LB0001 MAVRILIMUMAB IMPROVES OUTCOMES IN PHASE 2 TRIAL IN NON-MECHANICALLY-VENTILATED PATIENTS WITH SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPERINFLAMMATION

Background:Granulocyte/macrophage-colony stimulating factor (GM-CSF) is a cytokine both vital to lung homeostasis and important in regulating inflammation and autoimmunity1,2,3 that has been implicated in the pathogenesis of respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.4-6 Mavrilimumab is a human anti GM-CSF receptor α monoclonal antibody capable of blocking GM-CSF signaling and downregulating the inflammatory process.Objectives:To evaluate the effect of mavrilimumab on clinical outcomes in patients hospitalized with severe COVID-19 pneumonia and systemic hyperinflammation.Methods:This on-going, global, randomized, double-blind, placebo-controlled seamless transition Phase 2/3 trial was designed to evaluate the efficacy and safety of mavrilimumab in adults hospitalized with severe COVID-19 pneumonia and hyperinflammation. The Phase 2 portion comprised two groups: Cohort 1 patients requiring supplemental oxygen therapy without mechanical ventilation (to maintain SpO2 ≥92%) and Cohort 2 patients requiring mechanical ventilation, initiated ≤48 hours before randomization. Here, we report results for Phase 2, Cohort 1: 116 patients with severe COVID- 19 pneumonia and hyperinflammation from USA, Brazil, Chile, Peru, and South Africa; randomized 1:1:1 to receive a single intravenous administration of mavrilimumab (10 or 6 mg/kg) or placebo. The primary efficacy endpoint was proportion of patients alive and free of mechanical ventilation at Day 29. Secondary endpoints included [1] time to 2-point clinical improvement (National Institute of Allergy and Infectious Diseases COVID-19 ordinal scale), [2] time to return to room air, and [3] mortality, all measured through Day 29. The prespecified evidentiary standard was a 2-sided α of 0.2 (not adjusted for multiplicity).Results:Baseline demographics were balanced among the intervention groups; patients were racially diverse (43% non-white), had a mean age of 57 years, and 49% were obese (BMI ≥ 30). All patients received the local standard of care: 96% received corticosteroids (including dexamethasone) and 29% received remdesivir. No differences in outcomes were observed between the 10 mg/kg and 6 mg/kg mavrilimumab arms. Results for these groups are presented together. Mavrilimumab recipients had a reduced requirement for mechanical ventilation and improved survival: at day 29, the proportion of patients alive and free of mechanical ventilation was 12.3 percentage points higher with mavrilimumab (86.7% of patients) than placebo (74.4% of patients) (Primary endpoint; p=0.1224). Mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death through Day 29 (Hazard Ratio (HR) = 0.35; p=0.0175). Day 29 mortality was 12.5 percentage points lower in mavrilimumab recipients (8%) compared to placebo (20.5%) (p=0.0718). Mavrilimumab recipients had a 61% reduction in the risk of death through Day 29 (HR= 0.39; p=0.0726). Adverse events occurred less frequently in mavrilimumab recipients compared to placebo, including secondary infections and thrombotic events (known complications of COVID-19). Thrombotic events occurred only in the placebo arm (5/40 [12.5%]).Conclusion:In a global, diverse population of patients with severe COVID-19 pneumonia and hyperinflammation receiving supplemental oxygen therapy, corticosteroids, and remdesivir, a single infusion of mavrilimumab reduced progression to mechanical ventilation and improved survival. Results indicate mavrilimumab, a potent inhibitor of GM-CSF signaling, may have added clinical benefit on top of the current standard therapy for COVID-19. Of potential importance is that this treatment strategy is mechanistically independent of the specific virus or viral variant.References:[1]Trapnell, Nat Rev Dis Pri, 2019[2]Wicks, Nat Rev Immunology, 2015[3]Hamilton, Exp Rev Clin Immunol, 2015[4]De Luca, Lancet Rheumatol, 2020[5]Cremer, Lancet Rheumatol, 2021[6]Zhou, Nature, 2020Disclosure of Interests:Lara Pupim Employee of: Kiniksa, Shareholder of: Kiniksa, Tisha S. Wang Consultant of: Partner Therapeutics; steering committee for Kinevant BREATHE clinical trial, Kristin Hudock: None declared, Joshua Denson: None declared, Nyda Fourie: None declared, Luis Hercilla Vasquez: None declared, Kleber Luz: None declared, Mohammad Madjid Grant/research support from: Kiniksa, Kirsten McHarry: None declared, José Francisco Saraiva: None declared, Eduardo Tobar: None declared, Teresa Zhou Employee of: Kiniksa, Shareholder of: Kiniksa, Manoj Samant Employee of: Kiniksa, Shareholder of: Kiniksa, Joseph Pirrello Employee of: Kiniksa, Shareholder of: Kiniksa, Fang Fang Employee of: Kiniksa, Shareholder of: Kiniksa, John F. Paolini Employee of: Kiniksa, Shareholder of: Kiniksa, Arian Pano Employee of: Kiniksa, Shareholder of: Kiniksa, Bruce C. Trapnell: None declared

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Design and rationale of a randomized, double-blind, placebo-controlled, Phase 2/3 study evaluating dociparstat in acute lung injury associated with severe COVID-19

10.21203/rs.3.rs-52289/v2 ◽

2020 ◽

Author(s):

Joseph A. Lasky ◽

Jyotsna Fuloria ◽

Marion E. Morrison ◽

Randall Lanier ◽

Odin Naderer ◽

...

Keyword(s):

Mechanical Ventilation ◽

Critical Care ◽

Standard Of Care ◽

Supplemental Oxygen ◽

Phase 2 ◽

Double Blind ◽

Double Blind Placebo ◽

Critical Care Units ◽

Soluble Rage ◽

Novel Coronavirus

Abstract Introduction: The COVID-19 Global Pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure, threaten to overrun hospital critical care units globally. New agents that address the hyperinflammatory “cytokine storm” and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, with the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding compared to commercially available heparin. Methods: This study is a randomized, double-blind, placebo-controlled, Phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care, in hospitalized adults with COVID-19 who require supplemental oxygen. Phase 2 will enroll 12 participants in each of two dose escalating cohorts, to confirm the safety of DSTAT in this population. Following review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, Phase 3 will enroll approximately 450 participants randomized to DSTAT or placebo. The primary endpoint is the proportion of participants who survive and do not require mechanical ventilation through day 28. Discussion: Advances in standard of care, recent emergency use authorizations, and positive data with dexamethasone, has likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement in the NIAID score will be essential to provide a measure of drug effect on recovery. Analysis of additional endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble-RAGE, D-dimer) will be performed to further define the effect of DSTAT in patients with COVID-19 infection. Trial Registration: ClinicalTrials.gov identifier NCT04389840, Registered 13 May 2020, https://clinicaltrials.gov/ct2/keydates/NCT04389840

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546. Therapeutic Effect of Regdanvimab in Patients with Mild to Moderate COVID-19: Day 28 Results from a Multicentre, Randomised, Controlled Pivotal Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.745 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S375-S375

Author(s):

Michael G Ison ◽

Jin Yong Kim ◽

Oana Sandulescu ◽

Liliana-Lucia Preotescu ◽

Norma Erendira Rivera Martinez ◽

...

Keyword(s):

High Risk ◽

Adverse Events ◽

Oxygen Therapy ◽

Research Study ◽

Scientific Research ◽

Supplemental Oxygen ◽

Phase 2 ◽

Study Investigator ◽

Supplemental Oxygen Therapy ◽

Research Grant

Abstract Background Regdanvimab is a monoclonal antibody with activity against SARS-CoV-2. A Phase 2/3 study with two parts is currently ongoing and data up to Day 28 of Part 1 is available while the data from 1315 patients enrolled in Part 2 are expected in June 2021. Methods This phase 2/3, randomized, parallel-group, placebo-controlled, double-blind study with 2 parts is aimed to assess the therapeutic efficacy of regdanvimab in outpatients with mild to moderate COVID-19, not requiring supplemental oxygen therapy. Patients aged >18 with the onset of symptoms within 7 days were eligible to be enrolled. Results In Part 1, 307 patients (101, 103, and 103 patients in the regdanvimab 40 mg/kg, regdanvimab 80 mg/kg, and placebo groups, respectively) were confirmed to have COIVD-19 by RT-qPCR at Day 1 (or Day 2). Regdanvimab significantly reduced the proportion of patients who required hospitalization or supplemental oxygen therapy compared to placebo (8.7% in the placebo vs. 4.0% in the regdanvimab 40 mg/kg). The difference in events rate was even larger in patients who met the high-risk criteria and confirmed a 66.1% reduction in patients receiving regdanvimab 40 mg/kg (Table 1). The median time to clinical recovery was shortened by 2.9 days (7.18 days for regdanvimab 40 mg/kg and 10.03 days for placebo; high-risk). Also, greater reductions from baseline viral load were shown in regdanvimab groups (Figure 1). The safety results confirmed that the regdanvimab was safe and well-tolerated. Occurrence of adverse events (Table 2) and results of other safety assessments were generally comparable among the 3 groups. The overall rate of infusion-related reaction was low and no serious adverse events or deaths were reported. The anti-drug antibody positive rate was low in the regdanvimab groups (1.4% in regdanvimab vs. 4.5% in placebo), and no antibody-dependent enhancement was reported. Conclusion Results from the first part of the study indicate that regdanvimab may lower the rate of hospitalisation or requirement of oxygen supplementation, with the greatest benefit noted in patients at high-risk of progressing to severe COVID-19. The second part of the study remains ongoing and blinded. Therefore, results for the primary endpoint are forthcoming and will be presented at IDWeek. Disclosures Michael G. Ison, MD, MS, Celltrion, Inc. (Consultant) Jin Yong Kim, MD, MPH, Celltrion, Inc. (Scientific Research Study Investigator) Oana Sandulescu, MD, PhD, Algernon Pharmaceuticals (Scientific Research Study Investigator)Atea Pharmaceuticals (Scientific Research Study Investigator)Celltrion, Inc. (Scientific Research Study Investigator)Diffusion Pharmaceuticals (Scientific Research Study Investigator)Regeneron Pharmaceuticals (Scientific Research Study Investigator) Liliana-Lucia Preotescu, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator) Norma Erendira Rivera Martinez, MD, Celltrion, Inc. (Scientific Research Study Investigator) Marta Dobryanska, MD, Celltrion, Inc. (Scientific Research Study Investigator) Victoria Birlutiu, Assoc. Prof. M.D. Ph.D., Celltrion, Inc. (Scientific Research Study Investigator)Lucian Blaga University of Sibiu, Romania & Hasso Plattner Foundation (Research Grant or Support) Egidia Gabriela Miftode, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator) Natalia Gaibu, MD, Celltrion, Inc. (Scientific Research Study Investigator) Olga Adriana Caliman-Sturdza, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator)Stefan cel Mare University of Suceava, Romania (Research Grant or Support) Simin-Aysel Florescu, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator) Anca Streinu-Cercel, MD, PhD, Assoc.Prof. Infectious diseases, Algernon Pharmaceuticals (Scientific Research Study Investigator)Atea Pharmaceuticals (Scientific Research Study Investigator)Celltrion, Inc. (Scientific Research Study Investigator)Diffusion Pharmaceuticals (Scientific Research Study Investigator)Regeneron Pharmaceuticals (Scientific Research Study Investigator) Sang Joon Lee, n/a, Celltrion, Inc. (Employee) Sung Hyun Kim, n/a, Celltrion, Inc. (Employee) Il Sung Chang, n/a, Celltrion, Inc. (Employee) Yun Ju Bae, n/a, Celltrion, Inc. (Employee) Jee Hye Suh, n/a, Celltrion, Inc. (Employee) Mi Rim Kim, n/a, Celltrion, Inc. (Employee) Da Re Chung, n/a, Celltrion, Inc. (Employee) Sun Jung Kim, n/a, Celltrion, Inc. (Employee) Seul Gi Lee, n/a, Celltrion, Inc. (Employee) Ga Hee Park, n/a, Celltrion, Inc. (Employee) Joong Sik Eom, MD, PhD, Celltrion, Inc. (Consultant)

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Supplemental oxygen therapy in trauma patients: an exploratory registry‐based study

Acta Anaesthesiologica Scandinavica ◽

10.1111/aas.13829 ◽

2021 ◽

Author(s):

Mathias A. Christensen ◽

Jacob Steinmetz ◽

George Velmahos ◽

Lars S. Rasmussen

Keyword(s):

Oxygen Therapy ◽

Supplemental Oxygen ◽

Trauma Patients ◽

Supplemental Oxygen Therapy

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Defining Hazards of Supplemental Oxygen Therapy in Neonatology Using the FMEA Tool

MCN The American Journal of Maternal/Child Nursing ◽

10.1097/nmc.0b013e31828da238 ◽

2013 ◽

Vol 38 (4) ◽

pp. 221-228 ◽

Cited By ~ 7

Author(s):

Anne Catherine van der Eijk ◽

Denise Rook ◽

Jenny Dankelman ◽

Bert Johan Smit

Keyword(s):

Oxygen Therapy ◽

Supplemental Oxygen ◽

Supplemental Oxygen Therapy

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Reply: Access to Supplemental Oxygen Therapy: A Crisis

Annals of the American Thoracic Society ◽

10.1513/annalsats.201804-266le ◽

2018 ◽

Vol 15 (7) ◽

pp. 894-894

Author(s):

Susan S. Jacobs ◽

Kathleen O. Lindell ◽

Eileen G. Collins ◽

Chris M. Garvey ◽

Carme Hernandez ◽

...

Keyword(s):

Oxygen Therapy ◽

Supplemental Oxygen ◽

Supplemental Oxygen Therapy

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Effects of supplemental oxygen therapy in patients with suspected acute myocardial infarction: a meta-analysis of randomised clinical trials

Heart ◽

10.1136/heartjnl-2018-313089 ◽

2018 ◽

Vol 104 (20) ◽

pp. 1691-1698 ◽

Cited By ~ 14

Author(s):

Nariman Sepehrvand ◽

Stefan K James ◽

Dion Stub ◽

Ardavan Khoshnood ◽

Justin A Ezekowitz ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Infarct Size ◽

Oxygen Therapy ◽

Meta Analysis ◽

Normal Pressure ◽

Supplemental Oxygen ◽

Usual Practice ◽

Supplemental Oxygen Therapy ◽

Suspected Acute Myocardial Infarction

BackgroundAlthough oxygen therapy has been used for over a century in the management of patients with suspected acute myocardial infarction (AMI), recent studies have raised concerns around the efficacy and safety of supplemental oxygen in normoxaemic patients.ObjectiveTo synthesise the evidence from randomised controlled trials (RCTs) that investigated the effects of supplemental oxygen therapy compared with room air in patients with suspected or confirmed AMI.MethodsFor this aggregate data meta-analysis, multiple databases were searched from inception to 30 September 2017. RCTs with any length of follow-up and any outcome measure were included if they studied the use of supplemental O2 therapy administered by any device at normal pressure compared with room air. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, an investigator assessed all the included studies and extracted the data. Outcomes of interests included mortality, troponin levels, infarct size, pain and hypoxaemia.ResultsEight RCTs with a total of 7998 participants (3982 and 4002 patients in O2 and air groups, respectively) were identified and pooled. In-hospital and 30-day death occurred in 135 and 149 patients, respectively. Oxygen therapy did not reduce the risk of in-hospital (OR, 1.11 (95% CI 0.69 to 1.77)) or 30-day mortality (OR, 1.09 (95% CI 0.80 to 1.50)) in patients with suspected AMI, and the results remained similar in the subgroup of patients with confirmed AMI. The infarct size (based on cardiac MRI) in a subgroup of patients was not different between groups with and without O2 therapy. O2 therapy reduced the risk of hypoxaemia (OR, 0.29 (95% CI 0.17 to 0.47)).ConclusionAlthough supplemental O2 therapy is commonly used, it was not associated with important clinical benefits. These findings from eight RCTs support departing from the usual practice of administering oxygen in normoxaemic patients.

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Evaluation of Knowledge of Oxygen Therapy and Reading of Flowmeter among the Health Workers in the Pediatric Unit of the Hospital Universitario San Ignacio, Bogotá, Colombia

Universitas Médica ◽

10.11144/javeriana.umed59-3.oxig ◽

2018 ◽

Vol 59 (3) ◽

pp. 1-8

Author(s):

Elly Morros González ◽

Diana Estrada Cano ◽

Marcela Murillo Galvis ◽

Jos Carlos Montes Correa ◽

Nelcy Rodríguez Malagón ◽

...

Keyword(s):

Adverse Effects ◽

Oxygen Saturation ◽

Oxygen Therapy ◽

Health Workers ◽

Supplemental Oxygen ◽

Cross Sectional Study ◽

Peripheral Oxygen Saturation ◽

Cross Sectional ◽

Fraction Of Inspired Oxygen ◽

Supplemental Oxygen Therapy

Introduction: Supplemental oxygen is considered a pharmaceutical drug; therefore, it can produce adverse effects. Lack of consensus regarding the reading of oxygen flowmeters and the peripheral oxygen saturation (SpO2) goals can influence clinical and paraclinical decisions and hospital stay length. Objective: To assess knowledge on oxygen therapy, adverse effects, SpO2 goals and reading of oxygen flowmeters among personnel in the Pediatric Unit at Hospital Universitario San Ignacio, Bogotá, Colombia. Methodology: Cross-sectional study derived from convenience sampling through a self-applied survey between December 2016 and January 2017. The poll evaluated topics on supplemental oxygen therapy fundamentals and adverse effects, SpO2 goals and flowmeter readings through flowmeters photographs indicating a specific fraction of inspired oxygen (FiO2). Results: The response rate was 77% from 259 subjects. 22% considered that the oxygen saturation either increases or remains the same during sleep periods in children. 78% of participants knew at least one complication associated to prolonged oxygen therapy and 67% due to supplemental oxygen concentration greater than required. In neonatal population, 10% considered oxygen saturation goals equal to or greater than 96%. In the flowmeter’s reading evaluation, incorrect answers ranged from 9 to 19%. Conclusion: It is imperative to reinforce updated concepts on oxygen therapy, with emphasis in SpO2 goals, adverse effects and appropriate flowmeter’s readings through periodic educational campaigns.

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