Clinical trial NCT04291508: Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
Official title: Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome
Critical Illness
Respiratory Failure
Sepsis
Keywords: ARDS
Acetaminophen
Vitamin C
Sepsis
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
First posted: 2020-03-02
Enrollment: 488
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized to at a ratio of 2:1 active versus placebo.
Primary purpose: TREATMENT

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.

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, 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).

Eligibility criteria: 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).

Primary outcomes:
measure: Days Alive and Free of Organ Support to Day 28
timeFrame: 28 days after randomization
measure: 28-day All Cause Mortality
timeFrame: 28 days after randomization
measure: Days Free of Assisted Ventilation to Day 28
timeFrame: 28 days after randomization
measure: Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort
timeFrame: 28 days after randomization
measure: Days Free of Vasopressors to Day 28 in Overall Cohort
timeFrame: 28 days after randomization
Secondary outcomes:
measure: Ventilator-free Days (VFD)
timeFrame: 28 days after randomization
measure: Vasopressor-free Days
timeFrame: 28 days after randomization
measure: Renal Replacement-free Days
timeFrame: 28 days after randomization
measure: 28 Day Hospital Mortality
timeFrame: 28 days after randomization
measure: ICU Free Days
timeFrame: 28 days after randomization
measure: Hospital Free Days to Discharge Home
timeFrame: Up to day 28
measure: Number of Subjects With Initiation of Assisted Ventilation
timeFrame: Up to day 28
measure: Number of Subjects With Initiation of Renal Replacement Therapy
timeFrame: Up to day 28
measure: Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7
timeFrame: Day 0-Day 7
measure: Renal Calculi to Day 90
timeFrame: Up to day 90
measure: 90-day All-cause Mortality
timeFrame: 90 days after randomization
measure: 90-day Hospital Mortality
timeFrame: 90 days after randomization
measure: Number of Subjects Who Developed ARDS Within 7 Days of Randomization
timeFrame: Up to day 7
measure: Change in Serum Creatinine Concentration
timeFrame: Up to day 28
measure: Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28)
timeFrame: 28 days after randomization
measure: ICU Days to Day 28
timeFrame: To day 28
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Medical Center
state: Alabama
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Fresno
country: United States
facility: UCSF Fresno
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: New Orleans
country: United States
facility: University Medical Center
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Medical Center
state: Michigan
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center-Moses
state: New York
city: New York
country: United States
facility: Mt. Sinai Hospital
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian/Mercy/Shadyside/Magee
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Norfolk
country: United States
facility: Sentara/EVMS
state: Virginia
city: Richmond
country: United States
facility: VCU Medical Center
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Hospital First Hill
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: Boyd Taylor Thompson, MD
role: PRINCIPAL_INVESTIGATOR
References: