Zingonia- Osio Sotto, Italy

Observational Study on the Use of Ropeginterferon Alfa-2b in Polycythemia Vera (ROPEG-PV)

Classical Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are characterized by uncontrolled clonal proliferation of multipotent bone marrow progenitors, sustained by acquired mutations in JAK2, CALR and MPL genes. Natural history of PV is marked by life threatening outcomes such as thrombosis, bleeding and clonal evolution towards myelofibrosis and acute myeloid leukemia. Treatment-relevant risk stratification is designed to estimate the likelihood of thrombotic complications, which is estimated to occur before or after diagnosis in 20-30% of patients according disease and patient-related risk factors. The cornerstone of treatment in PV includes scheduled phlebotomy, with a hematocrit (Hct) target of <45% and low-dose aspirin in all patients, regardless of risk category. There is currently broad consensus regarding the need for cytoreductive drugs in high-risk patients with PV identified by age >60 years and prior history of thrombosis. The results of several andomized trials for the treatment of PV are now available, and, in addition to the standard drug hydroxyurea (HU), both a new ropegylated formulation of interferon alfa-2b3 and ruxolitinib4 are now available have been approved in Europe and US and European LeukemiaNet (ELN) investigators have recently provided recommendations for the use of these drugs in clinical practice in low-risk as well as high-risk patients. After approval by EMA (2019) and FDA (2021), the drug (ROPEGINTERFERON ALFA-2B) was very recently approved and reimbursed by AIFA (2022) in some subgroups of patients with PV. The use of this drug in clinical practice is an opportunity for a prospective observational study in a rare disease such as PV; the aim is to evaluate its impact in the practical management of these patients, according to Determinazione AIFA 20 marzo 2008 about observational clinical studies, and Decreto Ministeriale 17 dicembre 2004 on non-profit studies. It is not entirely known which is the percentage of patients who, after careful screening as required in good clinical practice, will fail the indications for concomitant clinical or laboratory abnormalities. Furthermore, the proportion of patients who discontinue the drug during follow-up for intolerance or other reasons is currently unknown and data on the benefit-risk ratio are limited. Moreover, it should be noted that the haematological and clinical responses obtained in clinical trials not always are replicated in the studies of the real-world clinical practice. In fact, daily management of PV patients does not require the same stringent enrollment and follow-up criteria as instead are necessary in clinical trials. Our proposal may also contribute to better implement the results following the recent guidelines, particularly in some subgroups of patients in which AIFA has established the use with reimbursement by Italian National Health System (NHS) (i.e., patients intolerant to HU, women of childbearing age who plan pregnancy and patients with history of skin cancer).

Study to Evaluate the Effect of Balcinrenone/Dapagliflozin in Patients With Heart Failure and Impaired Kidney Function

The purpose of this study is to investigate the effect of balcinrenone/dapagliflozin compared with dapagliflozin, on the risk of CV death, HF event with and without hospitalisation, in patients with chronic HF, impaired kidney function, and who have had a recent HF event. Eligible patients will randomly be assigned with a 1:1:1 ratio to receive once daily administration of one capsule and one tablet of one of the following treatments: 1. Balcinrenone/dapagliflozin 15 mg/10 mg capsule and matching placebo for dapagliflozin 10 mg tablet 2. Balcinrenone/dapagliflozin 40 mg/10 mg capsule and matching placebo for dapagliflozin 10 mg tablet 3. Dapagliflozin 10 mg tablet and matching placebo for balcinrenone/dapagliflozin capsule The study is event driven, and the average study duration for a participant is estimated to be 22 months including screening period, 20 months blinded treatment period and a one-month follow-up period on open-label dapagliflozin. The study will be conducted at approximately 700 sites in approximately 40 countries globally.

Prospective and Multicenter Italian Registry of Locally Advanced-Metastatic Urothelial Carcinoma

This is a multicentre, prospective and non-interventional study in which all patients treated according to clinical practice will be included. The registry will include all patients with metastatic urothelial carcinoma or with lymph node involvement defined as unsuitable for surgery. The study involves medical visits and clinical-radiological re-evaluations according to clinical practice. There are no additional procedures. The clinician will establish the number of visits necessary for each patient according to the needs encountered and depending on the treatment chosen. The participating centers were selected in such a way as to adequately represent all the different geographical areas. The duration of the study is 24 months: 12 months of enrollment plus 12 months of further follow-up.

A Study of Vedolizumab With and Without Upadacitinib in Adults With Crohn's Disease

The drug being tested in this study is vedolizumab. Vedolizumab is being tested to treat people with moderately to severely active CD. The study will look at the efficacy and safety of vedolizumab with and without upadacitinib. The study will enroll approximately 396 patients. Participants will be assigned in a 1:1 ratio to one of the two treatment groups in the 12-weeks Induction Phase: - Induction Phase: Vedolizumab + Upadacitinib - Induction Phase: Vedolizumab + Placebo Participants who achieve a Crohn's disease activity index (CDAI) reduction of greater than or equal to (>=)70 points from baseline at Week 12 will enter the main study Maintenance Phase (40 weeks) of the study to receive vedolizumab monotherapy. Participants will be followed for a further 18-week safety follow-up period up to Week 70. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 70 weeks.

European Myeloma Network (EMN) Sample Project

PATHophysiology of OSteoporosis: Role of Hidden Cortisol Excess and Its Predictors in Bone Fragility

Clinically overt hypercortisolism leads to hypertension, diabetes and osteoporosis. More recently, even the condition of mild and asymptomatic hypercortisolism has been described to be associated with increased prevalence of chronic complications of cortisol excess and mortality. In patients with osteoporosis this form of hypercortisolism may remain occult (hidden hypercortisolism, HidHyCo). The HidHyCo prevalence in the general population is estimated to be 0.2-2%, but it has been reported up to 9.9% and 17.6% in patients with low bone mineral density and with fragility fracture, respectively. However, given the high prevalence of bone fragility and the relatively low specificity of the available tests for the HidHyCo detection, screening all osteoporotic patients for HidHyCo is considered unthinkable and no guidelines are available for addressing the HidHyCo screening in osteoporosis. At present, data regarding the osteoporosis characteristics more frequently associated with HidHyCo have been not reported, even though some data suggest that the coexistence of osteopenia with hypertension treated with at least 2 drugs or with not well controlled hypertension and/or diabetes or with a history of cardiovascular events may increase the probability of HidHyCo. Moreover, scarce and discordant data are available on the pathogenesis of the bone damage due to a subtle cortisol excess and on the possible role of individual bone sensitivity to cortisol and of microbiome composition. Therefore, the aims of the current project are the following: i) to assess the prevalence of HidHyCo, ii) to determine the characteristics predictive of the presence of this condition in patients with apparently primary osteoporosis, iii) to evaluate the pathogenetic mechanisms explaining the negative effects of this slight cortisol excess on bone and the potential role of the genetic background and of the gut microbiome. In all patients who have been included in the study and who have given the informed consent to participate in the study 1 mg overnight dexamethasone suppression test (F-1mgDST) will be performed. In all subjects with F-1mgDST >1.8 mcg/dL, cortisol levels after two-day low dose (2 mg/day) dexamethasone suppression test (F-2mgx2dDST) will be measured. Patients with F-2mgx2dDST above >1.8 mcg/dL will be considered affected with HidHyCo and will be managed following the available guidelines for hypercortisolism. The HidHyCo prevalence in osteopenic/osteoporotic patients and its 95% interval confidence will be calculated. Moreover, in all recruited patients the following vital and anthropometric parameters will be recorded: blood pressure, heart rate, weight, height, body mass index (BMI), abdominal circumference and waist-to-hip ratio. Moreover, the following variables will be collected: familiar history of fragility fracture, smoking habit, main comorbidities, history of falls, previous clinical fragility fractures, ongoing pharmacological treatment (in particular type and number of antihypertensive, lipid lowering, anti-diabetic and anti-osteoporotic drugs), previous anti-osteoporotic treatments, in females regularity of menses or age of menopause and in males testosterone levels. Questionnaires for assessing daily calcium intake and physical activity will be administered to all patients. At the time of enrolment, the results of first tier investigations according to national guidelines (i.e. serum erythrocyte sedimentation rate, complete blood count, serum protein electrophoresis, serum calcium levels, serum phosphate levels, total alkaline phosphatase, serum creatinine, 24-h urinary calcium) will be also registered. Moreover, other calcium-phosphate metabolism parameters (i.e. serum ionized calcium, serum parathyroid hormone, serum 25-OH-vitamin D, serum ß-CrossLaps, bone alkaline phosphatase) and routine determinations (i.e. fasting glucose, insulin, glycated haemoglobin, total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, transaminases) will be recorded, if available. According to the good clinical practice, in all patients bone mineral density will be assessed by dual-energy X-ray Absorptiometry (Hologic or Lunar bone densitometers) and the presence of asymptomatic vertebral fractures will be checked by conventional spinal radiographs using the semi-quantitative visual assessment described by Genant et al., defined as a reduction of >20% in anterior, middle, or posterior vertebral height. The investigators will compare the clinical and biochemical characteristics of osteoporotic/osteopenic patients with HidHyCo and those without HidHyCo. The sample size has been calculated in order to have an adequate number of HidHyCo cases to determine the characteristics of osteoporotic patients suggestive for the presence of HidHyCo. Since HidHyCo may be estimated to have at least a 3% prevalence in osteoporotic patients, a sample of 1500 osteoporotic patients should be adequate to find no less than 45 HidHyCo cases. To further investigate bone quality and turnover in HidHyCo patients, to characterize HidHyco patients from a molecular and genetic point of view and to evaluate the pathogenetic mechanisms explaining the negative effects of endogenous subtle cortisol excess on bone health and the potential role of the genetic background and of the gut microbiome. In patients found to be affected with HidHyCo and in age-, sex- and BMI-matched patients without HidHyCo (with a case-control ratio of 1:2) the investigators will: i) assess bone turnover markers and new potential serum markers of bone status, such as those involved in the Wnt-ßcatenin signaling; ii) perform Radiofrequency echographic multi spectrometry (REMS), a non-ionizing skeleton technique performed employing a new dedicated echographic device (EchoStation, Echolight Spa, Lecce, Italy) to further investigate bone quality characteristics that are not included in DXA-measured BMD, such as the Fragility Score (FS). iii) assess circulating microRNAs (miRNAs, i.e. small non coding single-stranded RNAs that have emerged as important post transcriptional regulators of gene expression) expression profile; iv) assess cortisol peripheral activation, as expressed by the 24-hour urinary free cortisol/free cortisone ratio (i.e., the higher the R-UFF/UFE, the higher tissues exposure to active glucocorticoids), measured by liquid chromatography-tandem mass spectrometry and its relationship with the polymorphic variants of the 11beta-hydroxysteroid dehydrogenase type 1 (11ßHSD1) gene; v) assess cortisol sensitivity, expressed by the polymorphisms of the glucocorticoid receptor (GR) gene from DNA isolated from peripheral blood; vi) assess beta-2 adrenergic activity, regulated by the polymorphism (rs1800544) of the beta-2 adrenergic receptor (B2AR) gene from DNA isolated from peripheral blood, which could have an impact on cortisol effect due to the multiple interactions between the sympathetic and the hypothalamic-pituitary-adrenal systems via adrenoceptors; vii) assess gut microbiome composition, using fecal samples. To avoid the confounding effect of bone-active drugs, i), ii) and iii) will not be assessed in patients on treatment with bone-active drugs, but exclusively in naïve-treatment patients or in patients not recently treated (over 12 months previously for oral bisphosphonates and teriparatide and over 24 months previously for intravenous bisphosphonates and denosumab). The HidHyCo case finding is of utmost importance since an underlying condition of HidHyco is associated with an increased risk of osteoporosis and fragility fractures and can decrease the response to bone-active drugs. Conversely, the resolution of cortisol excess can result in the improvement of bone strength and in the reduction of fracture risk. However, HidHyCo is by definition an occult condition, until its presence is suspected on the basis of particular characteristics of the underlying disease. Based on preliminary data, it is possible to assume that HidHyCo is present in a not negligible percentage of osteopenic/osteoporotic patients. The investigators hypothesize a 3% HidHyCo prevalence in the osteoporotic population. The presence of osteoporosis associated with a poorly controlled hypertension and/or diabetes or with a history of cardiovascular events (osteopenia with comorbidities) or the presence of fragility fractures in the presence of not osteoporotic bone density, in an eugonadal state and/or on osteoporotic treatment with bone-active drugs may be the variables potentially associated with an increased probability of having HidHyCo. By testing our sample of osteoporotic patients for HidHyCo, the investigators aim at obtaining information regarding the pre-test probability of a single individual of having a subtle cortisol excess and, if feasible, at developing a clinical model for the identification in outpatient osteoporosis clinics of subjects worthy of HidHyCo testing, thus avoiding a mass screening. Moreover, the evaluation of circulating miRNAs expression profile can help to distinguish primary osteoporosis and secondary osteoporosis due to subtle cortisol excess. From a pathophysiological point of view, the condition of HidHyCo in our patients, differently from the exogenous hypercortisolism, may represent a pure form of slight cortisol excess, without the confounding effect of the diseases for which therapeutic glucocorticoids are given. Therefore, the assessment of bone involvement in HidHyCo patients may consent to evaluate the pure role of glucocorticoid excess on bone metabolism and bone quality, as expressed for example by the markers of bone turnover and of the Wnt-ß-catenin signaling and by the REMS parameters, respectively. In addition, the glucocorticoid secretion and sensitivity evaluation in our osteoporotic population can also consent us to study the impact of cortisol peripheral activation and of the polymorphisms of 11ßHSD1, GR and B2AR genes in modulating the skeletal sensitivity and damage to the subtle cortisol excess. If the importance of these parameters for bone health was confirmed, it would be possible to personalize the clinical workup on the basis of the individual risk of fracture and to try to counteract in selected patients the adverse effects of the relatively increased cortisol secretion with the 11ßHSD1 inhibitors. Indeed, some studies showed that the inhibition of the 11ßHSD1 may protect bone against the deleterious effects of glucocorticoids. Finally, investigators will obtain information on whether or not microbiome composition differs between osteoporotic patients with and without HydHyCo. This information could suggest new pathophysiological mechanisms underlying the relationship between cortisol excess and bone fragility. If there were interactions between these factors (microbiome and cortisol milieu) on the clinical outcomes of bone fragility, investigators might suggest the gut as a novel therapeutic target for preventing the adverse systemic effects of cortisol excess, as suggested by experimental observations. Overall, information from this study will make possible to unmask the presence of HidHyCo in patients evaluated for osteoporosis and/or bone fragility and to personalize the clinical management of these patients, in relation to the genetic background, the GC sensitivity and the microbiome composition

Phase 2 Study Applying MRD Techniques for Participants With Previously Untreated Multiple Myeloma Treated With D-VRd Prior To and After High-dose Therapy Followed by ASCT - TAURUS

Prevalence of Hidden Hypercortisolism in Osteoporosis

Clinically overt hypercortisolism (i.e. Cushing's syndrome) leads to hypertension, central obesity, diabetes and osteoporosis. More recently, even the condition of mild and asymptomatic hypercortisolism has been associated with increased prevalence of chronic complications of cortisol excess and mortality. In patients with osteoporosis this form of hypercortisolism may remain occult (hidden hypercortisolism, HidHyCo), until its presence is suspected on the basis of particular characteristics of the underlying disease. By definition, HidHyCo is a condition of cortisol excess in the absence of its classical signs and symptoms. Although asymptomatic, however, this subtle cortisol excess is associated with an increased risk of osteoporosis and fragility fractures. Moreover, HidHyCo prevalence seems to be increased in osteoporotic patients. In particular, the prevalence of HidHyCo in patients with low bone mineral density and with fragility fracture has been reported to be 1.7-9.9% and 1.9-17.6%, respectively. The HidHyCo case finding is of utmost importance since these patients experience an impressive reduction of the fracture risk after the normalization of cortisol levels. However, given the high prevalence of bone fragility and the relatively low diagnostic accuracy of the currently available tests for the HidHyCo detection, a mass screening for HidHyCo is considered unthinkable. Therefore, the issue of which osteoporotic patient has to be screened for HidHyCo has recently become a widely debated topic, but as now, no guidelines are available for addressing the HidHyCo screening in osteoporosis. Therefore, the aims of the present study protocol are the following: i) to assess the HidHyCo prevalence in a sample of osteoporotic patients; ii) to compare the clinical characteristics between osteoporotic/osteopenic patients with HidHyCo and those without HidHyCo in order to determine the clinical characteristics more frequently associated with the HidHyCo presence in the osteoporotic population and to identify those osteoporotic patients worthy of HidHyCo screening. In all patients who have been included in the study and who have given the informed consent to participate in the study the following vital and anthropometric parameters will be recorded: blood pressure, heart rate, weight, height, body mass index (BMI), abdominal circumference and waist-to-hip ratio. Moreover, the following variables will be collected: familiar history of fragility fracture, smoking habit, main comorbidities, history of falls, previous clinical fragility fractures, ongoing pharmacological treatment (in particular type and number of antihypertensive, lipid lowering, anti-diabetic and anti-osteoporotic drugs), previous anti-osteoporotic treatments, in females regularity of menses or age of menopause and in males testosterone levels. Questionnaires for assessing daily calcium intake and physical activity will be administered to all patients. At the time of enrolment, the results of first tier investigations according to national guidelines (i.e. serum erythrocyte sedimentation rate, complete blood count, serum protein electrophoresis, serum calcium levels, serum phosphate levels, total alkaline phosphatase, serum creatinine, 24-h urinary calcium) will be also registered. Moreover, other calcium-phosphate metabolism parameters (i.e. serum ionized calcium, serum parathyroid hormone, serum 25-OH-vitamin D, serum ß-CrossLaps, bone alkaline phosphatase) and routine determinations (i.e. fasting glucose, insulin, glycated haemoglobin, total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, transaminases) will be recorded, if available. According to the good clinical practice, in all patients bone mineral density will be assessed by dual-energy X-ray Absorptiometry (Hologic or Lunar bone densitometers) and the presence of asymptomatic vertebral fractures will be checked by conventional spinal radiographs using the semi-quantitative visual assessment described by Genant et al., defined as a reduction of >20% in anterior, middle, or posterior vertebral height. Finally, iIn all patients who have been included in the study and who have given the informed consent to participate in the study we will perform 1 mg overnight dexamethasone suppression test (F-1mgDST). In all subjects with F-1mgDST >1.8 mcg/dL, cortisol levels after two-day low dose (2 mg/day) dexamethasone suppression test (F-2mgx2dDST) will be measured. Patients with F-2mgx2dDST above >1.8 mcg/dL will be considered affected with HidHyCo and will be managed following the available guidelines for hypercortisolism. The HidHyCo prevalence in osteopenic/osteoporotic patients and its 95% interval confidence will be calculated.Then, we will compare the clinical and biochemical characteristics of osteoporotic/osteopenic patients with HidHyCo and those without HidHyCo. The sample size has been calculated in order to have an adequate number of HidHyCo cases to determine the characteristics of osteoporotic patients suggestive for the presence of HidHyCo. Since HidHyCo may be estimated to have at least a 3% prevalence in osteoporotic patients, a sample of 1500 osteoporotic patients should be adequate to find no less than 45 HidHyCo cases. Indeed, based on preliminary data, it is possible to assume that HidHyCo is present in a not negligible percentage of osteopenic/osteoporotic patients. The presence of osteoporosis associated with a poorly controlled hypertension and/or diabetes or with a history of cardiovascular events (osteopenia with comorbidities) or the presence of fragility fractures in the presence of not osteoporotic bone density, in an eugonadal state and/or on osteoporotic treatment with bone-active drugs may be the variables potentially associated with an increased probability of having HidHyCo. By testing our sample of osteoporotic patients for HidHyCo, we aim at obtaining information regarding the pre-test probability of a single individual of having a subtle cortisol excess and, if feasible, at developing a clinical model for the identification in outpatient osteoporosis clinics of subjects worthy of HidHyCo testing, thus avoiding a mass screening. In HidHyCo patients, osteoporosis and, if present, other comorbidities (i.e. hypertension and/or diabetes) can improve by the surgical resection of the adrenal or pituitary adenoma if feasible, or by the use of drugs able to modulate cortisol secretion or glucocorticoid sensitivity.

Study of XL092 + Nivolumab vs Sunitinib in Subjects With Advanced or Metastatic Non-Clear Cell Renal Cell Carcinoma

DESTINY Breast Respond HER2-low Europe

This non-interventional study will investigate the effectiveness withT-DXd, the demographic and clinical characteristics of the patients, treatment patterns, tolerability, management of adverse drug reactions (ADRs), and patient experience of T-DXd in patients with HER2-low unresectable and/or metastatic breast cancer. Patients will be treated according to the proposed indication statement in the Summary of Product Characteristics (SmPC). No drug product will be administered as part of this study. Data on conventional chemotherapy (i.e., including but not limited to capecitabine, eribulin, gemcitabine, paclitaxel and nab-paclitaxel) will also be collected in a disease registry part of the study.