Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

NCT04291508 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: PETAL04ASTER
• Study Type: interventional
• Target: 488
• Locations: 1 country
• Sites: 41

Brief 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.

Conditions

Acute Respiratory Distress Syndrome; Critical Illness; Respiratory Failure; Sepsis

Keywords

ARDS; Acetaminophen; Vitamin C; Sepsis

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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.

  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.

  28 days after randomization

Secondary Outcomes (16)

• Ventilator-free Days (VFD)

  28 days after randomization

• Vasopressor-free Days

  28 days after randomization

• Renal Replacement-free Days

  28 days after randomization

• 28 Day Hospital Mortality

  28 days after randomization

• ICU Free Days

  28 days after randomization

Study Arms (4)

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).

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.

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).

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.

Drug: 5% Dextrose refrigerated

Interventions

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)

IV Acetaminophen-Active

Intravenous Vitamin C (refrigerated) DRUG

Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)

Also known as: Ascor

IV Vitamin C-Active

5% Dextrose (room temperature) DRUG

Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)

Acetaminophen-Placebo

5% Dextrose refrigerated DRUG

Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)

Vitamin C-Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (41)

University of Alabama Medical Center

Birmingham, Alabama, 35249, United States

Location

University of Arizona

Tucson, Arizona, 85721, United States

Location

UCSF Fresno

Fresno, California, 93701, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Ronald Reagan UCLA Medical Center

Los Angeles, California, 90095, United States

Location

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

UCSF Medical Center

San Francisco, California, 94143, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Denver Health Medical Center

Denver, Colorado, 80204, United States

Location

University Medical Center

New Orleans, Louisiana, 70112, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115, United States

Location

Baystate Medical Center

Springfield, Massachusetts, 01199, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

Henry Ford Medical Center

Detroit, Michigan, 48025, United States

Location

Fairview Southdale Hospital

Edina, Minnesota, 55435, United States

Location

Hennepin County Medical Center

Minneapolis, Minnesota, 55415, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Mt. Sinai Hospital

New York, New York, 10029, United States

Location

Montefiore Medical Center-Weiler

The Bronx, New York, 10461, United States

Location

Montefiore Medical Center-Moses

The Bronx, New York, 10467, United States

Location

Carolinas Medical Center

Charlotte, North Carolina, 28204, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

Location

UPMC Presbyterian/Mercy/Shadyside/Magee

Pittsburgh, Pennsylvania, 15261, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37221, United States

Location

University of Texas Health Science Center

Houston, Texas, 77030, United States

Location

Intermountain Medical Center

Murray, Utah, 84107, United States

Location

University of Utah Hospital

Salt Lake City, Utah, 84132, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22903, United States

Location

Sentara/EVMS

Norfolk, Virginia, 23507, United States

Location

VCU Medical Center

Richmond, Virginia, 23298, United States

Location

Harborview Medical Center

Seattle, Washington, 98104, United States

Location

Swedish Hospital First Hill

Seattle, Washington, 98122, United States

Location

Related Publications (1)

• 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.

  PMID: 38762798 DERIVED

Related Links

• Website for the PETAL Network

MeSH Terms

Conditions

Respiratory Distress Syndrome; Critical Illness; Respiratory Insufficiency; Sepsis

Interventions

Glucose

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Infections; Systemic Inflammatory Response Syndrome; Inflammation

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates

Results Point of Contact

• Title: PETAL Network Coordinatine Center PI, B. Taylor Thompson, MD
• Organization: Massachsetts General Hospital

tthompson1@mgh.harvard.edu

617 872-2882

Study Officials

• Boyd Taylor Thompson, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Vitamin C or Vitamin C-placebo will be refrigerated. Acetaminophen or acetaminophen-placebo will be stored at room temperature and the volume will be reduced for patients less than 50 kg. Investigators will be informed of which of the two placebo controlled groups the patient was randomized to.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PETAL CCC Principal Investigator

Model Details: Patients will be randomized to at a ratio of 2:1 active versus placebo.

Study Record Dates

• First Submitted: February 27, 2020
• First Posted: March 2, 2020
• Study Start: October 13, 2021
• Primary Completion: April 27, 2023
• Study Completion: July 27, 2023
• Last Updated: September 27, 2024
• Results First Posted: September 27, 2024

Record last verified: 2024-09

Locations

US (41)