PegvisOMant and the Immune SystEm (PROMISE)

Study Overview
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Brief Summary
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This is a prospective observational pilot study for the evaluation of immune cells phenotype in acromegalic patients in comparison with a control population and to investigate the impact of disease control and different medical treatments (particularly Pegvisomant) on immune function and its implication on insulin resistance, metabolic complications and fat accumulation.

Detailed Description
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The observational study will concern the collection of data from patients who, as they are not controlled by SSAs therapy (cohort 1), require PEG therapy in monotherapy (group 1) or in combination with SSAs (group 2), according to common clinical practice. The investigators will enroll also acromegalic patients adequately controlled by medical therapy (cohort 2), respectively treated by any kind of SSAs (group 3) and by PEG (group 4) for comparison between different medical treatments. The data will be prospectively collected at baseline and after 8 weeks of treatment. A control group will be enrolled including healthy volunteers matched with patients for age and sex. The primary outcome will be the immune profiling by quantification of peripheral blood mononuclear cells (PBMC) subpopulations. Secondary outcome measures will be Evaluation of inflammatory cytokines and adipokines production. Evaluation of glucose, insulin, c-peptide, HbA1c, triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol apolipoprotein B and A. Insulin resistance and β cell function will be assessed by the homeostasis model assessment for insulin resistance (HOMA-IR) index and for β cell secretion (HOMA-β). Anthropometric measurements will include body weight, height and waist and hip circumference. Evaluation of body composition. Composite outcome measure consisting of lean mass, skeletal muscle and fat distribution analysis. Fasting samples from all patients will be assayed for disease control parameters. Evaluation of quality of life. Quality of life will be measured by Short Form (SF)-36-Item Health Survey total score, SF-36-Item Health Survey physical component summary score and SF-36-Item Health Survey mental component summary score and Acromegaly quality of life (AcroQol) questionnaire. Evaluation of sleep disturbances. Sleep disturbances will be measured by Epworth Sleepiness Scale (ESS) and by polysomnography when appropriate.

Official Title
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The PrOMISE Study: PegvisOMant and the Immune SystEm

Conditions
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Acromegaly

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously diagnosed acromegaly not adequately controlled by surgery and/or radiation therapy and in whom an appropriate medical treatment with any kind of somatostatin analogs (SSAs) did not control the disease or was not tolerated; Previously diagnosed acromegaly adequately controlled by medical treatment; Signed informed consent to participate in the study. Exclusion Criteria: Adequately controlled disease by surgery and/or radiation; Patients with transaminases more than 3 times the upper limit of normal; Hypersensitivity to PEG or any of its ingredients; History of other neoplasms, radiotherapy or chemotherapy in the last 5 years; Clinical or laboratory signs of significant hepatobiliary, or pancreatic disease; Severe infections, surgery, trauma requiring hospitalization within 3 months before enrolment; Severe chronic kidney disease (stage 4-5); Any active blood or rheumatic disorders in the last 5 years; Pregnant or nursing women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Acromegaly patients not adequately controlled by any kind of SSAs monotherapy<br>Acromegaly patients not adequately controlled by any kind of SSAs monotherapy, requiring PEG in combination with SSAs or PEG monotherapy | |
| Acromegaly patients adequately controlled by medical treatment<br>Acromegaly patients adequately controlled by medical treatment, by any kind of SSAs or by PEG | |
| Healthy controls<br>Healthy volunteers matched with patients for age and sex | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral blood mononuclear cell subpopulations | Number of cells (number per mm3) of peripheral blood mononuclear cell subpopulations | baseline | 
| Change of peripheral blood mononuclear cell subpopulations | Number of cells (number per mm3) of peripheral blood mononuclear cell subpopulations | baseline and after 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor necrosis factor alfa (TNFα) | Chemiluminescence measurement of TNFα serum concentrations (pg/ml) | baseline and post 8 weeks | 
| Transforming growth factor beta (TGF-β) | Chemiluminescence measurement of TGF-β serum concentrations (pg/ml) | baseline and post 8 weeks | 
| Interleukin-1 (IL-1) | Chemiluminescence measurement of IL-1 serum concentrations (pg/ml) | baseline and post 8 weeks | 
| Interleukin-6 (IL-6) | Chemiluminescence measurement of IL-6 serum concentrations (pg/ml) | baseline and post 8 weeks | 
| Interleukin-10 (IL-10) | Chemiluminescence measurement of IL-10 serum concentrations (pg/ml) | baseline and post 8 weeks | 
| Interferon gamma | Chemiluminescence measurement of interferon gamma serum concentrations (pg/ml) | baseline and post 8 weeks | 
| Monocyte chemoattractant protein (MCP-1) | Chemiluminescence measurement of MCP-1 (pg/ml) | baseline and post 8 weeks | 
| Adipokines production (visfatin) | Measurement of visfatin serum concentrations | baseline and post 8 weeks | 
| Adipokines production (adiponectin) | Measurement of adiponectin serum concentrations | baseline and post 8 weeks | 
| Adipokines production (vaspin) | Measurement of vaspin serum concentrations | baseline and post 8 weeks | 
| Adipokines production (omentin) | Measurement of omentin serum concentrations | baseline and post 8 weeks | 
| Metabolic parameters: glycemia | Evaluation of glucose (mmol/l) | baseline and post 8 weeks | 
| Insulin production | Evaluation of insulin (mU/L) | baseline and post 8 weeks | 
| Insulin secretion | Evaluation of c-peptide (ng/ml) | baseline and post 8 weeks | 
| Metabolic parameters: glycosylated haemoglobin | Evaluation of HbA1c (mmol/mol) | baseline and post 8 weeks | 
| Lipid profile: triglycerides | Evaluation of triglycerides (mmol/l) | baseline and post 8 weeks | 
| Lipid profile: cholesterol | Evaluation of total cholesterol (mmol/l) | baseline and post 8 weeks | 
| Lipid profile: HDL-cholesterol | Evaluation of HDL-cholesterol (mmol/l) | baseline and post 8 weeks | 
| Lipid profile: LDL-cholesterol | Evaluation of LDL-cholesterol (mmol/l) | baseline and post 8 weeks | 
| Lipid profile: Apo B | Evaluation of apolipoprotein B (mmol/l) | baseline and post 8 weeks | 
| Lipid profile: Apo A | Evaluation of apolipoprotein A (mmol/l) | baseline and post 8 weeks | 
| Insulin resistance | Evaluation of the homeostasis model assessment for insulin resistance (HOMA-IR) index | baseline and post 8 weeks | 
| beta cell function | Evaluation of the homeostasis model assessment for β cell secretion (HOMA-β) | baseline and post 8 weeks | 
| Body mass index (BMI) | Body weight and height weight will be combined to report BMI in kg/m^2 | baseline and post 8 weeks | 
| Anthropometric parameters | Waist and hip circumference will be combined to report waist-hip ratio | baseline and post 8 weeks | 
| Body composition: lean mass | Lean mass distribution (%) evaluated by a whole-body dual-energy x-ray absorptiometry (DEXA) scan | baseline and post 8 weeks | 
| Body composition: fat mass | Fat mass distribution (%) evaluated by a whole-body dual-energy x-ray absorptiometry (DEXA) scan | baseline and post 8 weeks | 
| Biochemical control | Fasting samples from all patients will be assayed for disease control parameters (insulin-growth factor and growth hormone) | baseline and post 8 weeks | 
| Quality of life SF-36-Item Health Survey questionnaire | 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 | baseline and post 8 weeks | 
| Acromegaly Quality of Life Questionnaire | Evaluation of quality of life by the Acromegaly Quality of Life Questionnaire (ACROQOL), a disease specific questionnaire to measure quality of life in patients with acromegaly. It contains 22 items divided in two scales that measure physical and psychological aspects. Each of the 22 items of the AcroQoL is answered in a 1 to 5. A global score is obtained adding the results of the 22 items using a specific formula, from a minimum of 22 - worse QoL - until 110 - best QoL - | baseline and post 8 weeks | 
| Sleep apnea | Sleep disturbances will be measured by Epworth Sleepiness Scale (ESS). The ESS consists of eight questions regarding eight activities. Each of the activities listed has an assigned score from 0 to 3 that indicates how likely a person is to fall asleep during the activity: 0 = would never doze, 1 = slight chance of dozing, 2 = moderate chance of dozing, 3 = high chance of dozing. The total score can range from 0 to 24. A higher score is associated with increased sleepiness. | baseline and post 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acromegaly, Pegvisomant, Immunity, Immune function, Metabolism, Body composition, Quality of life, Sleep disturbances