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Principal Investigator: Lorraine B Ware
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $431,046
Funding agency: National Heart Lung and Blood Institute
Sepsis with acute organ dysfunction is a common condition with high morbidity and mortality and no specific
therapies other than antimicrobials. The NHLBI PETAL Network Phase 2B Acetaminophen and Ascorbate in
Sepsis: Targeted Therapy to Enhance Recovery (ASTER trial) is a randomized double blind platform trial that
will test the effect of two potential therapies, acetaminophen or vitamin C versus a common placebo to improve
lung, cardiovascular and kidney dysfunction in 900 patients with sepsis and pulmonary or cardiovascular
dysfunction including patients with sepsis due to COVID-19. The rationale for this clinical trial rests, in part, on
novel findings from our group and others that (1) circulating cell-free hemoglobin (CFH) is elevated in patients
with sepsis, including those with COVID-19; (2) higher plasma CFH in sepsis is associated with death and
organ dysfunction including ARDS and acute kidney injury; (3) both acetaminophen and vitamin C are
hemoprotein reductants that reduce the capacity of CFH to cause lipid peroxidation and other oxidant injury
and (4) acetaminophen and vitamin C can reduce the injurious effects of CFH on the microvascular
endothelium both in vitro and in the isolated perfused human lung. Although ASTER is well designed to test
the clinical efficacy of acetaminophen and vitamin C, key information will be needed to understand trial results
and plan for potential phase 3 studies. The proposed studies in this R01 will define the mechanisms by which
acetaminophen and vitamin C affect organ dysfunction in sepsis (Aim 1) and determine whether there are
subgroups that can be identified within the trial for whom a differential treatment effect exists (Aim 2). Specific
Aim 1 will determine the mechanisms by which acetaminophen and vitamin C improve lung and kidney
dysfunction in sepsis by testing the hypothesis that acetaminophen and vitamin C reduce levels of oxidized
ferryl (4+) hemoglobin resulting in decreased oxidative injury, inflammation, and endothelial injury as measured
by plasma, distal airspace fluid, and urinary biomarkers of hemoglobin oxidation (ferryl hemoglobin) lipid
peroxidation (F2-Isoprostanes, Isofurans), inflammation and endothelial injury. Distal airspace fluid will be
sampled at ten participating PETAL Network sites by collecting fluid that condenses on heat moisture
exchanger filters placed in the mechanical ventilator circuit, a method that has been developed and validated
by Dr. Ware's research group. Specific Aim 2 will identify whether previously described and validated
hyperinflammatory or hypoinflammatory subgroups of sepsis patients benefit more from treatment with
acetaminophen or vitamin C. A finding of heterogeneity of treatment effect in Aim 2 would be of great value for
predictive enrichment in a future phase 3 clinical trial. In summary, the proposed studies will greatly enhance
the value of the ASTER clinical trial by determining the biologic mechanisms of the therapeutic effects of
acetaminophen and Vitamin C and assessing for heterogeneity of treatment effect in this NHLBI-funded Phase
2B clinical trial.
Terms: <3-10C><AMCF-I><APAP><ARDS><Acetamidophenol><Acetaminophen><Acetominophen><Acute><Acute Renal Failure with Renal Papillary Necrosis><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Alveolar><Ang-2><Ang2><Angiopoietin-2><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Ascorbic Acid><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Bicarbonates><Biological><Biological Markers><Blood Plasma><Blood Plasma Cell><Blood capillaries><COVID-19><CSIF><CSIF-10><CV-19><CXCL8><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Cessation of life><Classification><Clinical><Clinical Trials><Coronavirus Infectious Disease 2019><Cytokine Synthesis Inhibitory Factor><Da Nang Lung><Data><Death><Distal><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Dysfunction><Endothelium><Epithelium><F2-Isoprostanes><Functional disorder><Funding><Future><GCP1><HCO3><HPGF><Health Expenditures><Heart Vascular><Heme Proteins><Hemeproteins><Hemodialyses><Hemodialysis><Hemoglobin><Hemoglobin concentration result><Hepatocyte-Stimulating Factor><Heterogeneity><Human><Hybridoma Growth Factor><Hydrogen Carbonates><Hydroxyacetanilide><IFN-Gamma-Inducing Factor Gene><IFN-beta 2><IFN-gamma-Inducing Factor><IFNB2><IGIF><IGIF Gene><IL-1 Gamma><IL-1 Gamma Gene><IL-1 beta><IL-1 β><IL-1-b><IL-10><IL-18><IL-18 Gene><IL-1g><IL-1g Gene><IL-1β><IL-6><IL-8><IL1-Beta><IL1-β><IL10><IL10A><IL18><IL18 Protein><IL18 gene><IL1B Protein><IL1F2><IL1F4><IL1F4 Gene><IL1β><IL6 Protein><IL8><IL8 gene><In Vitro><Incidence><Infection><Inflammation><Inflammatory><Injury><Injury to Kidney><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interleukin 10 Precursor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin 1beta><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-1 beta><Interleukin-10><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Interleukin-1β><Interleukin-6><Intravenous><Isolated Perfusion><Isolation Perfusion><Isolation Perfusion Therapy><K60><LCN2><LCN2 gene><Life><Lipid Peroxidation><Lipocalin 2><Liquid substance><Lung><Lung Inflammation><Lung Respiratory System><MGC12320><MGC12320 Gene><MGI-2><Measures><Mechanical Ventilators><Mechanical ventilation><Methods><Miscellaneous Antibiotic><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Myeloid Differentiation-Inducing Protein><NGAL><NHLBI><National Heart, Lung, and Blood Institute><Neutrophil Gelatinase-Associated Lipocalin><Oncogenic Lipocalin 24P3><Organ><Outcome><Oxidants><Oxidizing Agents><Paracetamol><Patients><Permeability><Phase><Phase 3 Clinical Trials><Phase III Clinical Trials><Phase III study><Phenotype><Physiopathology><Placebos><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Plasmacytoma Growth Factor><Pneumonitis><Predictive Value><Preinterleukin 1 Beta><Protein C><Proteins><Pulmonary Inflammation><Pulmonary Ventilators><Randomized><Recovery><Reducing Agents><Reductants><Regional Perfusion><Research><Rest><Reticuloendothelial System, Serum, Plasma><SCYB8><Sampling><Sepsis><Sham Treatment><Shock Lung><Site><Stiff lung><Subgroup><Supportive Therapy><Supportive care><Systematics><TSG-1><Testing><Therapeutic Effect><Tubular><Tubular formation><Urine><Uterocalin><VIT C><Vascular Endothelium><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Vitamin C><acute kidney injury><anti-microbial><antimicrobial><ascorbate><b-ENAP><bio-markers><biologic><biologic marker><biomarker><blood infection><bloodstream infection><capillary><circulatory system><clinical efficacy><compare treatment><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><critical injury><cytokine><design><designing><devastating injury><electron acceptor><fluid><health care expenditure><healthcare expenditure><hemoglobin level><hemoprotein><improved><injuries><interferon beta 2><kidney dysfunction><kidney injury><liquid><mechanical respiratory assist><mechanically ventilated><medical expenditure><mortality><novel><oxidation><oxidative damage><oxidative injury><pathophysiology><phase 3 study><phase 3 trial><phase III protocol><phase III trial><plasmocyte><precision medicine><precision-based medicine><prospective><pulmonary><randomisation><randomization><randomly assigned><renal dysfunction><renal injury><response><sepsis patients><septic patients><severe injury><sham therapy><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><treatment comparison><treatment effect><treatment group><urinary><vasopressor><ventilation><wet lung>