Acute Respiratory Distress SyndromePhase 2ASTERNCT04291508

Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

A Phase 2 study testing Intravenous Acetaminophen (room temperature), Intravenous Vitamin C (refrigerated) and 5% Dextrose (room temperature) in people with Acute Respiratory Distress Syndrome and Critical Illness, run by Massachusetts General Hospital at 41 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Prospective multi-center phase 2b randomized placebo-controlled double-blinded interventional platform trial of two different pharmacologic therapies (intravenous Vitamin C or intravenous Acetaminophen) for patients with sepsis-induced hypotension or respiratory failure. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Acute Respiratory Distress Syndrome, Critical Illness, Respiratory Failure
What is being tested?: Intravenous Acetaminophen (room temperature), Intravenous Vitamin C (refrigerated) and 5% Dextrose (room temperature)
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 488 participants
Where: 41 sitesUnited States
Study dates: 13 Oct 2021to 27 Jul 2023
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Age ≥ 18 years
Sepsis defined as:
Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND
Hypotension as defined by the need for any vasopressor (and 1 liter of fluid already administered intravenously for resuscitation) OR respiratory failure defined by mechanical ventilation, BIPAP or CPAP at any level, or greater than or equal to 6 liters/minute of supplemental oxygen (criterion b must be met at time of enrollment)
Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital

Who cannot join

No consent/inability to obtain consent from the participant or a legally authorized representative
Patient unable to be randomized within 36 hours of presentation to the ED or within 36 hours of presentation to any acute care hospital
Diagnosis of cirrhosis by medical chart review
Liver transplant recipient
AST or ALT greater than five times upper limit of normal
Diagnosis of ongoing chronic alcohol use disorder/abuse by chart review; if medical record unclear, use Appendix F

Show all 21Show fewer

Clinical diagnosis of diabetic ketoacidosis or other condition such as profound hypoglycemia that requires hourly blood glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
Hypersensitivity to Acetaminophen or Vitamin C
Patient, surrogate or physician not committed to full support (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)
Home assisted ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing
Chronic dialysis
Current active kidney stone (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
Multiple (>1) episodes of prior kidney stones, known history of oxalate kidney stones, or history of oxalate nephropathy. (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
Kidney transplant recipient (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
Use of home oxygen >3L/minute via nasal cannula for chronic cardiopulmonary disease
Moribund patient not expected to survive 24 hours
Underlying malignancy or other condition with estimated life expectancy of less than 1 month
Pregnant woman, woman of childbearing potential without a documented negative urine or serum pregnancy test during the current hospitalization, or woman who is breast feeding
Prisoner
Treating team unwilling to enroll because of intended use of Acetaminophen or Vitamin C
Treating team unwilling to use plasma (as opposed to point of care testing) for glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial).

Trial locations and contacts

41 sites in 1 country.

City, postcode or hospital

41 sites in 1 country

United States41 sites

University of Michigan Medical Center
Ann Arbor, Michigan, 48109
University of Colorado Hospital
Aurora, Colorado, 80045
University of Alabama Medical Center
Birmingham, Alabama, 35249
Massachusetts General Hospital
Boston, Massachusetts, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02115
Medical University of South Carolina
Charleston, South Carolina, 29425
Carolinas Medical Center
Charlotte, North Carolina, 28204
University of Virginia Health System
Charlottesville, Virginia, 22903
University of Cincinnati Medical Center
Cincinnati, Ohio, 45219
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Ohio State University Wexner Medical Center
Columbus, Ohio, 43210
Denver Health Medical Center
Denver, Colorado, 80204
Henry Ford Medical Center
Detroit, Michigan, 48025
Fairview Southdale Hospital
Edina, Minnesota, 55435
UCSF Fresno
Fresno, California, 93701
University of Texas Health Science Center
Houston, Texas, 77030
University of Mississippi Medical Center
Jackson, Mississippi, 39216
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Ronald Reagan UCLA Medical Center
Los Angeles, California, 90095
Hennepin County Medical Center
Minneapolis, Minnesota, 55415
Intermountain Medical Center
Murray, Utah, 84107
Vanderbilt University Medical Center
Nashville, Tennessee, 37221
University Medical Center
New Orleans, Louisiana, 70112
Mt. Sinai Hospital
New York, New York, 10029
Sentara/EVMS
Norfolk, Virginia, 23507
Temple University Hospital
Philadelphia, Pennsylvania, 19140
UPMC Presbyterian/Mercy/Shadyside/Magee
Pittsburgh, Pennsylvania, 15261
Maine Medical Center
Portland, Maine, 04102
Oregon Health and Science University
Portland, Oregon, 97239
VCU Medical Center
Richmond, Virginia, 23298
UC Davis Medical Center
Sacramento, California, 95817
University of Utah Hospital
Salt Lake City, Utah, 84132
UCSF Medical Center
San Francisco, California, 94143
Harborview Medical Center
Seattle, Washington, 98104
Swedish Hospital First Hill
Seattle, Washington, 98122
Baystate Medical Center
Springfield, Massachusetts, 01199
Stanford University
Stanford, California, 94305
Montefiore Medical Center-Weiler
The Bronx, New York, 10461
Montefiore Medical Center-Moses
The Bronx, New York, 10467
University of Arizona
Tucson, Arizona, 85721
Wake Forest Baptist Medical Center
Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

Read the detailed description

Hypothesis 1A: Acetaminophen (APAP) or Vitamin C infusion will increase the days alive and free of organ support to day 28.

Hypothesis 1B: APAP or Vitamin C will have a favorable effect on other secondary outcomes including pulmonary and non-pulmonary organ dysfunction and biomarkers of inflammation and endothelial injury

The investigators plan to carry out two multi-center phase 2b randomized double-blinded placebo-controlled trials of two different pharmacologic therapies within a single platform trial.

One trial will assess the efficacy of Acetaminophen (1 gram intravenously every 6 hours) for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.
A second trial will assess the efficacy of Vitamin C (50 mg/kg every 6 hours) infused intravenously for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.

A total of 900 participants who meet all of the inclusion criteria and none of the exclusion criteria, were planned be randomized in a 2:1:2:1 fashion (APAP-Active: APAP-Placebo: Vit C-Active: Vit C-Placebo). The APAP and Vitamin C trials were planned to be resulted separately. With the closure of the Vitamin C arm in June 2022; the study proceeded with the APAP and Placebo arms with a 1:1 randomization scheme. The total sample size for the APAP trial was 447 participants (227 in the active arm and 220 in the placebo arm). The total sample size for the Vitamin C trial was 79 (40 in the active arm and 39 in the placebo arm). The total combined number in the 4 arms of the ASTER trial was 526 (227 APAP active, 220 APAP placebo, 40 Vit C active, 39 Vit C placebo), although a total of only 487 patients were actually randomized (this is due to the 39 pooled placebo patients that appear in both trials).

Conditions: Acute Respiratory Distress Syndrome, Critical Illness, Respiratory Failure, Sepsis
Being tested: Intravenous Acetaminophen (room temperature), Intravenous Vitamin C (refrigerated), 5% Dextrose (room temperature), 5% Dextrose refrigerated
Keywords: ARDS, Acetaminophen, Vitamin C, Sepsis
Medical subject headings: Respiratory Distress Syndrome, Critical Illness, Respiratory Insufficiency, Sepsis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Intravenous Acetaminophen (room temperature)Drug
Acetaminophen given intravenously at the dose of 1 gram (or 15 mg/kg if patient weighs < 50 kg) every six hours for 5 days (20 doses)
Intravenous Vitamin C (refrigerated)Drug
Also called Ascor
Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)
5% Dextrose (room temperature)Drug
Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)
5% Dextrose refrigeratedDrug
Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)

Study groups in NCT04291508
Study group	Role	What they receive
IV Acetaminophen-Active	Active comparator	Patients randomized to the Acetaminophen arm will receive Acetaminophen at the dose of 1 gram (or 15 mg/kg if actual body weight < 50kg) in 100 ml 5% dextrose in water every 6 hours intravenously for 5 days (20 doses). Receives: Drug: Intravenous Acetaminophen (room temperature)
IV Vitamin C-Active	Active comparator	Patients randomized to the Vitamin C arm will receive Vitamin C at the dose of 50 mg/kg in 100 ml 5% dextrose in water every 6 hours intravenously for 5 days (20 doses). Note: This arm is now closed. Receives: Drug: Intravenous Vitamin C (refrigerated)
Acetaminophen-Placebo	Placebo comparator	Patients randomized to placebo will receive an identical-appearing intravenous infusion of 100 ml of 5% dextrose in water every 6 hours for 5 days (20 doses). Receives: Drug: 5% Dextrose (room temperature)
Vitamin C-Placebo	Placebo comparator	Patients randomized to placebo will receive an identical-appearing intravenous infusion of 100 ml of 5% dextrose in water every 6 hours for 5 days (20 doses). Note: This arm is now closed. Receives: Drug: 5% Dextrose refrigerated

What is being measured

The primary outcome is the main question the study is designed to answer.

Days Alive and Free of Organ Support to Day 28
Defined as the days alive and free of organ support (dialysis, assisted ventilation, and vasopressors) to day 28. Participants will need to be free of all three components (assisted ventilation, vasopressors, new renal replacement therapy) to qualify for a day alive and free from organ failures. Patients on chronic dialysis will not be scored for the new renal failure free component of this outcome.
Measured: 28 days after randomization
28-day All Cause Mortality
Vital status at study day 28 regardless of location or cause of death. Patients discharged from the study hospital are followed to day 29 to determine this endpoint.
Measured: 28 days after randomization
Days Free of Assisted Ventilation to Day 28
The number of days alive and without assisted ventilation (midnight to midnight) in the overall cohort. No penalty for death.
Measured: 28 days after randomization
Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort
The number of days alive and without renal replacement (RRT) in the overall cohort. If a participant was not on RRT at randomization, received RRT every other day, and stopped RRT before day 28, the number of renal replacement free days is the sum of the days free of RRT prior to dialysis starting and the number of days after dialysis stopped (begins with the first day, midnight to midnight, the participant was free of RRT). No penalty for death.
Measured: 28 days after randomization
Days Free of Vasopressors to Day 28 in Overall Cohort
Days free of vasopressors to day 28 are defined as the number of calendar days (midnight to midnight) between randomization and 28 days later that the patient is alive and did not receive vasopressor therapy.
Measured: 28 days after randomization

Secondary outcomes (16)

Ventilator-free Days (VFD)
VFDs depend on both duration of ventilation and mortality through study day 28. In participants who survive 28 days, VFD is defined as 28 minus days of invasive or noninvasive ventilation to day 28. Duration of ventilation is counted from the first study day of assisted breathing through the last day of assisted breathing provided the last day is prior to day 28. Isolated periods of ventilation briefer than 24 hours for surgical procedures and ventilation solely for sleep disordered breathing do not count towards duration of ventilation. In participants who never require assisted breathing, duration of ventilation is zero. Participants who do not survive 28 days will be assigned zero VF
Measured: 28 days after randomization
Vasopressor-free Days
Vasopressor free days to day 28 are defined as the number of calendar days between randomization and 28 days later that the patient is alive and without the use of vasopressor therapy. Patients who die prior to day 28 and those who receive vasopressor therapy for the entire first 28 days are assigned zero vasopressor free days.
Measured: 28 days after randomization
Renal Replacement-free Days
Renal replacement free days to day 28 are defined as the number of calendar days between randomization and 28 days later that the patient is alive and without renal replacement therapy. We also follow the "last off" method. Patients who died prior to day 28 and those who receive renal replacement therapy for the entire first 28 days are assigned zero renal replacement free days.
Measured: 28 days after randomization
28 Day Hospital Mortality
All deaths occuring in the study hospital until study day 28.
Measured: 28 days after randomization
ICU Free Days
The number of days spent alive out of the ICU to day 28.
Measured: 28 days after randomization
Hospital Free Days to Discharge Home
Defined as 28 days minus the number of days from randomization to discharge home. If a patient has not been discharged home prior to study day 28 or dies prior to day 28, hospital free days will be zero. Patients transferred to another hospital or other health care facility will be followed to day 28 to assess this endpoint.
Measured: Up to day 28
Number of Subjects With Initiation of Assisted Ventilation
Any patient who received assisted ventilation during the study hospitalization to study day 28 days meets this endpoint.
Measured: Up to day 28
Number of Subjects With Initiation of Renal Replacement Therapy
Patients who receive (new) renal replacement therapy through day 28 will meet this endpoint. Patients with chronic renal replacement therapy initiated prior to the current sepsis illness will not be eligible to meet this endpoint.
Measured: Up to day 28
Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7
SOFA score calculated upon enrollment and at day 7 using clinically available data. If a value is not available at baseline, it will be assumed to be normal. Missing values at day 7 assessment were carried forward to the closest known value. GSC was omitted for patients intubated/heavily sedated at either 0 or day 7 when calculating the change in score. Renal dysfunction component was omitted for patients RRT prior to presentation.Higher SOFA score=worse outcome.ASTER clinically significant organ failure:SOFA score 2 or more points higher than baseline.Total score range: 0(min)-24(max) Score:Coag(platelets x10³/µL:0:>150;1:</=150; 2:</=100; 3:</=50; 4:</=20. Liver(bilirubin, mg/dL): 0:<1.2; 1: 1.2-1.9; 3: 2.0-5.9; 3: 6.0-11.9; 4:>11.9. Cardio(hypotension): 0:none; 1: MAP <70 mmHg; 2: Dop</=5 or dob (any dose); 3:dop>5, epi</=0.1, or norepi</=0.1; 4: Dop>15, epi>0.1, or norepi>0.1. Renal(Cr, mg/dL or urine output,ml/d): 0:<1.2; 1: 1.2-1.9; 3: 2.0-3.4; 3: 3.5-4.9 or <500; 4:>4.9 or<200.
Measured: Day 0-Day 7
Renal Calculi to Day 90
Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group.
Measured: Up to day 90
90-day All-cause Mortality
Vital status of the patient at day 90 will be determined using any of the following methods: medical record review, phone calls to patient, proxy or healthcare facility, review of obituaries, or information from the Centers for Disease Control and Prevention's National Death Index (NDI).
Measured: 90 days after randomization
90-day Hospital Mortality
Vital status prior to discharge home before day 90.
Measured: 90 days after randomization
Number of Subjects Who Developed ARDS Within 7 Days of Randomization
The presence of ARDS for each day is defined as receiving assisted ventilation with P/F <300 or imputed P/F <300, FiO2 ≥40%, and PEEP ≥5 cm H2O and not fully explained by CHF or fluid overload. ARDS imaging criteria are met if clinically available chest images (CT or CXR) are consistent with ARDS (bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules).
Measured: Up to day 7
Change in Serum Creatinine Concentration
We will measure the change in serum creatinine from enrollment to discharge, death, initiation of dialysis or 28 days, whichever occurs first
Measured: Up to day 28
Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28)
Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death
Measured: 28 days after randomization
ICU Days to Day 28
ICU free days to day 28 are defined as the number of days spent alive and out of the ICU to day 28.
Measured: To day 28

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

13 Oct 202127 Jul 2023

First posted2 Mar 2020
Study start13 Oct 2021
Primary completion27 Apr 2023
Study completion27 Jul 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Acute Respiratory Distress SyndromeStudies of the same condition, open and under way.
More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: Patients will be randomized to at a ratio of 2:1 active versus placebo.
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 488 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04291508
Sponsor's protocol ID: PETAL04ASTER
Acronym: ASTER
Status last verified: Sep 2024
First submitted: 27 Feb 2020
Last updated: 27 Sep 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Ware LB, Files DC, Fowler A, Aboodi MS, Aggarwal NR, Brower RG, Chang SY, Douglas IS, Fields S, Foulkes AS, Ginde AA, Harris ES, Hendey GW, Hite RD, Huang W, Lai P, Liu KD, Thompson BT, Matthay MA; National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial. JAMA. 2024 Aug 6;332(5):390-400. doi: 10.1001/jama.2024.8772.
PubMed 38762798

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 27 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
ClinicalTrials.gov ID: NCT04291508
Acronym / sponsor ID: ASTER / PETAL04ASTER
Conditions: Acute Respiratory Distress Syndrome, Critical Illness, Respiratory Failure, Sepsis
Keywords: ARDS, Acetaminophen, Vitamin C, Sepsis
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 488 participants (actual)
Lead sponsor: Massachusetts General HospitalUniversity, hospital or other
Study start: 13 Oct 2021 (actual)
Primary completion: 27 Apr 2023 (actual)
Study completion: 27 Jul 2023 (actual)
First posted: 2 Mar 2020 (actual)
Results: Posted 27 Sep 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Hypothesis 1A: Acetaminophen (APAP) or Vitamin C infusion will increase the days alive and free of organ support to day 28.

Hypothesis 1B: APAP or Vitamin C will have a favorable effect on other secondary outcomes including pulmonary and non-pulmonary organ dysfunction and biomarkers of inflammation and endothelial injury

The investigators plan to carry out two multi-center phase 2b randomized double-blinded placebo-controlled trials of two different pharmacologic therapies within a single platform trial.

One trial will assess the efficacy of Acetaminophen (1 gram intravenously every 6 hours) for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.
A second trial will assess the efficacy of Vitamin C (50 mg/kg every 6 hours) infused intravenously for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4
Model description: Patients will be randomized to at a ratio of 2:1 active versus placebo.

Arm	Type	Receives
IV Acetaminophen-Active	Active comparator	Drug: Intravenous Acetaminophen (room temperature)Patients randomized to the Acetaminophen arm will receive Acetaminophen at the dose of 1 gram (or 15 mg/kg if actual body weight < 50kg) in 100 ml 5% dextrose in water every 6 hours intravenously for 5 days (20 doses).
IV Vitamin C-Active	Active comparator	Drug: Intravenous Vitamin C (refrigerated)Patients randomized to the Vitamin C arm will receive Vitamin C at the dose of 50 mg/kg in 100 ml 5% dextrose in water every 6 hours intravenously for 5 days (20 doses). Note: This arm is now closed.
Acetaminophen-Placebo	Placebo comparator	Drug: 5% Dextrose (room temperature)Patients randomized to placebo will receive an identical-appearing intravenous infusion of 100 ml of 5% dextrose in water every 6 hours for 5 days (20 doses).
Vitamin C-Placebo	Placebo comparator	Drug: 5% Dextrose refrigeratedPatients randomized to placebo will receive an identical-appearing intravenous infusion of 100 ml of 5% dextrose in water every 6 hours for 5 days (20 doses). Note: This arm is now closed.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Age ≥ 18 years
Sepsis defined as:
Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital

Key exclusion criteria (21 listed)

No consent/inability to obtain consent from the participant or a legally authorized representative
Patient unable to be randomized within 36 hours of presentation to the ED or within 36 hours of presentation to any acute care hospital
Diagnosis of cirrhosis by medical chart review
Liver transplant recipient
AST or ALT greater than five times upper limit of normal

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Intravenous Acetaminophen (room temperature)Acetaminophen given intravenously at the dose of 1 gram (or 15 mg/kg if patient weighs < 50 kg) every six hours for 5 days (20 doses)	Drug	IV Acetaminophen-Active
Intravenous Vitamin C (refrigerated)Also: AscorVitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)	Drug	IV Vitamin C-Active
5% Dextrose (room temperature)Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)	Drug	Acetaminophen-Placebo
5% Dextrose refrigeratedPlacebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)	Drug	Vitamin C-Placebo

Primary outcome

Days Alive and Free of Organ Support to Day 28
Time frame: 28 days after randomization
Defined as the days alive and free of organ support (dialysis, assisted ventilation, and vasopressors) to day 28. Participants will need to be free of all three components (assisted ventilation, vasopressors, new renal replacement therapy) to qualify for a day alive and free from organ failures. Patients on chronic dialysis will not be scored for the new renal failure free component of this outcome.
28-day All Cause Mortality
Time frame: 28 days after randomization
Vital status at study day 28 regardless of location or cause of death. Patients discharged from the study hospital are followed to day 29 to determine this endpoint.
Days Free of Assisted Ventilation to Day 28
Time frame: 28 days after randomization
The number of days alive and without assisted ventilation (midnight to midnight) in the overall cohort. No penalty for death.
Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort
Time frame: 28 days after randomization
The number of days alive and without renal replacement (RRT) in the overall cohort. If a participant was not on RRT at randomization, received RRT every other day, and stopped RRT before day 28, the number of renal replacement free days is the sum of the days free of RRT prior to dialysis starting and the number of days after dialysis stopped (begins with the first day, midnight to midnight, the participant was free of RRT). No penalty for death.
Days Free of Vasopressors to Day 28 in Overall Cohort
Time frame: 28 days after randomization
Days free of vasopressors to day 28 are defined as the number of calendar days (midnight to midnight) between randomization and 28 days later that the patient is alive and did not receive vasopressor therapy.

16 secondary outcomes

Ventilator-free Days (VFD)
Time frame: 28 days after randomization
Vasopressor-free Days
Time frame: 28 days after randomization
Renal Replacement-free Days
Time frame: 28 days after randomization
28 Day Hospital Mortality
Time frame: 28 days after randomization
ICU Free Days
Time frame: 28 days after randomization
Hospital Free Days to Discharge Home
Time frame: Up to day 28
Number of Subjects With Initiation of Assisted Ventilation
Time frame: Up to day 28
Number of Subjects With Initiation of Renal Replacement Therapy
Time frame: Up to day 28
Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7
Time frame: Day 0-Day 7
Renal Calculi to Day 90
Time frame: Up to day 90
90-day All-cause Mortality
Time frame: 90 days after randomization
90-day Hospital Mortality
Time frame: 90 days after randomization
Number of Subjects Who Developed ARDS Within 7 Days of Randomization
Time frame: Up to day 7
Change in Serum Creatinine Concentration
Time frame: Up to day 28
Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28)
Time frame: 28 days after randomization
ICU Days to Day 28
Time frame: To day 28

Results and safety

Results posted to the registry on 27 Sep 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
IV Acetaminophen-Active	228	223
IV Vitamin C-Active	40	40
Acetaminophen-Placebo	199	197
Vitamin C-Placebo	21	21

Primary outcome: Days Alive and Free of Organ Support to Day 28

Time frame: 28 days after randomization. Mean (Standard Deviation). Unit: days

Measure	IV Acetaminophen-Active n = 223	IV Vitamin C-Active n = 40	Acetaminophen-Placebo n = 197	Vitamin C-Placebo n = 21
Value	20.2 (10.6)	20.5 (9.5)	19.7 (10.5)	18.4 (11.7)

IV Acetaminophen-Active vs Acetaminophen-Placebo: Mean Difference (Final Values): 0.5 (95% CI -1.6 to 2.5), p = 0.65, t-test, 2 sided
IV Vitamin C-Active vs Vitamin C-Placebo: Mean Difference (Final Values): 2.0 (95% CI -3.5 to 7.6), p = 0.464, t-test, 2 sided

Population analysed: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.

Primary outcome: 28-day All Cause Mortality

Time frame: 28 days after randomization. Count of participants. Unit: Participants

Measure	IV Acetaminophen-Active n = 223	IV Vitamin C-Active n = 40	Acetaminophen-Placebo n = 197	Vitamin C-Placebo n = 21
Value	39	6	43	6

IV Acetaminophen-Active vs Acetaminophen-Placebo: Risk Difference (RD): -4.3 (95% CI -12.0 to 3.3), p = 0.26, Chi-squared
IV Vitamin C-Active vs Vitamin C-Placebo: Risk Difference (RD): -13.6 (95% CI -35.8 to 8.7), p = 0.31, Fisher Exact

Population analysed: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.

Primary outcome: Days Free of Assisted Ventilation to Day 28

Time frame: 28 days after randomization. Mean (Standard Deviation). Unit: days

Measure	IV Acetaminophen-Active n = 223	IV Vitamin C-Active n = 40	Acetaminophen-Placebo n = 197	Vitamin C-Placebo n = 21
Value	21.5 (10.2)	21.6 (9.4)	20.6 (10.5)	19.5 (11.7)

IV Acetaminophen-Active vs Acetaminophen-Placebo: Mean Difference (Final Values): 1.0 (95% CI -1.0 to 2.9), p = 0.35, t-test, 2 sided
IV Vitamin C-Active vs Vitamin C-Placebo: Mean Difference (Final Values): 2.1 (95% CI -3.4 to 7.6), p = 0.45, t-test, 2 sided

Population analysed: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.

Primary outcome: Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort

Time frame: 28 days after randomization. Mean (Standard Deviation). Unit: days

Measure	IV Acetaminophen-Active n = 223	IV Vitamin C-Active n = 40	Acetaminophen-Placebo n = 197	Vitamin C-Placebo n = 21
Value	23.7 (9.0)	24.8 (7.8)	23.9 (8.4)	20.8 (10.9)

IV Acetaminophen-Active vs Acetaminophen-Placebo: Mean Difference (Final Values): -0.2 (95% CI -1.9 to 1.5), p = 0.83, t-test, 2 sided
IV Vitamin C-Active vs Vitamin C-Placebo: Mean Difference (Final Values): 4.0 (95% CI -0.8 to 8.9), p = 0.10, t-test, 2 sided

Population analysed: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.

16 secondary outcomes are reported in the full results.

Adverse events

Time frame: Deaths were assessed up to 90 days post-randomization. Adverse events were assessed up to study day 10 (five days after completion of the study drug infusions) or Hospital discharge, whichever occurs first, with one exception, Major Adverse Kidney Events. Major Adverse Kidney Events (as defined in the protocol) were assessed beyond 10 days for up to 28 days post-randomization. All cause mortality to day 90 for APAP is reported for 223 (4 not reported) and 218 for APAP placebo (2 not reported).. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
IV Acetaminophen-Active	20 of 227 (8.8%)	12 of 227 (5.3%)	58 of 223
IV Vitamin C-Active	4 of 40 (10%)	2 of 40 (5%)	6 of 40
Acetaminophen-Placebo	18 of 199 (9%)	7 of 199 (3.5%)	60 of 197
Vitamin C-Placebo	4 of 21 (19%)	2 of 21 (9.5%)	9 of 21

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 27 Sep 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 38762798Ware LB, Files DC, Fowler A, Aboodi MS, Aggarwal NR, Brower RG, Chang SY, Douglas IS, Fields S, Foulkes AS, Ginde AA, Harris ES, Hendey GW, Hite RD, Huang W, Lai P, Liu KD, Thompson BT, Matthay MA; National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial. JAMA. 2024 Aug 6;332(5):390-400. doi: 10.1001/jama.2024.8772.
Website for the PETAL NetworkLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Boyd Taylor Thompson, MD principal investigator

Massachusetts General Hospital

41 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 41 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Days Alive and Free of Organ Support to Day 28 (time frame: 28 days after randomization). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04291508, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Sep 2024.