# Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in Sepsis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $431,046

## Abstract

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
ace...

## Key facts

- **NIH application ID:** 10875527
- **Project number:** 5R01HL164937-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Lorraine B Ware
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $431,046
- **Award type:** 5
- **Project period:** 2022-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875527

## Citation

> US National Institutes of Health, RePORTER application 10875527, Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in Sepsis (5R01HL164937-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10875527. Licensed CC0.

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