CD receiving a medical treatment
Time Frame
3 months after inclusion day

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: In the three groups: Age > 18 Cushing's disease medical history: histology confirming an ACTH staining adenoma, or ACTH-dependant Cushing syndrome with MRI confirmation of pituitary adenoma, or pituitary secretion of ACTH confirmed with petrosal sinus gradient Written informed consent Hair length ≥ 3 cm In patient group: Persistent CD diagnosed on usual criteria in expert centers including overt hypercortisolism with at least 2 UFC > 1.5 N prior to the start of medical treatment Previous treatment with pasireotide, cabergoline, metyrapone, ketoconazole (alone or in association) AND hypercortisolism considered as controlled for at least 3 months based on 2 normal UFC. In remission control group: o Patients cured of CD and having recovered a normal pituitary function for at least 12 months following pituitary surgery (normal UFC associated to: cortisol suppression following dexamethasone suppression test, or normal LNSC, or midnight serum cortisol < 200 nmol/L) In bilateral surrenalectomy control group: o Patients with previous CD, treated with bilateral adrenalectomy and receiving weight adjusted doses of hydrocortisone for at least 6 months. Last daily dose of Hydrocortisone should be administered no later than 5 pm. Exclusion Criteria: In the three groups: Renal Failure (Cl < 30 mL/min) Non-compliant patients Hair length < 3 cm Severe depression and psychosis Drug addiction and active alcoholism Myocardial infarction or cerebrovascular accident < 3 months Intense physical activity (marathon runner) Night-shifters Obesity with BMI > 35 kg/m2 Type 1 diabetes Type 2 diabetes with HbA1C > 9 % In patient group: Patients receiving mifepristone and/or mitotane Patients treated with anticortisolic agents during the titration process Patients requiring additional hydrocortisone supplementation or exogenous corticosteroids Pituitary radiotherapy < 5 years
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antoine TABARIN, Pr
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service d'Endocrinologie - CHU Caen
City
Caen
ZIP/Postal Code
14000
Country
France
Facility Name
Service d'endocrinologie - HCL
City
Lyon
ZIP/Postal Code
69000
Country
France
Facility Name
Service d'Endocrinologie, Diabète et Maladies Métaboliques - APHM
City
Marseille
ZIP/Postal Code
13000
Country
France
Facility Name
CIC d'Endocrinologie, Maladies Métaboliques et Nutrition - CHU de Nantes
City
Nantes
ZIP/Postal Code
44000
Country
France
Facility Name
Service d'Endocrinologie - APHP Cochin
City
Paris
ZIP/Postal Code
75000
Country
France
Facility Name
Service d'Endocrinologie et des Maladies de la Reproduction - APHP Bicêtre
City
Paris
ZIP/Postal Code
75000
Country
France
Facility Name
Service d'endocirnologie, diabète, nutrition, Hôpital Haut Lévêque - CHU de Bordeaux
City
Pessac
ZIP/Postal Code
33604
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No

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Hair Cortisol and Cushing's Disease

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