Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER)

HLB02942424a

PETAL-ASTER

False

ARDS

Acetaminophen

Vitamin C

Sepsis

Infections

Systemic Inflammatory Response Syndrome

Inflammation

Pathologic Processes

Lung Diseases

Respiratory Tract Diseases

Respiration Disorders

Infant, Premature, Diseases

Infant, Newborn, Diseases

Lung Injury

Disease Attributes

Sepsis

Toxemia

Respiratory Distress Syndrome

Respiratory Distress Syndrome, Newborn

Respiratory Insufficiency

Acute Lung Injury

Critical Illness

Physiological Effects of Drugs

Analgesics, Non-Narcotic

Analgesics

Sensory System Agents

Peripheral Nervous System Agents

Antipyretics

Acetaminophen

Released

True

True

Coded

https://petalnet.org/studies.html#aster

False

Clinical Trial

Open BioLINCC Study

Adult

Drug: Intravenous Acetaminophen (room temperature)

Drug: Intravenous Vitamin C (refrigerated)

Drug: 5% Dextrose (room temperature)

Drug: 5% Dextrose refrigerated

2024-11-14

2024-11-14

2024-11-14

None

10/2021 – 7/2023

DLD

Lung

non-HIV

COVID-Related

None

None

No

No

Yes

No

Yes, For Some Specimens

Yes

Use of specimens in non-genetic research is unrestricted. Use of specimens in genetic research is tiered with respect to research related to severe illness, and research related to other medical conditions. Specimens may not be used directly to produce commercial products.

ARDS
Critical Illness
Respiratory Failure
Sepsis

To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis patients compared with placebo.

Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis patients experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.

Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis patients with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis patient outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in patients with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for patients with sepsis and respiratory or circulatory organ dysfunction.

Eligible participants were 18 years or older with sepsis defined as clinical evidence of a known or suspected infection with antibiotics administration planned. Participants must have had either (1) hypotension defined as the need for any vasopressor after administration of at least 1 L of intravenous fluid or (2) respiratory failure defined by mechanical ventilation, noninvasive ventilatory support at any level, or greater than or equal to 6 L/min of supplemental oxygen. Eligible participants could be enrolled if they were admitted (or planned to be admitted) to a study site intensive care unit (ICU) within 36 hours of presentation to the emergency department or presentation to any acute care hospital. Demographic and clinical data were collected from the medical record for prespecified subgroup analysis, including sex, race, ethnicity, COVID-19 status, and receipt of acetaminophen between hospital presentation and randomization. A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm.

ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.

Patients randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was <50 kg) every 6 hours intravenously for 5 days for a total of 20 doses. Patients randomized to placebo received an identical appearing intravenous infusion of 100 mL of 5% dextrose in water every 6 hours for 5 days. In both arms, the study drug was discontinued prior to 120 hours, if one of the following occurred, (1) discharge from the study hospital, (2) discharge from the ICU, (3) withdrawal from the study, or (4) death. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were monitored on study day 0, and days 2 through 5 . New measured values of AST or ALT greater than or equal to 10 times the upper limit of normal on any measurement prompted permanent discontinuation of the study drug. The primary efficacy variable was days alive and free of any organ support (dialysis, assisted ventilation, and vasopressors) out to day 28.

Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

Ware LB, Files DC, Fowler A, et al. Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial. JAMA. 2024;332(5):390-400. doi:10.1001/jama.2024.8772

Plasma
Urine
Whole Blood

Prevention and Early Treatment of Acute Lung Injury (PETAL)