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

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Suspended

CT.gov ID

NCT04291508

Collaborator

(none)

900

Enrollment

Locations

Arms

20.6

Anticipated Duration (Months)

23.1

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome Critical Illness Respiratory Failure Sepsis	Drug: Intravenous Acetaminophen (room temperature) Drug: Intravenous Vitamin C (refrigerated) Drug: 5% Dextrose (room temperature) Drug: 5% Dextrose refrigerated	Phase 2

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 will be randomized in a 2:1:2:1 fashion (APAP-Active: APAP-Placebo: Vit C-Active: Vit C-Placebo).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

900 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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.

Primary Purpose:

Treatment

Official Title:

Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

Actual Study Start Date :

Oct 13, 2021

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

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).	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)
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)	Drug: Intravenous Vitamin C (refrigerated) 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).	Drug: 5% Dextrose (room temperature) 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).	Drug: 5% Dextrose refrigerated Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)

Outcome Measures

Primary Outcome Measures

Days alive and free of organ support to day 28 [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.

Secondary Outcome Measures

Ventilator-free days (VFD) [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.
Vasopressor-free days [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.
Renal replacement-free days [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-day hospital mortality [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.
ICU free days [28 days after randomization]
The number of days spent alive out of the ICU to day 28.
Hospital free days to discharge home [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.
Days in ICU among survivors and non-survivors [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
Number of subjects with initiation of assisted ventilation [Up to day 28]
Any patient who received assisted ventilation during the study hospitalization in the first 28 days meets this endpoint.
Number of subjects with initiation of renal replacement therapy [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.
Change in organ-specific Sepsis-related Organ Failure Assessment (SOFA) scores between enrollment and study day 7 [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
90-day hospital mortality [90 days after randomization]
Vital status prior to discharge home before day 90.
Number of subjects who developed ARDS [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.
Change in serum creatinine concentration [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
Number of subjects with Major Adverse Kidney Events at 28 days (MAKE28) [28 days after randomization]
Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death
Change in Radiographic Assessment of Lung Edema (RALE) score [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
90-day all-cause mortality [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).
Renal calculi to day 90 [Up to day 90]
Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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
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
Multiple (>1) episodes of prior kidney stones, known history of oxalate kidney stones, or history of oxalate nephropathy.
Kidney transplant recipient
Use of home oxygen 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85721
2	UCSF Fresno	Fresno	California	United States	93701
3	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
4	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
5	UC Davis Medical Center	Sacramento	California	United States	95817
6	UCSF Medical Center	San Francisco	California	United States	94143
7	Stanford University	Stanford	California	United States	94305
8	University of Colorado Hospital	Aurora	Colorado	United States	80045
9	Denver Health Medical Center	Denver	Colorado	United States	80204
10	St. Joseph Hospital	Denver	Colorado	United States	80218
11	University of Kentucky	Lexington	Kentucky	United States	40506
12	University Medical Center	New Orleans	Louisiana	United States	70112
13	Maine Medical Center	Portland	Maine	United States	04102
14	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
15	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
16	Baystate Medical Center	Springfield	Massachusetts	United States	01199
17	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
18	Henry Ford Medical Center	Detroit	Michigan	United States	48025
19	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
20	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
21	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
22	Montefiore Medical Center-Weiler	Bronx	New York	United States	10461
23	Montefiore Medical Center-Moses	Bronx	New York	United States	10467
24	Mt. Sinai Hospital	New York	New York	United States	10029
25	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
26	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
27	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
28	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
29	Oregon Health and Science University	Portland	Oregon	United States	97239
30	UPMC Presbyterian/Mercy/Shadyside/Magee	Pittsburgh	Pennsylvania	United States	15261
31	Medical University of South Carolina	Charleston	South Carolina	United States	29425
32	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37221
33	University of Texas Health Science Center	Houston	Texas	United States	77030
34	Intermountain Medical Center	Murray	Utah	United States	84107
35	University of Utah Hospital	Salt Lake City	Utah	United States	84132
36	University of Virginia Health System	Charlottesville	Virginia	United States	22903
37	VCU Medical Center	Richmond	Virginia	United States	23298
38	Harborview Medical Center	Seattle	Washington	United States	98104
39	Swedish Hospital First Hill	Seattle	Washington	United States	98122