Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

Massachusetts General Hospital488 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

488

Conditions

Acute Respiratory Distress Syndrome Critical Illness Respiratory Failure Sepsis

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)

Intravenous Vitamin C (refrigerated)DRUG

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

5% Dextrose (room temperature)DRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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).

Locations (41)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 28 days after randomization

Secondary Outcomes

Data from ClinicalTrials.gov

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Ventilator-free Days (VFD)

VFDs depend on both duration of ventilation and mortality through study day 28. In participants who survive 28 days, VFD is defined as 28 minus days of invasive or noninvasive ventilation to day 28. Duration of ventilation is counted from the first study day of assisted breathing through the last day of assisted breathing provided the last day is prior to day 28. Isolated periods of ventilation briefer than 24 hours for surgical procedures and ventilation solely for sleep disordered breathing do not count towards duration of ventilation. In participants who never require assisted breathing, duration of ventilation is zero. Participants who do not survive 28 days will be assigned zero VF

Time frame: 28 days after randomization

Vasopressor-free Days

Vasopressor free days to day 28 are defined as 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 and those who receive vasopressor therapy for the entire first 28 days are assigned zero vasopressor free days.

Time frame: 28 days after randomization

Renal Replacement-free Days

Renal replacement free days to day 28 are defined as the number of calendar days between randomization and 28 days later that the patient is alive and without renal replacement therapy. We also follow the "last off" method. Patients who died prior to day 28 and those who receive renal replacement therapy for the entire first 28 days are assigned zero renal replacement free days.

Time frame: 28 days after randomization

28 Day Hospital Mortality

All deaths occuring in the study hospital until study day 28.

Time frame: 28 days after randomization

ICU Free Days

The number of days spent alive out of the ICU to day 28.

Time frame: 28 days after randomization

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.

Time frame: Up to day 28

Number of Subjects With Initiation of Assisted Ventilation

Any patient who received assisted ventilation during the study hospitalization to study day 28 days meets this endpoint.

Time frame: Up to day 28

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.

Time frame: Up to day 28

Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7

SOFA score calculated 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. Missing values at day 7 assessment were carried forward to the closest known value. GSC was omitted for patients intubated/heavily sedated at either 0 or day 7 when calculating the change in score. Renal dysfunction component was omitted for patients RRT prior to presentation.Higher SOFA score=worse outcome.ASTER clinically significant organ failure:SOFA score 2 or more points higher than baseline.Total score range: 0(min)-24(max) Score:Coag(platelets x10³/µL:0:\>150;1:\</=150; 2:\</=100; 3:\</=50; 4:\</=20. Liver(bilirubin, mg/dL): 0:\<1.2; 1: 1.2-1.9; 3: 2.0-5.9; 3: 6.0-11.9; 4:\>11.9. Cardio(hypotension): 0:none; 1: MAP \<70 mmHg; 2: Dop\</=5 or dob (any dose); 3:dop\>5, epi\</=0.1, or norepi\</=0.1; 4: Dop\>15, epi\>0.1, or norepi\>0.1. Renal(Cr, mg/dL or urine output,ml/d): 0:\<1.2; 1: 1.2-1.9; 3: 2.0-3.4; 3: 3.5-4.9 or \<500; 4:\>4.9 or\<200.

Time frame: Day 0-Day 7

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.

Time frame: Up to day 90

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).

Time frame: 90 days after randomization

90-day Hospital Mortality

Vital status prior to discharge home before day 90.

Time frame: 90 days after randomization

Number of Subjects Who Developed ARDS Within 7 Days of Randomization

The presence of ARDS for each day is defined as receiving assisted ventilation with P/F \<300 or imputed P/F \<300, FiO2 ≥40%, and PEEP ≥5 cm H2O and not fully explained by CHF or fluid overload. ARDS imaging criteria are met if clinically available chest images (CT or CXR) are consistent with ARDS (bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules).

Time frame: Up to day 7

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

Time frame: Up to day 28

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

Time frame: 28 days after randomization

ICU Days to Day 28

ICU free days to day 28 are defined as the number of days spent alive and out of the ICU to day 28.

Time frame: To day 28