A Novel Anti-Thrombotic, Glenzocimab, in Covid-19 acute respiratory distress syndrome (Cov-ARDS)

Background: Platelets (plt) may contribute to the inflammatory thrombosis in Cov-ARDS. Glenzocimab a humanized monoclonal antibody fragment against plt glycoprotein VI, inhibiting plt binding to the thrombus does affect physiological hemostasis, is assessed in Stroke (ph.II/II) and thrombotic diseases. Method(s): GARDEN (NCT04659109) was a randomized, double -blind, multicenter, parallel group, ph.IIb trial. Patients (pts) randomized 1/1 to Glenzocimab (1000 mg/day/3days)-placebo. All had confirmed SARS-CoV2, moderate respiratory clinical signs and a prothrombotic status. Primary endpoint: day 4 severe progression. Result(s): 60 pts enrolled in Brazil & France, aged median 56yrs;75% male Caucasians with >= 1 comorbidity. All had thromboprophylaxis and steroids. Safety analysis confirmed good tolerance of Glenzocimab. No deaths, serious drug-related adverse event nor major bleeding. 31 SAEs in 15 pts mainly related to Cov-ARDS or infection. No difference for the primary endpoint. Insufficient power, imbalance of risk factors (within Glenzocimab group), or lesser role of GPVI in Cov-ARDS pathophysiology are possible reasons. Conclusion(s): The GARDEN study was set up to tackle a global Public Health emergency. Glenzocimab was safe in doses three times higher than used in stroke. Albeit efficacy was not shown, overall, GARDEN provides insights into Cov-ARDS.

Glenzocimab, a novel antiplatelet therapy in COVID-19 related acute respiratory distress syndrome (ARDS): the garden study, a phase 2 clinical trial

Background : Glenzocimab is a fully-humanized fragment of monoclonal antibody directed against the human platelet glycoprotein VI (GPVI), which is involved in the formation, growth and stability of thrombi. Thrombosis mechanism in COVID-19 has not been completely elucidated. In severe COVID-19 disease, platelets may contribute to both micro and macro-thrombosis (particularly involving lung vasculature) and to the inflammatory syndrome. Furthermore, evidence involving platelets in lung fibrosis, via GPVI, have been described. In COVID-19-induced ARDS, developing new treatments aiming at reducing the contribution of platelets to uncontrolled lung inflammation and at preventing pro-thrombotic downstream complications is an unmet medical need. Such treatments should also be safe, avoiding undesirable bleeding. Aims : The primary objective of GARDEN, a phase 2 clinical trial, is to offer an additional treatment option to SARS-CoV-2 infected patients presenting with an ARDS, and beyond, preventing downstream complications due to pro-thrombotic and pro-inflammatory conditions. Methods : GARDEN (NCT04659109) is a randomized, double blind, multicenter, placebo-controlled, parallel group, fixed dose phase 2b clinical trial. Sixty evaluable patients will be randomized in a 1/1 ratio to glenzocimab (1000 mg/day for 3 days, 6h IV infusion) or to a matching placebo. Main inclusion criteria are: a symptomatic and biologically-confirmed SARS-CoV-2 infection with signs of moderate but progressive pulmonary disease;a prothrombotic status and elevated inflammation markers. Patients requiring invasive mechanical ventilation or with a disseminated intravascular coagulation are excluded. The primary objective is to evaluate the effect of glenzocimab in preventing clinical progression of disease when added to standard-of-care. Secondary safety endpoints include mortality, chest CT scan, SAEs and bleeding-related events. Results : GARDEN study has been approved in France and Brazil. To date, 16 patients have been recruited, no safety signal requiring a DSMB evaluation occurred. Conclusions : The study is expected to be completed by June 2021.

Investigating the real impact of COVID-19 pandemic on the daily neurosurgical practice?

OBJECTIVE: The objective of this study was to relate the neurosurgical activity during a time of sanitary crisis such as experienced during the SARS-CoV-2 pandemic. METHODS: A monocentric retrospective analysis was made based on a prospectively gathered cohort of all patients requiring neurosurgical care between March 15th and May 12th, 2020. Local impact of SARS-CoV-2 was analysed regarding number of patients admitted in ICU. RESULTS: One hundred and sixty patients could benefit from neurosurgical care with a wide-ranging profile of clinical and surgical activities performed during the study that seemed similar to last year profile activity. Surgical indications were restricted to non-deferrable surgeries, leading to a drop in operative volume of 50%. Only 1.3% of patients required transfer to other units due to the impossibility of providing gold standard neurosurgical care in our centre. CONCLUSION: Despite the challenges represented by the SARS-CoV-2 pandemic, it was proven possible to ensure the routine neurosurgical continuity and provide high standards of neurosurgical care without compromising patients' access to the required treatments.

Stroke Thrombectomy in Patients with COVID-19: Initial Experience in 13 Cases.

We performed a retrospective review in both comprehensive stroke units of a region affected early by the coronavirus disease 2019 (COVID-19) pandemic, between March 1 and April 26, 2020, including patients with COVID-19 who underwent mechanical thrombectomy for ischemic stroke. We identified 13 cases, representing 38.2% of 34 thrombectomies performed during this period. We observed increased mortality and a high incidence of thrombotic complications during hospitalization. Given the high rate of infected patients, systematic use of full personal protection measures seems justified.

Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. 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.