Multi-centre, three arm, randomized controlled trial on the use of methylprednisolone and unfractionated heparin in critically ill ventilated patients with pneumonia from SARS-CoV-2 infection: A structured summary of a study protocol for a randomised controlled trial

OBJECTIVES: To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. TRIAL DESIGN: The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. PARTICIPANTS: Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units INCLUSION CRITERIA (ALL REQUIRED): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range EXCLUSION CRITERIA: 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit" 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: \u2022 LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. \u2022 LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. \u2022 UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. MAIN OUTCOMES: Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined as the total number of days that patient is alive and free of ventilation (either invasive or non-invasive) between randomization and day 28 (censored at hospital discharge). - Need of rescue administration of high-dose steroids or immune-modulatory drugs; - Occurrence of switch from non-invasive to invasive mechanical ventilation during ICU stay; - Delay from start of non-invasive ventilation to switch to invasive ventilation; - All-cause mortality at ICU discharge and hospital discharge; - ICU free days (IFDs) at day 28, defined as the total number of days between ICU discharge and day 28. - Occurrence of new infections from randomization to day 28; including infections by Candida, Aspergillus, Adenovirus, Herpes Virus e Cytomegalovirus - Occurrence of new organ dysfunction and grade of dysfunction during ICU stay. - Objectively confirmed venous thromboembolism, stroke or myocardial infarction; Safety endpoints: - Occurrence of major bleeding, defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); - Occurrence of clinically relevant non-major bleeding, defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm2, intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug. RANDOMIZATION: A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by 3 factors: Centre, BMI (<30/ 6530) and Age (<75/ 6575). Central randomisation will be performed using a secure, web-based, randomisation system with an allocation ratio of 1:1:1. The allocation sequence will be generated by the study statistician using computer generated random numbers. BLINDING (MASKING): Participants to the study will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that the combined use of UHF and steroid versus the LMWH group will significantly reduce the risk of death at day 28. The overall sample size in this study is expected to be 210 with a randomization 1:1:1 and seventy patients in each group. Assuming an alpha of 2.5% (two tailed) and mortality rate in LMWH group of 50%, as indicated from initial studies of ICU patients, the study will have an 80% power to detect at least a 25 % absolute reduction in the risk of death between: a) LMHW + steroid group and LMWH group or b) UHF + steroid group and LMWH group. The study has not been sized to assess the difference between LMHW + steroid group and UHF + steroid group, therefore the results obtained from this comparison will need to be interpreted with caution and will need further adequately sized studies confirm the effect. On the basis of a conservative estimation, that 8 participating sites admit an average of 3 eligible patients per month per centre (24 patients/month). Assuming that 80 % of eligible patients are enrolled, recruitment of 210 participants will be completed in approximately 10 months. TRIAL STATUS: Protocol version 1.1 of April 26th, 2020. Recruitment start (expected): September 1st, 2020 Recruitment finish (expected): June 30th, 2021 TRIAL REGISTRATION: EudraCT number 2020-001921-30 , registered on April 15th, 2020 AIFA approval on May 4th, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol.

To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a)more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were receiving standard oxygen therapy5.IMV in patients who at randomisation were receiving non-invasive mechanical ventilationb)Similar in terms of major bleeding risk TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study

A novel Rule-based Semantic Architecture for IoT Building Automation Systems

The ever growing number of smart devices connected to the Internet of Things is giving users the chance to sense data from surrounding environment and act upon it. However, interpreting raw data coming from heterogeneous sensors and applying control algorithms to actuators is not a simple task for the common end-user who wants to create applications for smart environments. For these reasons, this work deals with the definition of a novel rule-based semantic architecture for the implementation of building automation applications in an IoT context. Sensor data are abstracted at a high semantic level related to the properties they are associated to and interactions with actuators are driven by high-level desired actions. Applications have the form of an Event- Condition-Action (ECA) rule and the layered architecture separates high-level semantic reasoning aspects from low-level execution details. The proposed architecture is also compared with main state-of-the-art solutions and some suitable technologies for its implementation are suggested

An IoT-aware System for Elderly Monitoring

The aging population is a global phenomenon, characterized by many interesting challenges. In this context, the Internet of Things technologies could allow to analyze the elderly’s behavioral in an unobtrusive way, thus helping to prevent Mild Cognitive Impairment and frailty problems. To this end, this work aims to define a reliable system for controlling the position and the body motility of the elderly in low-cost and low- power way. Movements and body motility are, indeed, good indicators of behavioral changes. The system represents the basis of a complete architecture for behavioral analysis and risk detection developed within the City4Age project, funded by the Horizon 2020 Programme of the European Commission

An ECA-based Semantic Architecture for IoT Building Automation Systems

The Internet of Things (IoT), with its plethora of smart objects and technologies, allows to realize smart environments in several scenarios. However, the existing solutions are strictly intended for specific applications and their customization is often limited to what developers have considered at the design and implementation time. So, the integration of new functionalities requires significant changes by developers, while common users cannot make personalizations by themselves. For these reasons, this work deals with the definition of a novel rule-based semantic architecture for the easy implementation of building automation applications in an IoT context. Applications are structured as an Event-Condition-Action (ECA) rule and the layered architecture separates high-level semantic reasoning aspects from low-level execution details. The proposed architecture is also compared with main state-of-the-art solutions and a standard-based implementation framework is suggested. The last aspect is treated by referring to standardized guidelines and widely- accepted platforms, in order to make the proposal more attractive and robust

Il ruolo dello standard KNX nell'impiantistica

Lo standard KNX offre la possibilità di migliorare e ottimizzare il consumo energetico e il comfort soprattutto nel building automation di grandi strutture pubbliche e aziendali dove il controllo capillare di dispositivi e impianti tecnologici rappresenta un’attività onerosa

A novel architecture enabling the visual implementation of Web of Things applications

The concept of Internet of Things is becoming one of the key aspects for the future Internet, where embedded devices will be responsible for collecting data from the surrounding environment and making them available to useful mash-up applications. In order to guarantee a high feasibility of this scenario, it would be appropriate to have a flexible and intuitive architecture for the implementation of such applications without knowing specific details about the constrained hardware and operating system. Therefore, in this work, a software system for the graphical development of mash-up applications, dedicated to Wireless Sensor Networks, was designed and implemented. It is based on a Constrained Application Protocol application server, called Actinium, and on a graphical editor, called ClickScript. Especially the latter one has been substantially modified in order to communicate with Actinium and to interact with the constrained resources made available by the WSN. The effectiveness of the proposed solution has been tested through a real use case that has demonstrated the validity of the whole system

KNX-Based Home Automation Systems for Android Mobile Devices

The adoption of smart environments is becoming more and more important in many applicative scenarios such as healthcare, asset management, environmental monitoring, and building automation. This last issue represents a very attractive use-case because of several scientific challenges that must be addressed in order to satisfy user requirements, which are mainly focused on the management of home’s comfort parameters. The main goal of this work is to develop and validate an architecture, both hardware and software, able to monitor and manage a Konnex-based home automation system through an Android mobile device in an efficient and safe way. In this perspective, an Android application is realized based on a specific Java library, called Calimero, that provides several methods for interaction with the Konnex implant. Furthermore, a software system able to configure the Android application consistently with the home automation implant is designed and implemented. The proposed architecture was tested from both functional and performance point of view and the obtained results prove that it provides high performance in comparison with other solutions already affirmed on the market

Vertical Handover Algorithm for Heterogeneous Wireless Networks

Recently, there has been much effort to integrate heterogeneous wireless technologies in order to make overlay networks able to provide mobile users with ubiquitous Internet access. Handover management is still one of the most challenging issues to be solved for seamless integration of wireless networks. In this paper, an algorithm for vertical handover with QoS guarantees between IEEE 802.16e and IEEE 802.11e networks, without computational complexity added on mobile nodes, has been proposed. It uses a decision mechanism based on the following metrics: the available bandwidth, the signal-to-noise ratio (SNR) and the access delay. Its characteristics are perfectly compatible with the guidelines specified in the IEEE 802.21 standard. The effectiveness of the defined algorithm has been evaluated, using the ns-2 tool, in terms of packet loss rate (PLR), satisfaction of minimum applications requirements and number of useless handovers. The performance of the defined algorithm has been compared with that obtained by using the algorithm suggested by IEEE 802.21 standard that exploits only the SNR in the decision procedure

The use of NFC and Android technologies to enable a KNX-based Smart Home

In recent years, due the improvement of humans’ living standard, smart homes are receiving an increasing interest. They can provide several useful services such as support for the elderly and disabled people, access control, environmental monitoring, and home automation. Furthermore, with the widespread diffusion of mobile devices (i.e., smartphones, tablets) and their integration with new auto-identification technologies (such as the NFC technology), the need to control and manage the smart home through these devices is increasing. In this context, the main goal of this work is to develop and validate an architecture, both hardware and software, able to monitor and manage a KNX-based home automation system through an Android mobile device in an efficient and safe way. More in detail, a software system able to configure an Android application consistently with the home automation implant was designed and implemented as well as an Android application able to manage the entire home automation system based on the KNX standard. A further Android module, which exploits NFC technology, was developed in order to address the access control issue. A real use case is presented, which demonstrate the effectiveness of the proposed software system