Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery (ASTER)

October 13, 2023 updated by: Boyd Taylor Thompson, Massachusetts General Hospital
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.

Study Overview

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.

  1. 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.
  2. 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 will be randomized in a 2:1:2:1 fashion (APAP-Active: APAP-Placebo: Vit C-Active: Vit C-Placebo). With the closure of the Vitamin C arm in June 2022; the study is proceeding with the APAP and Placebo arms with a 1:1 randomization scheme. The total sample size is 450 participants (225 in the active arm and 225 in the placebo arm).

Study Type

Interventional

Enrollment (Actual)

488

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Sepsis defined as:

    1. Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND
    2. 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)
  3. 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

Exclusion Criteria:

  1. No consent/inability to obtain consent from the participant or a legally authorized representative
  2. Patient unable to be randomized within 36 hours of presentation to the ED or within 36 hours of presentation to any acute care hospital
  3. Diagnosis of cirrhosis by medical chart review
  4. Liver transplant recipient
  5. AST or ALT greater than five times upper limit of normal
  6. Diagnosis of ongoing chronic alcohol use disorder/abuse by chart review; if medical record unclear, use Appendix F
  7. 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)
  8. Hypersensitivity to Acetaminophen or Vitamin C
  9. 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)
  10. Home assisted ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing
  11. Chronic dialysis
  12. Current active kidney stone (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
  13. 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)
  14. Kidney transplant recipient (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
  15. Use of home oxygen >3L/minute via nasal cannula for chronic cardiopulmonary disease
  16. Moribund patient not expected to survive 24 hours
  17. Underlying malignancy or other condition with estimated life expectancy of less than 1 month
  18. 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
  19. Prisoner
  20. Treating team unwilling to enroll because of intended use of Acetaminophen or Vitamin C
  21. 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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: IV Acetaminophen-Active
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).
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)
Active Comparator: IV Vitamin C-Active
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.
Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)
Other Names:
  • Ascor
Placebo Comparator: Acetaminophen-Placebo
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).
Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)
Placebo Comparator: Vitamin C-Placebo
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.
Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Days alive and free of organ support to day 28
Time Frame: 28 days after randomization
Defined as 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 days after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ventilator-free days (VFD)
Time Frame: 28 days after randomization
Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.
28 days after randomization
Vasopressor-free days
Time Frame: 28 days after randomization
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 are assigned zero vasopressor free days.
28 days after randomization
Renal replacement-free days
Time Frame: 28 days after randomization
The number of calendar days between randomization and 28 days later that the patient is alive and without new renal replacement therapy. Patients who died prior to day 28 are assigned zero renal replacement free days.
28 days after randomization
28-day hospital mortality
Time Frame: 28 days after randomization

Vital status prior to discharge home before day 28.

"Home" is defined as a patient's place of residence prior to enrollment. Thus, if a patient is discharged to a location that is different from the place of residence prior to enrollment (e.g. rehabilitation facility or hospice) then the patient will be followed until they return to their original location, 90 days, or death, whichever comes first.

28 days after randomization
ICU free days
Time Frame: 28 days after randomization
The number of days spent alive out of the ICU to day 28.
28 days after randomization
Hospital free days to discharge home
Time Frame: Up to day 28
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.
Up to day 28
Days in ICU among survivors and non-survivors
Time Frame: Up to day 28
The total number of days spent in the ICU until hospital discharge or death during the first 28 days. If a patient is discharged alive from the study hospital we assume they are no longer in the ICU
Up to day 28
Number of subjects with initiation of assisted ventilation
Time Frame: Up to day 28
Any patient who received assisted ventilation during the study hospitalization in the first 28 days meets this endpoint.
Up to day 28
Number of subjects with initiation of renal replacement therapy
Time Frame: Up to day 28
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.
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
We will calculate the SOFA score 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. At the day 7 assessment, if a value is missing then we will carry forward the closest previously known value. If a patient is intubated or heavily sedated at either 0 or day 7, the GCS will be omitted when calculating the change in score. If a patient was on renal replacement therapy prior to presentation, then the renal dysfunction component to the SOFA score will be omitted as well
Day 0-Day 7
90-day hospital mortality
Time Frame: 90 days after randomization
Vital status prior to discharge home before day 90.
90 days after randomization
Number of subjects who developed ARDS
Time Frame: Up to day 7
Presence and severity of ARDS is determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and confirmation of ARDS through chest x-ray reviews.
Up to day 7
Change in serum creatinine concentration
Time Frame: Up to day 28
We will measure the change in serum creatinine from enrollment to discharge, death, initiation of dialysis or 28 days, whichever occurs first
Up to day 28
Number of subjects with Major Adverse Kidney Events at 28 days (MAKE28)
Time Frame: 28 days after randomization
Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death
28 days after randomization
Change in Radiographic Assessment of Lung Edema (RALE) score
Time Frame: Up to 72 hours after randomization
We will determine the change in Radiographic Assessment of Lung Edema (RALE) score from enrollment to 72 hours in patients who are receiving assisted ventilation or high flow nasal oxygen at the time of study randomization
Up to 72 hours after randomization
90-day all-cause mortality
Time Frame: 90 days after randomization
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).
90 days after randomization
Renal calculi to day 90
Time Frame: Up to day 90
Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group.
Up to day 90

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Boyd Taylor Thompson, MD, Massachusetts General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 13, 2021

Primary Completion (Actual)

April 27, 2023

Study Completion (Actual)

July 27, 2023

Study Registration Dates

First Submitted

February 27, 2020

First Submitted That Met QC Criteria

February 27, 2020

First Posted (Actual)

March 2, 2020

Study Record Updates

Last Update Posted (Actual)

October 17, 2023

Last Update Submitted That Met QC Criteria

October 13, 2023

Last Verified

October 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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