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Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders (CHROnOS)

Primary Purpose

Cushing Syndrome, Adrenal Insufficiency, Cushing Disease

Status
Recruiting
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
circadian gene expression evaluation
Sponsored by
University of Roma La Sapienza
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Cushing Syndrome focused on measuring circadian rhythm, circadian genes, circadian clock, glucocorticoids, cortisol

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Primary or secondary chronic adrenal insufficiency, previously or newly diagnosed.
  • ACTH-dependent or ACTH-independent Cushing's Syndrome diagnosis during active disease (new diagnosis or recidivating).

    • Signed informed consent to participate in the study.

Exclusion Criteria:

- acute adrenal insufficiency;

  • clinical or laboratory signs of significant respiratory, hepatobiliary, or pancreatic disease;
  • pregnancy;
  • severe infections, surgery, trauma requiring hospitalization within 3 months before study entry;
  • any active blood or rheumatic disorders, and active liver disease in the previous 5 years;
  • clinically significant chronic kidney disease;
  • severe psychiatric diseases;
  • history of neoplasms in the last 5 years (except for adrenal or pituitary adenoma in Cushing Syndrome, pituitary adenoma or related neolpasms in secondary adrenal insufficiency);
  • heart disease with a class III or class IV functional capacity;
  • BMI greater than 40 kg/m²;
  • use of medication that interferes with cortisol metabolism within 1 month before study entry;
  • treatment with systemic Glucocorticoid (GC) therapy other than hydrocortisone (HC), or cortisone acetate (CA);
  • alcoholism and/or drug addictions;
  • night-shift workers;
  • use of melatonin, antipsychotic medications, estroprogestinic preparations

Sites / Locations

  • Department of Experimental Medicine, "Sapienza" University of RomeRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Patients with Adrenal Insufficiency

Patients with Cushing's Syndrome

Healthy Controls

Arm Description

Patients with Adrenal Insufficiency established or newly diagnosed, under glucocorticoid replacement therapy.

patients with adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent Cushing's Syndrome diagnosis during active disease (new diagnosis or recidivating) at enrollment.

Age-, sex- and BMI- matched patients referring to our center for diagnostic procedures not affected by Adrenal Insufficiency or Cushing's Syndrome.

Outcomes

Primary Outcome Measures

Circadian genes CLOCK and ARNTL expression evaluation
Change in relative expression circadian genes of CLOCK and ARNLT from baseline compared to healthy controls. After PBMC isolation by Ficoll-Plaque gradient, complementary DNA (cDNA) pool will be extracted and used as the template for subsequent Polymerase Chain Reaction (PCR) amplification in Real time PCR; Gene expression will be quantified as relative expression compared to housekeeping genes.

Secondary Outcome Measures

Circadian gene expression profile
Change from baseline in relative expression and variations throughout the day of circadian genes (CLOCK and ARNTL) compared to healthy controls at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM. After PBMC isolation by Ficoll-Plaque gradient, cDNA pool will be extracted and used as the template for subsequent Polymerase Chain Reaction (PCR) amplification in Real time PCR; Gene expression will be quantified as relative expression compared to housekeeping genes.
Peripheral Blood Mononuclear Cells circadian profiling
Number of cells (number per mm3) of peripheral blood mononuclear cell subpopulations at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM
Circadian cortisol rhythm
Circadian cortisol rhythm by serum and salivary dosage at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM.
Sleep Disturbances
Sleep disturbances will be evaluated by The Pittsburgh Sleep Quality Index (PSQI). This questionnaire contains 19 self-related questions which are combined to create 7 component scores with a range of 0-3 points (0:no difficulty, 3: severe difficulty). Global score is the result to the addition of all component scores with a range of 0-21 points (0:no difficulty, 21: severe difficulty).
Infectious Diseases Frequency and Severity
Frequencies and severity of infectious diseases will be evaluated by modified Infectious Diseases Questionnaire (GNC). This questionnaire includes questions on infectious diseases of upper and lower respiratory tract, gastrointestinal tract, skin and urogenital tract contracted during the previous 12 months. Questions investigate on the number and duration of infections, necessity of antibiotic or antifungal therapy, hospital stay and days of absence from work. Final score represents the frequency of infections. Moreover, some questions investigate possible susceptible or protective factors for infectious diseases: vaccinations, use of corticosteroids, concomitant diseases, previous appendectomy, tonsillectomy, adenoidectomy, splenectomy or thymectomy.
Circadian blood pressure
Circadian blood pressure will be evaluated using ambulatory blood pressure monitoring blood pressure waves for a noninvasive estimation
Quality of life evaluation
Quality of life will be evaluated by the Physical Component score and the Mental Component score of the self-administered questionnaire SF-36-Item Health Survey questionnaire. This questionnaire measures eight scales: physical functioning, role physical, bodily pain, general health (physical component) and vitality, social functioning, role emotional, mental health (mental component). Interpretation of the score will be the following: at each item of the questionnaire corresponds a percentage value (from 0% to 100%). The average of the single items constitutes the scale total percentage (from 0% to 100%); missing data are not considered during calculation. High score defines a more favorable health state.
Psychometric Evaluation
Psychometric Evaluation will be evaluated using Beck Depression Inventory questionnaire. : a 21-item measure of depressive symptoms. Each answer is scored on a scale value (from 0 to 3 points). The global score is obtained adding all single scores, with a range of 0-63. Higher score constitutes worse burden of symptoms (0-13: minimal depression, 14-19: mild depression, 20-28: moderate depression, 29-63: severe depression).
Sexual dysfunction in women
Evaluation of sexual dysfunction will be evaluated in women using FSFI questionnaire. This is a 19-item questionnaire that covers six domains: desire, arousal, lubrication, and orgasm, satisfaction, and pain. The ranges of the domain scores are as follows: for desire 1.2 - 6.0, for arousal, lubrication, orgasm and pain 0 - 6.0 and for satisfaction 0.8 - 6.0. The higher scores of the six domains indicate better sexual functioning about that domain. The overall FSFI score is obtained by summing the six domain scores. The overall FSFI scores range from 2.0 to 36.0, with higher scores indicating better sexual functioning.
Sexual dysfunction in men
Evaluation of sexual dysfunction will be evaluated in men using IIEF questionnaire. The IIEF is an internationally validated test. It is used to assign a score of erectile dysfunction: severe score 1 to 10; moderate score 11 to 16; low to moderate score 17 to 21; Low score 22 to 25; no erectile dysfunction score 26 to 30
insuline resistance
Measurement of HOMA index calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.
blood lipid profile
Measurement of Total Cholesterol, LDL cholesterol, HDL cholesterol, Triglyceredes
Inflammatory cytokines levels
Evaluation of Tumor Necrosis Factor alpha (TNFα), Transforming Growth Factor beta (TGF-β), Interferon gamma (IFN-γ), Leptin, Resistin, Adiponectin, Adipsin, Monocyte Chemoattractant Protein-1 (MCP-1), Serpin, C Reactive Protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10) serum concentrations at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM

Full Information

First Posted
April 23, 2020
Last Updated
November 22, 2022
Sponsor
University of Roma La Sapienza
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1. Study Identification

Unique Protocol Identification Number
NCT04374721
Brief Title
Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders
Acronym
CHROnOS
Official Title
Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 4, 2018 (Actual)
Primary Completion Date
June 1, 2023 (Anticipated)
Study Completion Date
December 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Roma La Sapienza

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
This is a multicentric, prospective, intervention study on circadian genes expression in peripheral blood mononuclear cells as biomarkers of circadian rhythm derangement in patients affected by alterations of endogenous glucocorticoids secretion (Cushing's Syndrome during active phase, treatment and under remission and newly or on established glucocorticoid replacement therapy adrenal insufficiency)
Detailed Description
This is an intervention, prospective, multicentric study. Enrolled patients will undergo 4 visits: Adrenal insufficiency (AI) patients: patients affected by primary or secondary adrenal insufficiency, whether newly diagnosed or on established glucocorticoid therapy, will be evaluated at baseline and after one, three and six months. Cushing's Syndrome (CS) patients: patients affected by Cushing's Syndrome will be evaluated at baseline during active phase of the disease and one, three and six months after treatment or remission. Patients affected by Cushing's Syndrome who will require glucocorticoid replacement therapy after remission will be evaluated three and six months after remission and then three and six months after the eventual glucocorticoid replacement therapy withdrawal. CS treatment will be surgery or medical therapy according to guidelines. Timing of medical therapy administration will change during protocol according to circadian rhythms. Age-, sex- and BMI- matched healthy controls will be enrolled. Patients and controls will undergo the same procedures at baseline and after 1, 3 and 6 months. The primary outcome measure will be the evaluation of circadian genes CLOCK and Aryl Hydrocarbon Receptor Nuclear Translocator Like (ARNTL) expression in peripheral blood mononuclear cells (PBMC) compared to healthy controls. Secondary Outcomes measures will be: Circadian genes expression assessment compared to healthy controls at 7:00-8:00 Ante Meridiem (AM) (before breakfast), 12:00 AM (before lunch), 3:00-4:00 Post Meridiem (PM) (after lunch), 7:00 PM (before dinner), 12:00 PM; Immune profiling compared to healthy controls by the quantification of peripheral blood mononuclear cells (PBMC) subpopulations assessed by flow cytometry at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM; Evaluation of inflammatory cytokines and adipokines production compared to healthy controls at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM; Circadian cortisol rhythm by serum and salivary dosage at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM; Sleep disturbances evaluation by The Pittsburgh Sleep Quality Index (PSQI) self reported questionnaire Evaluation of infectious diseases frequencies and severity compared to healthy controls. Infectious diseases will be evaluated by an adaptation of Infectious Diseases Questionnaire (GNC) Circadian blood pressure using ambulatory blood pressure monitoring blood pressure waves for a noninvasive estimation Quality of life using SF-36-Item Health Survey questionnaire Psychometric Evaluation using Beck Depression Inventory questionnaire Evaluation of sexual dysfunction using FSFI questionnaire in woman and IIEF questionnaire in man Evaluation of insuline resistance calculated with HOMA index Evaluation of body weight (kg) Evaluation of blood lipid profile

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cushing Syndrome, Adrenal Insufficiency, Cushing Disease, Addison Disease
Keywords
circadian rhythm, circadian genes, circadian clock, glucocorticoids, cortisol

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
patients will undergo circadian genes evaluation in peripheral blood mononuclear cells
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
44 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Patients with Adrenal Insufficiency
Arm Type
Experimental
Arm Description
Patients with Adrenal Insufficiency established or newly diagnosed, under glucocorticoid replacement therapy.
Arm Title
Patients with Cushing's Syndrome
Arm Type
Experimental
Arm Description
patients with adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent Cushing's Syndrome diagnosis during active disease (new diagnosis or recidivating) at enrollment.
Arm Title
Healthy Controls
Arm Type
Experimental
Arm Description
Age-, sex- and BMI- matched patients referring to our center for diagnostic procedures not affected by Adrenal Insufficiency or Cushing's Syndrome.
Intervention Type
Diagnostic Test
Intervention Name(s)
circadian gene expression evaluation
Intervention Description
patients and controls will undergo circadian gene expression (CLOCK, ARNTL) evaluation at baseline and after 1, 3 and 6 months
Primary Outcome Measure Information:
Title
Circadian genes CLOCK and ARNTL expression evaluation
Description
Change in relative expression circadian genes of CLOCK and ARNLT from baseline compared to healthy controls. After PBMC isolation by Ficoll-Plaque gradient, complementary DNA (cDNA) pool will be extracted and used as the template for subsequent Polymerase Chain Reaction (PCR) amplification in Real time PCR; Gene expression will be quantified as relative expression compared to housekeeping genes.
Time Frame
baseline, +1 month, +3 months, +6 months
Secondary Outcome Measure Information:
Title
Circadian gene expression profile
Description
Change from baseline in relative expression and variations throughout the day of circadian genes (CLOCK and ARNTL) compared to healthy controls at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM. After PBMC isolation by Ficoll-Plaque gradient, cDNA pool will be extracted and used as the template for subsequent Polymerase Chain Reaction (PCR) amplification in Real time PCR; Gene expression will be quantified as relative expression compared to housekeeping genes.
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Peripheral Blood Mononuclear Cells circadian profiling
Description
Number of cells (number per mm3) of peripheral blood mononuclear cell subpopulations at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Circadian cortisol rhythm
Description
Circadian cortisol rhythm by serum and salivary dosage at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM.
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Sleep Disturbances
Description
Sleep disturbances will be evaluated by The Pittsburgh Sleep Quality Index (PSQI). This questionnaire contains 19 self-related questions which are combined to create 7 component scores with a range of 0-3 points (0:no difficulty, 3: severe difficulty). Global score is the result to the addition of all component scores with a range of 0-21 points (0:no difficulty, 21: severe difficulty).
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Infectious Diseases Frequency and Severity
Description
Frequencies and severity of infectious diseases will be evaluated by modified Infectious Diseases Questionnaire (GNC). This questionnaire includes questions on infectious diseases of upper and lower respiratory tract, gastrointestinal tract, skin and urogenital tract contracted during the previous 12 months. Questions investigate on the number and duration of infections, necessity of antibiotic or antifungal therapy, hospital stay and days of absence from work. Final score represents the frequency of infections. Moreover, some questions investigate possible susceptible or protective factors for infectious diseases: vaccinations, use of corticosteroids, concomitant diseases, previous appendectomy, tonsillectomy, adenoidectomy, splenectomy or thymectomy.
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Circadian blood pressure
Description
Circadian blood pressure will be evaluated using ambulatory blood pressure monitoring blood pressure waves for a noninvasive estimation
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Quality of life evaluation
Description
Quality of life will be evaluated by the Physical Component score and the Mental Component score of the self-administered questionnaire SF-36-Item Health Survey questionnaire. This questionnaire measures eight scales: physical functioning, role physical, bodily pain, general health (physical component) and vitality, social functioning, role emotional, mental health (mental component). Interpretation of the score will be the following: at each item of the questionnaire corresponds a percentage value (from 0% to 100%). The average of the single items constitutes the scale total percentage (from 0% to 100%); missing data are not considered during calculation. High score defines a more favorable health state.
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Psychometric Evaluation
Description
Psychometric Evaluation will be evaluated using Beck Depression Inventory questionnaire. : a 21-item measure of depressive symptoms. Each answer is scored on a scale value (from 0 to 3 points). The global score is obtained adding all single scores, with a range of 0-63. Higher score constitutes worse burden of symptoms (0-13: minimal depression, 14-19: mild depression, 20-28: moderate depression, 29-63: severe depression).
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Sexual dysfunction in women
Description
Evaluation of sexual dysfunction will be evaluated in women using FSFI questionnaire. This is a 19-item questionnaire that covers six domains: desire, arousal, lubrication, and orgasm, satisfaction, and pain. The ranges of the domain scores are as follows: for desire 1.2 - 6.0, for arousal, lubrication, orgasm and pain 0 - 6.0 and for satisfaction 0.8 - 6.0. The higher scores of the six domains indicate better sexual functioning about that domain. The overall FSFI score is obtained by summing the six domain scores. The overall FSFI scores range from 2.0 to 36.0, with higher scores indicating better sexual functioning.
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Sexual dysfunction in men
Description
Evaluation of sexual dysfunction will be evaluated in men using IIEF questionnaire. The IIEF is an internationally validated test. It is used to assign a score of erectile dysfunction: severe score 1 to 10; moderate score 11 to 16; low to moderate score 17 to 21; Low score 22 to 25; no erectile dysfunction score 26 to 30
Time Frame
baseline, +1 month, +3 months, +6 months
Title
insuline resistance
Description
Measurement of HOMA index calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.
Time Frame
baseline, +1 month, +3 months, +6 months
Title
blood lipid profile
Description
Measurement of Total Cholesterol, LDL cholesterol, HDL cholesterol, Triglyceredes
Time Frame
baseline, +1 month, +3 months, +6 months
Title
Inflammatory cytokines levels
Description
Evaluation of Tumor Necrosis Factor alpha (TNFα), Transforming Growth Factor beta (TGF-β), Interferon gamma (IFN-γ), Leptin, Resistin, Adiponectin, Adipsin, Monocyte Chemoattractant Protein-1 (MCP-1), Serpin, C Reactive Protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10) serum concentrations at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM
Time Frame
baseline, +1 month, +3 months, +6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Primary or secondary chronic adrenal insufficiency, previously or newly diagnosed. ACTH-dependent or ACTH-independent Cushing's Syndrome diagnosis during active disease (new diagnosis or recidivating). Signed informed consent to participate in the study. Exclusion Criteria: - acute adrenal insufficiency; clinical or laboratory signs of significant respiratory, hepatobiliary, or pancreatic disease; pregnancy; severe infections, surgery, trauma requiring hospitalization within 3 months before study entry; any active blood or rheumatic disorders, and active liver disease in the previous 5 years; clinically significant chronic kidney disease; severe psychiatric diseases; history of neoplasms in the last 5 years (except for adrenal or pituitary adenoma in Cushing Syndrome, pituitary adenoma or related neolpasms in secondary adrenal insufficiency); heart disease with a class III or class IV functional capacity; BMI greater than 40 kg/m²; use of medication that interferes with cortisol metabolism within 1 month before study entry; treatment with systemic Glucocorticoid (GC) therapy other than hydrocortisone (HC), or cortisone acetate (CA); alcoholism and/or drug addictions; night-shift workers; use of melatonin, antipsychotic medications, estroprogestinic preparations
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Andrea Isidori, MD,PhD
Phone
0039649970711
Email
andrea.isidori@uniroma1.it
Facility Information:
Facility Name
Department of Experimental Medicine, "Sapienza" University of Rome
City
Roma
ZIP/Postal Code
00161
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andrea M Isidori, MD,PhD
Phone
0039649970711
Email
andrea.isidori@uniroma1.it

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders

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