Clinical trial NCT04374721: Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders
Official title: Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cushing Syndrome
Adrenal Insufficiency
Cushing Disease
Addison Disease
Keywords: circadian rhythm
circadian genes
circadian clock
glucocorticoids
cortisol
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2020-05-05
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: patients will undergo circadian genes evaluation in peripheral blood mononuclear cells
Primary purpose: OTHER

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

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

Primary outcomes:
measure: Circadian genes CLOCK and ARNTL expression evaluation
timeFrame: baseline, +1 month, +3 months, +6 months
Secondary outcomes:
measure: Circadian gene expression profile
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Peripheral Blood Mononuclear Cells circadian profiling
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Circadian cortisol rhythm
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Sleep Disturbances
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Infectious Diseases Frequency and Severity
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Circadian blood pressure
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Quality of life evaluation
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Psychometric Evaluation
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Sexual dysfunction in women
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Sexual dysfunction in men
timeFrame: baseline, +1 month, +3 months, +6 months
measure: insuline resistance
timeFrame: baseline, +1 month, +3 months, +6 months
measure: blood lipid profile
timeFrame: baseline, +1 month, +3 months, +6 months
measure: Inflammatory cytokines levels
timeFrame: baseline, +1 month, +3 months, +6 months
Other outcomes:
Locations:
city: Roma
country: Italy
facility: Department of Experimental Medicine, "Sapienza" University of Rome
Study officials:
References: