Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

Sepsis Clinical Trial

— ASTER  

Official title:

Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04291508
• Other study ID #: PETAL04ASTER
• Status: Completed
• Phase: Phase 2
• Start date: October 13, 2021
• Est. completion date: July 27, 2023

Study information

• Verified date: October 2023
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 488
• Est. completion date: July 27, 2023
• Est. primary completion date: April 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Critical Illness
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Respiratory Failure
• Respiratory Insufficiency
• Sepsis
• Toxemia

Intervention

Drug:
• 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)
• Intravenous Vitamin C (refrigerated)
Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)
• 5% Dextrose (room temperature)
Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)
• 5% Dextrose refrigerated
Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	University of Colorado Hospital	Aurora	Colorado
United States	University of Alabama Medical Center	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center-Moses	Bronx	New York
United States	Montefiore Medical Center-Weiler	Bronx	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Denver Health Medical Center	Denver	Colorado
United States	Henry Ford Medical Center	Detroit	Michigan
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	UCSF Fresno	Fresno	California
United States	University of Texas Health Science Center	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	University Medical Center	New Orleans	Louisiana
United States	Mt. Sinai Hospital	New York	New York
United States	Sentara/EVMS	Norfolk	Virginia
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	UPMC Presbyterian/Mercy/Shadyside/Magee	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health and Science University	Portland	Oregon
United States	VCU Medical Center	Richmond	Virginia
United States	UC Davis Medical Center	Sacramento	California
United States	University of Utah Hospital	Salt Lake City	Utah
United States	UCSF Medical Center	San Francisco	California
United States	Harborview Medical Center	Seattle	Washington
United States	Swedish Hospital First Hill	Seattle	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Stanford University	Stanford	California
United States	University of Arizona	Tucson	Arizona
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Days alive and free of organ support to day 28	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	Ventilator-free days (VFD)	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
Secondary	Vasopressor-free days	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
Secondary	Renal replacement-free days	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
Secondary	28-day hospital mortality	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
Secondary	ICU free days	The number of days spent alive out of the ICU to day 28.	28 days after randomization
Secondary	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.	Up to day 28
Secondary	Days in ICU among survivors and non-survivors	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
Secondary	Number of subjects with initiation of assisted ventilation	Any patient who received assisted ventilation during the study hospitalization in the first 28 days meets this endpoint.	Up to day 28
Secondary	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.	Up to day 28
Secondary	Change in organ-specific Sepsis-related Organ Failure Assessment (SOFA) scores between enrollment and study 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
Secondary	90-day hospital mortality	Vital status prior to discharge home before day 90.	90 days after randomization
Secondary	Number of subjects who developed ARDS	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
Secondary	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	Up to day 28
Secondary	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	28 days after randomization
Secondary	Change in Radiographic Assessment of Lung Edema (RALE) score	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
Secondary	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).	90 days after randomization
Secondary	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.	Up to day 90

External Links

•   Website for the PETAL Network