Multicenter, prospective, randomized clinical trial for the treatment of patients with respiratory insufficiency due to COVID-19 at Federal University Hospitals of the Ebserh- HU-COmVIDA Network

Since April 22, 2020, the pandemic caused by the new coronavirus SARS-CoV-2 (COVID-19) has already caused 175,825 deaths worldwide and 2,906 deaths in Brazil, with a lethality of 6.4% in our country. It results in severe pneumonia and acute respiratory failure with a long period of intubation, a fact that associated with the growing number of cases may lead to the collapse of the SUS. Most deaths are due to acute respiratory failure (ARI), shock or thrombotic events secondary to local, systemic inflammatory hyperactivity (cytokine storm) and hypercoagulability. Thus, drugs with anti-inflammatory, immunomodulatory and / or anticoagulant effects can have a positive impact on the treatment of COVID-19. Rational In severe COVID-19 there is an exacerbated local and systemic inflammatory response initiated with invasion of epithelial and endothelial cells and alveolar macrophages, generating pro-inflammatory cytokines (IL-6, IP-10, MIP1α, MIP1β and MCP1), which attract monocytes, macrophages and LT to the infection site, promoting additional and systemic inflammation (IL-6, IP-10, IL-2, IL-7, IL-10, TNF, G-CSF, IFNγ, MIP1α, MIP1β and MCP1) (storm cytokines), which results in organ failure and shock. There is also a state of hypercoagulability. Upadacitinib inhibits the inflammatory pathway of IL-6 / JAK-1 / STAT and is approved for rheumatoid arthritis. A study in sickle cell disease demonstrated that hydroxyurea reduces monocytic activation, TNF-α, IL1-β, IL-6, IL-8 and tissue factor by activated monocytes, reducing inflammation and coagulation activation. TEP / DVT (19-58%), alveolar (45%) and glomerular (27%) microthrombi occurred at autopsy; and DVT / TEP (20 to 43%) in the ICU, despite prophylactic anticoagulation. It is necessary to assess whether full anticoagulation would be superior to prophylactic. Global design and methods Clinical intervention trial, open, prospective, randomized and multicentric. A) Protocol: Arm A: clinical support (control); Arm B: Upadacitinib 15mg orally for 15 days + prophylaxis for herpes + support. Arm C: enoxaparin SC 1mg / kg 12 / 12h (or UFH IV) until discharge + support. Arm D: Hydroxyurea 15mg / kg / d VO / SNE until discharge + support. Follow-up for 30 days to assess outcomes. B) Randomization: 1: 1: 1: 1, paired by sex and age. D) Inclusion criteria: d.1) Patients with acute respiratory syndrome (SARS) suspected of having COVID-19 (see item 3.3.1.4.) Or COVID-19 confirmed by PCR, aged 18 or over and presenting at least one of the criteria below: a) Need for nasal catheter O2> 3.0 l / min) to maintain SpO2 ≥94% or RR ≤ 24 rpm or b) Non-invasive ventilatory support to maintain SpO2≥94% or RR ≤ 24 rpm or c) Acute respiratory failure with need of invasive mechanical ventilation or d) Acute respiratory failure requiring noninvasive ventilation when (need for FiO2≥50% or PP with a 10 cmH20 delta or EPAP> 10 cm H20 to maintain SpO2> 94% or RR ≤ 24 rpm) or PaCO2 ≥ 50 mmHg and pH ≤ 7.35 or e) Patients with hemodynamic instability or shock (SBP <90mmHg or MBP <65 mmHg) or signs of poor organic perfusion (altered consciousness, oliguria, lactate ≥ 36 mg / dl, between others), with or without the use of a vasopressor, or f) Sepsis with arterial hypotension, need for vasopressor or lactate ≥ 36 mg / dl or g) Septic shock or h) Radiological evidence of pulmonary involvement> 50% in 24-48h i) PaO2 / FiO2 ratio ≤300 j) Tachypnea> 30 irpm (MS manual) d.2. In the intervention arms, medication should be started within 14 days of the onset of symptoms. d.3. Informed Consent Form, signed and dated, by the patient or guardian, obtained before inclusion in the protocol and starting the use of upadacitinib, hydroxyurea and LMWH or UFH d.4. If the viral panel is negative and the 1st PCR for COVID-19 is negative and there is a typical tomographic aspect, as long as aspects 1 to 3 above are considered, the patient may be included and the COVID-19 screening by PCR should be repeated 48 hours after the 1st negative PCR (3rd day of the protocol) and 48 hours after the 2nd negative PCR (5th day of the protocol). E. Exclusion criteria E.1. Patients whose first symptom started more than 14 days ago. E.2. Patients initially included (item 3.3.1.4.), But who during the clinical evaluation did not present any of the 3 positive CRP tests for COVID-19 (or CRP for tracheal or bronchoalveolar aspirate, if done). E.3. Patients using other experimental drugs for COVID-19 or convalescent serum. E.4. Have been using upadacitinib or hydroxyurea for underlying disease for the past 4 weeks. E.5. Be on full anticoagulation (any heparin, fondaparinux, warfarin or new oral anticoagulants) for underlying disease. E.6. Absolute contraindications to the use of upadacitinib1 or hydroxyurea2. E.7. Absolute or relative contraindication3 for the use of low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (see table 6). E.8. Pregnant women. E.9. Breastfeeding patients. F) Calculation of the sample: Sample was calculated by STATA® / SE 12.0 considering the expected mortality in the control group of 51% and a test of differences in proportions between 2 groups of the same size, with power of 80% and alpha of 5%, loss 10%. 388 participants (97 patients per arm) will be needed for an HR of 0.5 (50% reduction in mortality). Primary objective Assess whether the use of upadacitinib, full anticoagulation (LMWH or UFH) or hydroxyurea is able to increase overall survival at 50% at 30 days compared to the control (support) group Secondary objectives Estimate the overall survival curves (SG) and the mortality rate at 30 days. Calculate the median time to extubation (period between orotracheal intubation and extubation), oxygen therapy, total hospital stay and ICU stay in each arm and assess whether the intervention arms are capable of shortening that time. To assess the impact of the variables of comorbidities (hypertension, diabetes, chronic renal failure, coronary artery disease, heart disease, pneumopathy, obesity, cancer), use of corticosteroids, use of immunosuppressants and previous chemotherapy / radiotherapy treatment in SG. Assess d-dimer levels and correlate them with thromboembolic events. Primary outcome Survival at 30 days Secondary outcome Mortality at 30 days Orotracheal intubation time (time to extubation) D-dimer levels and association with thrombotic events Time of use of supplementary O2 Time of mechanical ventilation Time of hospitalization Time of stay in the ICU Adverse events associated with the medications used Statistical analysis SG curves at 30 days will be calculated using the Kaplan-Meier method. The log-rank test will be used to compare survival curves and to determine the univariate association between clinical characteristics and SG. The significant factors (p <0.05) for this test will be submitted to multivariate analysis by Cox stepwise backward selection regression. Univariate analysis of categorical variables will be performed using the Mantel-Haenszel chi-square test and quantitative variables using the T-test (normal curve) or Mann-Whitney (without normal curve). Logistic regression analysis will assess the association between the medication used and the times measured by secondary outcomes. The level of statistical significance was determined as p <0.05. Ethical aspects The study was submitted to CONEP in April 2020. The study amendment was submitted to CONEP in July 2020.