Clinical trial NCT06236932: Susceptibility to Infectious Diseases in obEsity: an endocRine trAnslational socioLogic Evaluation, "SIDERALE"
Official title: PRIN "SIDERALE": Susceptibility to Infectious Diseases in obEsity: an endocRine trAnslational socioLogic Evaluation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obesity
Type2diabetes
Lipodystrophy
Infections
Obesity Associated Disorder
Keywords: Obesity
Infections
Melatonin
Mediterranean Diet
Gut microbiota
Chronobiology
Lead sponsor: Federico II University
Sponsor class: OTHER
Collaborators: name: University of Roma La Sapienza
name: University of Pisa
name: Università degli Studi del Piemonte Orientale Amedeo Avogadro
name: University of Rome Foro Italico
First posted: 2024-02-01
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

Brief summary: Obesity is a life-threatening disease, defined by excessive fat accumulation that increases the risk of other diseases such as cardiovascular events, hypertension, diabetes and cancer. Obesity is also a risk factor for nosocomial infections and is associated with worse COVID-19 outcomes, although anthropometric measurements are not routinely recorded during hospitalization and lack of a registry data does not allow performing retrospective studies.Obesity is closely related to chronodisruption, characterized by deregulation of physiological and behavioral central and peripheral circadian rhythms contributing to the obesity-related metabolic impairment. Eating and sleeping time schedules are relevant synchronizers of humans' biological clock. Several studies suggest a role of dietary interventions in rewiring the circadian rhythm, with Mediterranean diet (MD) regulating nutritional patterns. Moreover, considering its positive impact on sleep quality, melatonin intake was suggested as a potential regulator of circadian rhythms. The relation between chronodisruption, obesity and infections has not been investigated, and a first proof of concept (Pilot study) will aim at investigating it. Three cohorts of obese patients with different aetiology (essential obesity, obesity with type 2 diabetes, genetic forms of obesity) and a cohort of lipodystrophic patients will be enrolled in the study, which is designed as a two-phases protocol. During the first phase (0-12 weeks (w)) patients will be subjected to dietary intervention with hypocaloric MD; in a second phase (12-24w), melatonin 1mg/die before sleep will be added to the hypocaloric MD. The susceptibility to infections will be investigated through the evaluation of 1) the number of events - i.e. flu- or flulike syndromes, skin, respiratory, digestive, urinary infections-per patient of the 4 groups and the blood assays to detect the infection with Epstein-Barr, Cytomegalovirus, Varicella, Measles and SARS-CoV-2 IgG and IgM; hepatitis C and hepatitis B core antibodies and Quantiferon TB Gold, 2) the clock genes rhythm and TLRs expression in patient immune cells at baseline, 12w and 24w.The mutual relationship between biomedical values, environmental and social conditions, and lifestyle habits will be evaluated by structured questionnaires. Validation of questionnaires to explore the susceptibility to infections is another delivery planned for the current study.

Detailed description: The current project aims at investigating 1) the susceptibility to infectious disease in obese patients, the role of tailored dietetic schemes of Mediterranean diet (MD), and melatonin supplementation on infective events; 2) association of the oral and/or gut microbiota signature with bacterial or viral infections in the above described obese cohorts; 3) the mutual relationship between biomedical values, environmental conditions and lifestyle habits through structured questionnaires and therefore the possible impact of this study on the National Health System (NHS).

The role of melatonin as chronobiologic influencer of circadian metabolic processes and as anti-obesogenic and weight-reducing effector comes to the fore in these last decades. Moreover, melatonin is also known to possess anti-inflammatory and antioxidant properties that may ameliorate the condition of low-grade chronic inflammation (metaflammation) observed in patients with obesity. Nevertheless, although there has been a tremendous interest in the role of the clock genes in regulating metabolic processes, relatively less effort has been expended examining how the regulation of circadian rhythms and metabolic inputs can affect the susceptibility to infections. To address this question, Unit 1 will enroll patients with essential obesity (20 subjects, BMI :30-35 Kg/m2) and with genetic forms of obesity (20 subjects) of both genders, aged 18-65yrs, to the main proof of concept pilot study.

At baseline (T0), patients will be subjected to anthropometric determinations, including body weight and height for BMI calculation, body composition by mean of DXA Scan, blood, serum and urine collection, oral cavity swab and stool sampling. Patients will undergo a session of behavioural dietary counselling by which patients will be educated to adhere to a hypocaloric MD for the first 12w (T1) and to add to the MD the supplementation with 1mg/die of melatonin for other 12w (T2). The same patients will be visited and subjected to the anthropometric determinations and biological samples at T0, T1, T2 of protocol. The endpoints for Unit 1 will be: 1.to investigate the impact of tailored hypocaloric MD and hypocaloric MD plus melatonin (supplement formulation, 1mg/die before sleep) on the number of events - i.e. flu- or flulike syndromes, skin, respiratory, digestive, urinary infections - per patient of the 4 groups, recording the number of infectious events during the clinical examinations in six months and 1 year follow up and detect the SARS-CoV-2, Epstein-Barr, Cytomegalovirus, Varicella and Measles IgG and IgM, hepatitis C and hepatitis B core antibodies and Quantiferon TB Gold (QFT-GIT). The obtained clinical results on infections events from the SIDERALE study will be used to formulate hypotheses for a prospective study and for the formulation of a specific validate questionnaire.

2.to assess the impact of a tailored hypocaloric MD and hypocaloric MD plus melatonin (supplement formulation, 1mg/die before sleep) on anthropometric determinations, glucose and lipid metabolism, thyroid and adrenal axis, leptin, adiponectin, IGFBP2, sirtuin 1 (SIRT1), ESR, high-sensitivity CRP, fibrinogen and inflammatory cytokines (TNF, IL-6, IL-1Beta, IL-18) and melatonin that will be evaluated at T0, T1, T2.

3.to assess the impact of a tailored hypocaloric MD and hypocaloric MD plus melatonin (supplement formulation, 1mg/die before sleep) on the entrainment of circadian clock misalignment, evaluating clock gene expression by RT-qPCR in peripheral blood mononuclear cells (PBMC) and concomitantly, on the regulation of Toll like-receptors (TLRs) and suppressor cytokine signaling 3 (SOCS3), known to play a crucial role in eliciting immunity and improving the well-known susceptibility to infections in patients with obesity, all evaluated by RT-qPCR in PBMC of all patients cohorts at 8 am, 12 pm and 12 am.

4.to quantify the impact of our intervention on the NHS in terms of decrease of antibiotic and antiviral treatment and ER (emergency room) admissions in six months and 1 year of follow up.

Moreover, an in vitro analysis will be performed on 3T3-L1 cells (mouse pre-adipocytes). 3T3-L1 differentiated in adipocytes will be synchronized and treated with melatonin in presence of TLRs agonists (i.e.

lipopolysaccharide, Pam3CSK, ssRNA40, imiquimod). Evaluation of TLRs signalling pathway will be performed by western blot. Evaluation of inflammatory cytokines (TNF, IL-6, IL-1, IL-18) and chemokines (MCP-1, CXCL5) will be performed by CLIA and/or ELISA and/or western blot.

Eligibility criteria: Inclusion Criteria:

* essential obesity (BMI : 30-35 Kg/m2)
* genetic forms of obesity (BMI: 30-35 Kg/m2)
* obesity (BMI:30-35 Kg/m2) associated with T2DM
* obesity (BMI:30-35 Kg/m2) associated with endocrinopathies
* lipodystrophy

Exclusion Criteria:

* pregnancy, breast-feeding, alcohol and drug abuse, known severe haematological, cardiac, liver, kidney, mental diseases, hypogonadisms, hormonal treatments including estroprogestins, intolerance to melatonin or excipients

Primary outcomes:
measure: Investigation of the impact of hypocaloric MD and hypocaloric MD plus melatonin on the number of events - i.e. flu- or flulike syndromes, skin, respiratory, digestive, urinary infections in patients with obesity and lipodystrophy
timeFrame: Change from baseline at 3-6-12 months
Secondary outcomes:
measure: Change in body weight (kg) after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: BMI modification after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy: body weight (kg) will be combined with height (m) to obtain BMI (kg/m^2)
timeFrame: Change from baseline at 3-6-12 months
measure: Change in waist and hip circumference after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in body composition assessed by Bioelectrical impedance analysis (BIA) after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy .
timeFrame: Change from baseline at 3-6-12 months
measure: Change in body composition assessed by DXA scan after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in glucose profile assessed by blood glucose levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in glucose profile assessed by blood glycated hemoglobin (HbA1c) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in insulin profile assessed by blood insulin levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in insulin resistance assessed by homeostasis model assessment - insulin resistance (HOMA-IR) Index after hypocaloric MD and hypocaloric MD plus in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in lipid profile assessed by blood total cholesterol levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in lipid profile assessed by blood LDL cholesterol levels after hypocaloric MD and hypocaloric MD plus in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in lipid profile assessed by blood HDL cholesterol levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in lipid profile assessed by blood triglycerides levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in leptin levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in adiponectin levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in IGFBP2 (insulin like growth factor binding protein 2) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in sirtuin 1 (SIRT1) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the thyroid axis assessed by thyroid stimulating hormone (TSH) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the thyroid axis assessed by free triiodothyronine (FT3) and free thyroxine (FT4) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the thyroid axis assessed by calcitonin levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the thyroid axis assessed by antibodies against thyroglobulin (AbTG) and against thyroperoxidase (AbTPO) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes in melatonin levels assessed by melatonin levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the adrenal axis assessed by adrenocorticotropic hormone (ACTH) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the adrenal axis assessed by cortisol levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the adrenal axis assessed by dehydroepiandrosterone sulphate (DHEAS) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Changes affecting the adrenal axis assessed by 17-hydroxyprogesterone (17-OHP) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in low grade inflammation assessed by erythrocyte sedimentation rate (ESR) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in low grade inflammation assessed by high-sensitivity CRP levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in low grade inflammation assessed by fibrinogen levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in low grade inflammation assessed by inflammatory cytokines (TNF, IL-6, IL-1Beta, IL-18) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in low grade inflammation assessed by inflammatory chemokines (MCP-1, CXCL5) levels after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Change in oral/gut microbiota after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months
measure: Evaluation of hypocaloric MD and hypocaloric MD plus melatonin effects on circadian gene expression in peripheral blood mononuclear cells (PBMCs) in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6 months
measure: Evaluation of hypocaloric MD and hypocaloric MD plus melatonin effects on circadian Toll-like receptors (TLRs) gene expression in peripheral blood mononuclear cells (PBMCs) in patients with obesity and lipodystrophy
timeFrame: Change from baseline at 3-6 months
measure: Evaluation of hypocaloric MD and hypocaloric MD plus melatonin effects on circadian Suppressor Cytokine Signaling 3 (SOCS3) gene expression in peripheral blood mononuclear cells (PBMCs) in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6 months
measure: In vitro analysis conducted on 3T3-L1 cells (mouse pre-adipocytes)
timeFrame: Change from baseline at 3-6 months
measure: Evaluation of adherence to MD (Mediterranean Diet) after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months.
measure: Evaluation of sleep habits after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months.
measure: Evaluation of circadian rhythms after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months.
measure: Reduction in the number of antibiotic and antiviral therapies after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months.
measure: Reduction in the number of ER (emergency room) admissions for infections after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months.
measure: Assessment of social determinants' impact on susceptibility to infections after hypocaloric MD and hypocaloric MD plus melatonin in patients with obesity and lipodystrophy.
timeFrame: Change from baseline at 3-6-12 months.
Other outcomes:
Locations:
city: Naples
country: Italy
facility: "Federico II" University of Naples, Department of Clinical and Molecular Endocrinology and Oncology
city: Novara
country: Italy
facility: Università del Piemonte Orientale
city: Pisa
country: Italy
facility: University of Pisa
city: Roma
country: Italy
facility: "Sapienza" University of Rome
Study officials:
affiliation: Federico II University
name: Annamaria Colao, Prof
role: PRINCIPAL_INVESTIGATOR
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