Husu, Finland

A Phase 3 Study of Barzolvolimab in Participants With Chronic Spontaneous Urticaria

This is a global, multicenter, randomized, double-blind, parallel group, placebo-controlled phase 3 study investigating the efficacy, safety and tolerability of barzolvolimab in adult participants with Chronic Spontaneous Urticaria (CSU) who are symptomatic despite treatment with non-sedating second generation H1-antihistamines at 1-4 times the locally approved dose. There is a screening period of up to 4 weeks, followed by a 24-week placebo-controlled treatment period, a 28-week active treatment period where all participants receive barzolvolimab followed by a 16-week treatment free period. Approximately 915 adult participants (610 in the active arms and 305 in the placebo arm) will be randomly assigned to the treatment arms.

Pulmonary Embolism International THrOmbolysis Study-3

In patients with intermediate-risk pulmonary embolism, full-dose thrombolytic treatment was associated with a reduction in the combined risk of hemodynamic instability or death but was also associated with an increased risk of major and intracranial bleeding. Previous studies suggest that reduced dose of thrombolytic treatment may be as effective as the full dosage, but with a decreased risk of life-threatening bleeding. In this study, we will assess the efficacy and safety of a reduced dosage of thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism. The study is a randomized, placebo-controlled, double blind, multicenter, multinational trial with long-term follow-up. Patients fulfilling the inclusion criteria and without any of the exclusion criteria will be randomized within 6 hours after the investigator had confirmed the diagnosis. Patients will receive: - Alteplase (if randomized in the experimental group) or placebo (if randomized in the reference group) given within 30 minutes of randomization as a 15 min intravenous infusion at a dosage of 0.6 mg/kg with a total dose not exceeding 50 mg. - Parenteral anticoagulation with low molecular weight heparin, unfractionnated heparin or fondaparinux Primary objective is to assess the efficacy of reduced dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30. Secondary objectives are: 1. To assess the safety of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30 2. To assess the net clinical benefit of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30 3. To assess the effect of reduced dose thrombolytic therapy on overall mortality of patients with intermediate-high-risk acute pulmonary embolism at day 30 4. To assess the effect of reduced dose thrombolytic therapy on long-term mortality, functional impairment, residual right ventricular dysfunction and chronic thromboembolic pulmonary hypertension at 6 months and 2 years 5. To assess the effect of reduced-dose thrombolytic therapy on utilization of health care resources at day 30 and day 180

Why Does Aspirin Fail in Secondary Cerebrovascular Prevention? A Multicenter Prospective Case - Control Study

Chocolate and Physical Exercise to Reduce Malnutrition in Pre-dementia Aged People

BACKGROUND Older adults are particularly vulnerable to undernutrition, a state resulting from defective food intake or uptake (nutrient deficiencies) leading to altered body composition and weight loss. Muscle wasting is a major drawback of this condition and a symptom of protein-energy malnutrition (PEM) and metabolic reprogramming of tissues that increase the ageing process. These changes sustain insulin resistance and impaired mitochondrial metabolism of critical organs and tissues, including skeletal muscle. Prevention of undernutrition is critical. Undernutrition correlates with an accelerated and general decline in health conditions (worsening both physical and cognitive/mental aspects), thus increasing the risk of frailty and finally accelerating physical and cognitive decline. Under these circumstances, the majority of people experience a significant loss of locomotor function, with a significant decline in quality of life, and a high risk of falls which often represents the terminal event in life. These factors can lower the frailty threshold for the oldest-old, with the consequent loss of adaptability, which is an essential feature of successful ageing. This process of deteriorating mobility is multifactorial and also includes decline in cognitive function, increased bone fragility, and reduced joint flexibility. Strong evidence suggests that ageing and cognitive decline are associated with dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis), with a clear increase in cortisol levels. The effects of hypercortisolism are far-reaching, affecting the skeletal muscle widely, thus leading to significant sarcopenia and fragility. It is well known that HPA axis activity is impaired in Alzheimer's disease (AD) patients. This dysregulation induces an increase in cortisol levels. High levels of cortisol, one of the most catabolic hormones, also lead to noticeable sarcopenia. Mechanistic aspects include antagonistic effects on the insulin axis (secondary insulin resistance) and consequent metabolic reprogramming of tissues to gluconeogenesis sustained by non-carbohydrate precursors that include amino acids derived from the proteolytic degradation of muscle proteins. Comorbidity in frail people can further sustain the secretion and metabolic effects of cortisol, especially undernutrition and PEM. Some of us previously showed that cortisol levels are significantly higher in patients with AD and severity of the behavioural symptoms, and more importantly, changes in body mass, significantly correlated with cortisol levels. Therefore, cortisol levels, which are not regularly evaluated in AD patients, would help predict patients at risk of weight loss. Moreover, recent findings revealed a significant decrease in cortisol levels in response to chronic physical activity in healthy individuals and patients with dementia. Physical activity treatment (PT) is a non-pharmacological treatment with great potential to attenuate the cognitive decline in healthy elderly. In patients with Mild Cognitive Impairment (MCI) it was observed that 6 months of PT significantly ameliorates BMI, 6' Walking Test (6MWT), systolic and diastolic blood pressure, glucose, cholesterol, and triglycerides. Importantly, PT may preferably be undertaken as high aerobic intensity (85-95% of maximal heart rate) intervals (HIT), as this yields superior effects on the cardiovascular system compared with PT of moderate or low intensity. HIT has successfully been applied in older individuals (8,9), and in frail populations such as patients with heart failure. Along with physical activity, macro and micronutrients, are reported to interact with the activity of HPA-axis and to help reducing cortisol levels. Chocolate polyphenols appear to have significant effects with impact on both mental well-being and metabo-inflammatory symptoms of chronic exposure to such stress hormone (3,11-13). Cocoa-derived flavonoids can lower the levels of the active hormone cortisol. Mechanistically, these natural molecules inhibit 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1, an enzyme involved in reducing cortisone to the active form cortisol. The intake of these and many other micronutrients and homeostatic factors decrease with aging due to general worsening of quantity and quality of food intake. Together with micronutrients, protein intake is a critical aspect and a major risk factor for PEM and frailty. Nutritional supplementation for frail people has been shown to slow their functional decline, improving both muscle mass and strength, particularly if this is combined with physical activity. It is now established that nutritional recommendations, including adequate protein and micronutrient intake, are important for a better quality of life in the elderly, which is common management approach of older people who are frail or at risk for developing frailty. Vitamin E is a fat-soluble essential micronutrient with unique properties as antioxidant and cell protection factor. It is present in cellular membranes of all tissues to scavenge peroxyl radicals formed by free radical attack on polyunsaturated fatty acids. This function is particularly important to prevent mitochondrial damage and the uncontrolled release of free radicals from these organelles in the muscle. Its intake and function as cell protection factor and immune system modulator can be compromised in the elderly (20); moreover, preclinical and human experimental studies show that vitamin E positively influences myoblast proliferation, differentiation, survival, membrane repair, mitochondrial efficiency, muscle mass, muscle contractile properties, and exercise capacity. Furthermore, recent studies on the human metabolism of vitamin E demonstrated that the biotransformation of this vitamin in human tissues forms bioavailable long-chain metabolites with a role as tissue detoxification (PXR and PPAR-gamma agonist activity) and anti-inflammatory (LOX-5 inhibition) mediators. Therefore, for multiple reasons, vitamin E supplementation in the diet as a measure to support physical training in preventing age-associated PEM is worth investigating. AIMS The study aims to investigate if regular consumption of vitamin E-functionalized and polyphenol-rich chocolate can support physical exercise high-protein diet to slow down the progression of protein-energy undernutrition in pre-dementia elderly people. Specifically, the primary aim is to investigate whether regular consumption of vitamin E-functionalized and polyphenol-rich chocolate and regular exercise practice boost lower limb muscle mass in pre-dementia elderly people. The secondary aims are to investigate the effect of regular consumption of vitamin E-functionalized and polyphenol-rich chocolate and regular exercise practice on muscle strength, cognitive function, vascular function, metabolic and physical functions, as well as mitochondrial respiration, circadian cortisol curve, blood hormones, and inflammatory status in blood and mRNA in pre-dementia elderly people. PROCEDURE The study will be a randomized, double blinded, controlled trial with parallel groups including active control and shame groups. One hundred and fifty individuals with MCI and subjective cognitive decline without functional deficits will be screened for eligibility and those that comply with inclusion and exclusion criteria will be confirmed and the informed consent will be allocated for testing and undergo preliminary evaluations (T00). After preliminary evaluation, all the individuals included in the study will undergo a 4 to 6-week "Run-in" phase during which the high protein diet (HPro) will be introduced and all subjects will be trained to implement the High-Intensity Training physical exercise (HIT) program that will be developed during the study. Immediately after the "Run-in", a pre-intervention (T0) evaluation will be undertaken. Consequently, participants stabilized on the HPro Diet + HIT which will be the common treatment for all participants, will be randomly assigned (utilizing an online statistical computing web program) to one of the three arms of the nutritional intervention in which the effect of vitamin E (VE) will be investigated separate or combined with the effect of chocolate polyphenols (HPP) compared to control treatment. The intervention will last six months; assessments will be performed after three months (halfway through the intervention) and at the end of the intervention (T1 and T2, respectively). A follow-up assessment will be performed three months after the end of the intervention after the restoration of baseline diet and physical activity conditions (T3). Each group will include 34 participants; a 20% dropout has been estimated based on previous studies. SAMPLE SIZE CALCULATION Considering an alpha = 0.05, a power = 0.8 and the 20% of estimated drop out, we aim to recruit 102 subjects (34 in each group). Main outcome is "muscle mass", and for all the groups treatment duration will be 6 months. In 6 months in the target population the loss of muscle mass is assumed to be 1.0-1.5% (+/- 0.5%) [5] [48]. In Control group (Group A), which includes people undergoing targeted exercise, the expected increase is 2% 1.5% (+-0.5%) [5] [48]. In treatment groups (Groups B and C) the median average expected increase at second follow-up is 4% 2% (+-0.5%), and 1.5% 4% (+-0.5%) at 6 months [6] [49]. The rate of lost at follow-up, derived from previous studies, is 20% (+-2%) [7] [50]. Correlation between repeated measures is assumed to be 0.5, variance explained by the between-subjects effect 6.25 and error variance 65. All estimates were performed using Stata v.16.1 (StataCorp LP, College Station, TX, USA) by "power repeated" command. STATISTICAL ANALYSIS Statistical analysis will be conducted under the supervision of an expert in biostatistics (dr Gili, at Coordinator Unit) and with the support of LIPOSTAR software provided by external collaborator C2. A two-way repeated measures ANOVA, including age and gender as covariates, with "time" as within-group factor and "treatment" as between-groups factor will be utilized to calculate difference between groups. In the presence of significant effects, a multiple comparisons tests with Bonferroni's correction will be performed. The familywise alpha level for significance will be set at 0.05 (two-tails), with Bonferroni's correction when needed, for all the analyses. SIDE EFFECTS Sides effects may be related to the assessment procedures: strength, voluntary activation, and electrically evoked potential tests may cause muscle soreness and discomfort during the procedures. In case of persistent discomfort the procedure will be immediately stopped. Also, side effect might be caused by blood draw and muscle biopsy: subjects may experience some side effects related to the blood draw in the draw site, which normally gets between the following days. Also, subjects may experience some soreness in the site of the biopsy, muscle tightness and fatigue in the few days after biopsy was taken. In the case of these events, subject will be monitored and the family doctor will be informed. DATA AND SAFETY MONITORING COMMITTEE A log-diary will be kept by each participant and will be checked weekly by the investigators and collaborators. In the diary participants will include information about possible adverse events caused by assessment procedures or related to the diet and training, any important points about the response to the interventions, any possible discomfort experienced during or after the training, or notes regarding diet and supplementation. Prof. Gianluca-Svegliati Baroni of the Gastroenterology Division of the University Hospital of Ancona, Italy will serve as external scientific supervisor of the clinical trial. He is an expert in clinical and preclinical studies of human nutrition and metabolism. He will advise on specific Code: CHOKO-AGE Data: 10/06/2021 Version:1 30 tasks and monitor the different phases of clinical trial from organization to implementation of activities, data gathering and evaluation/interpretation. The quality assurance standards of University of Verona will be adopted to monitor the clinical trial. A delegate of this University will be nominated to perform the monitoring of the different phases of the trial utilizing internal SOPs. The entire set of clinical procedures, operator's activity and collection of experimental data will be verified during a series of visits by the monitor that will occur at the beginning and the end of each time point in the study (Time T00 to T3).

Comparison of CRT-D and CRT-DX Systems (CRT-NEXT)

Resting heart rate is strongly associated with incident worsening Heart Failure (HF) and mortality. Current devices for cardiac resynchronization (CRT-D) normally provide atrio-ventricular (AV) sequential pacing modes during resynchronization, but the best pacing programming strategy is not clear. On the one hand a basic rate of 50 to 70 bpm (optionally with some rate-responsive function) could be considered for therapy up-titration, specifically betablockers; on the other hand, increasing pacing rates may partially reduce benefits from resynchronization, reducing filling time and contractility reservoir. The Pegasus investigation is the only large randomized investigation comparing DDD with 70 bpm basic rate to DDD(R) @40 bpm. Results showed no difference in investigation endpoints, including mortality and HF-hospitalization. These results may support the use of a device implementing both a CRT function and a right ventricular single-lead with and an atrial sensing dipole (CRT-DX system). This system can track ventricular pacing and resynchronization following atrial sensing, even if it cannot provide atrial pacing support. It should be assessed whether such limitation is counterbalanced by the advantages related to the reduced number of necessary leads, with simplified implantation and less complications. The objective of the investigation is to assess whether atrial pacing support is really necessary in the subset of patients with indication to CRT-D and no evidence of sinus dysfunction on optimal therapy. The investigation will test the hypothesis that a CRT-DX system is not inferior to a conventional CRT-D system in this class of subjects.

A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome

Evaluation of Medical Treatments in MBC Patients According Biological Subtype and Line of Treatments

The primary objectives are to evaluate the duration of metastatic breast cancer treatments (chemotherapy, hormonal therapy and biological therapies) according to biological subtype (Luminal A, Luminal B, HER2 positive, triple-negative) and to evaluate the number of lines of metastatic breast cancer treatments according to biological subtype (Luminal A, Luminal B, HER2 positive, triple-negative). The secondary Objectives are to evaluate overall survival according to duration and to number of lines of metastatic breast cancer treatments and to identify predictive factors of number of lines of treatment as for example age, treatment response, biological subtype, metastatic sites, etc and to identify possible elements of different treatment management between participating sites. The aim of this retrospective and prospective study is to identify the duration of treatments (chemotherapy, hormonal therapy and biological therapies) according to biological subtype and line of treatment in metastatic breast cancer patients. An ancillary study will be conducted on part of population (HR+/HER2- patients newly diagnosed for mBC receiving first line CDk4/6 inhibitors). For the ancillary study, it is expected to enroll at least 400 patients, who will be asked to fill in some questionnaires at the following visits, scheduled as per clinical practice: - PROFFIT: baseline, day 1 cycle 3, day 1 cycle 5, every 6 months thereafter; - Patient-reported outcomes (PRO): EORTC-QLQ-C30, FACT-B, COST-FACIT at baseline, day 1 cycle 3, day 1 cycle 5, every 6 months thereafter. The ancillary study could evaluate: - the impact of first line CDk4/6 inhibitors on HR+/HER2- metastatic breast cancer patients' financial toxicity - retrospectively, the correlation between NLR and outcome in patients with breast cancer and in treatment with a CDk4/6 Inhibitor (as first line vs as second line) - the correlation between BMI and outcome in patients with breast cancer and in treatment with a CDk4/6 Inhibitor (as first line vs as second line).