Acute Respiratory Distress Syndrome, Critical Illness, Respiratory Failure, Sepsis
Conditions
Keywords
ARDS, Acetaminophen, Vitamin C, Sepsis
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).
Interventions
DRUGIntravenous 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)
DRUGIntravenous Vitamin C (refrigerated)
Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)
DRUG5% Dextrose (room temperature)
Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)
DRUG5% Dextrose refrigerated
Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
Patients will be randomized to at a ratio of 2:1 active versus placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days Alive and Free of Organ Support to Day 28 | 28 days after randomization | 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-day All Cause Mortality | 28 days after randomization | 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. |
| Days Free of Assisted Ventilation to Day 28 | 28 days after randomization | The number of days alive and without assisted ventilation (midnight to midnight) in the overall cohort. No penalty for death. |
| Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort | 28 days after randomization | 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. |
| Days Free of Vasopressors to Day 28 in Overall Cohort | 28 days after randomization | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 28 Day Hospital Mortality | 28 days after randomization | All deaths occuring in the study hospital until study day 28. |
| 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. |
| 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 | 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. |
| 90-day Hospital Mortality | 90 days after randomization | Vital status prior to discharge home before day 90. |
| 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). |
| Number of Subjects Who Developed ARDS Within 7 Days of Randomization | Up to day 7 | 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). |
| 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 |
| ICU Days to Day 28 | 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. |
| 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. |
| Number of Subjects With Initiation of Assisted Ventilation | Up to day 28 | Any patient who received assisted ventilation during the study hospitalization to study day 28 days meets this endpoint. |
| Ventilator-free Days (VFD) | 28 days after randomization | 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 |
| Vasopressor-free Days | 28 days after randomization | 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. |
| Renal Replacement-free Days | 28 days after randomization | 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. |
Countries
United States
Participant flow
Pre-assignment details
There were 488 participants randomized overall. 228 to APAP, 199 to matching APAP placebo, 40 to Vit C, 21 to matching Vit C placebo. Thirty-nine patients appear in both placebo arms in our published results (these were pooled placebos). Clinical Trials.gov does not allow reporting pooled placebo patients twice in each of these two studies. Therefore, the results reported herein don't mirror our published results which were reported per protocol and as specified in our SAP.
Participants by arm
| Arm | Count |
|---|---|
| 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).
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) | 227 |
| 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). Note: This arm is now closed.
Intravenous Vitamin C (refrigerated): Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses) | 40 |
| 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).
5% Dextrose (room temperature): Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses) | 199 |
| 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). Note: This arm is now closed.
5% Dextrose refrigerated: Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses) | 21 |
| Total | 487 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | lost to follow up | 4 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | IV Acetaminophen-Active | Total | Vitamin C-Placebo | Acetaminophen-Placebo | IV Vitamin C-Active |
|---|---|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 15.9 | 63.9 years STANDARD_DEVIATION 15.5 | 67.6 years STANDARD_DEVIATION 16.4 | 63.8 years STANDARD_DEVIATION 14.7 | 62.4 years STANDARD_DEVIATION 17 |
| Age, Customized Yes | 57 Participants | 122 Participants | 8 Participants | 47 Participants | 10 Participants |
| ARDS at baseline no. (%) | 41 Participants | 81 Participants | 2 Participants | 28 Participants | 10 Participants |
| Assisted ventilation at baseline, no. (%) | 99 Participants | 202 Participants | 5 Participants | 81 Participants | 17 Participants |
| Baseline Acetaminophen no. (%) | 106 Participants | 224 Participants | 7 Participants | 84 Participants | 27 Participants |
| Baseline ALT (U/L) | 30.9 U/L STANDARD_DEVIATION 26.6 | 31.3 U/L STANDARD_DEVIATION 30.1 | 35.7 U/L STANDARD_DEVIATION 36.2 | 31.0 U/L STANDARD_DEVIATION 34.2 | 32.5 U/L STANDARD_DEVIATION 23.6 |
| Baseline AST (U/L) | 45.5 U/L STANDARD_DEVIATION 35 | 43.5 U/L STANDARD_DEVIATION 35.7 | 45.3 U/L STANDARD_DEVIATION 27.1 | 40.4 U/L STANDARD_DEVIATION 37.2 | 46.9 U/L STANDARD_DEVIATION 35.9 |
| Baseline bilirubin (mg/dL) | 0.9 mg/dL STANDARD_DEVIATION 0.9 | 0.9 mg/dL STANDARD_DEVIATION 1 | 1.1 mg/dL STANDARD_DEVIATION 2.1 | 0.9 mg/dL STANDARD_DEVIATION 1 | 0.8 mg/dL STANDARD_DEVIATION 0.5 |
| Baseline creatinine (mg/dL) | 1.6 mg/dL STANDARD_DEVIATION 1.3 | 1.6 mg/dL STANDARD_DEVIATION 1.3 | 1.4 mg/dL STANDARD_DEVIATION 1 | 1.7 mg/dL STANDARD_DEVIATION 1.3 | 1.8 mg/dL STANDARD_DEVIATION 1.6 |
| Baseline outpatient creatinine in 365 days prior to admission (mg/dL) | 1.1 mg/dL STANDARD_DEVIATION 0.8 | 1.2 mg/dL STANDARD_DEVIATION 0.9 | 0.9 mg/dL STANDARD_DEVIATION 0.5 | 1.3 mg/dL STANDARD_DEVIATION 1.1 | 1.1 mg/dL STANDARD_DEVIATION 1 |
| Baseline plasma cell-free Hemoglobin | 8.3 mg/dL | 8.6 mg/dL | 15.9 mg/dL | 8.3 mg/dL | 14.2 mg/dL |
| Baseline Plasma cell-free hemoglobin (mg/dL) | 24.1 mg/dL STANDARD_DEVIATION 60.3 | 23.9 mg/dL STANDARD_DEVIATION 60.5 | 64.9 mg/dL STANDARD_DEVIATION 167.7 | 18.9 mg/dL STANDARD_DEVIATION 40.7 | 26.6 mg/dL STANDARD_DEVIATION 31.2 |
| Baseline platelets (×1000/mm³) | 218.9 (cells*1000/mm^3) STANDARD_DEVIATION 125.9 | 219.0 (cells*1000/mm^3) STANDARD_DEVIATION 127.6 | 180.7 (cells*1000/mm^3) STANDARD_DEVIATION 107.6 | 225.3 (cells*1000/mm^3) STANDARD_DEVIATION 135.5 | 208.9 (cells*1000/mm^3) STANDARD_DEVIATION 104.2 |
| Baseline total SOFA score (no-GCS) | 5.5 Units on a scale STANDARD_DEVIATION 2.5 | 5.3 Units on a scale STANDARD_DEVIATION 2.5 | 4.8 Units on a scale STANDARD_DEVIATION 2.4 | 5.3 Units on a scale STANDARD_DEVIATION 2.5 | 5.2 Units on a scale STANDARD_DEVIATION 2.3 |
| Body Mass Index (BMI) | 29.3 kg/m^2 STANDARD_DEVIATION 10.2 | 29.5 kg/m^2 STANDARD_DEVIATION 10.7 | 27.5 kg/m^2 STANDARD_DEVIATION 7.4 | 29.1 kg/m^2 STANDARD_DEVIATION 9.6 | 33.9 kg/m^2 STANDARD_DEVIATION 17.3 |
| COVID-19 status in 3 weeks prior to admission no. (%) Negative (only negative tests with 3 weeks prior to admission) | 163 Participants | 361 Participants | 16 Participants | 154 Participants | 28 Participants |
| COVID-19 status in 3 weeks prior to admission no. (%) Positive test within 3 weeks prior to admission | 17 Participants | 45 Participants | 4 Participants | 18 Participants | 6 Participants |
| COVID-19 status in 3 weeks prior to admission no. (%) Unknown | 47 Participants | 81 Participants | 1 Participants | 27 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 62 Participants | 4 Participants | 24 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 191 Participants | 414 Participants | 16 Participants | 170 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 1 Participants | 5 Participants | 0 Participants |
| HFNO at baseline no.(%) | 33 Participants | 78 Participants | 6 Participants | 33 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 20 Participants | 0 Participants | 12 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 45 Participants | 87 Participants | 2 Participants | 30 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 8 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 44 Participants | 2 Participants | 23 Participants | 2 Participants |
| Race (NIH/OMB) White | 153 Participants | 326 Participants | 17 Participants | 131 Participants | 25 Participants |
| Region of Enrollment United States | 227 Participants | 487 Participants | 21 Participants | 199 Participants | 40 Participants |
| Screening hospital location no. (%) Emergency department | 95 Participants | 201 Participants | 8 Participants | 74 Participants | 24 Participants |
| Screening hospital location no. (%) Floor | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Screening hospital location no. (%) Intensive care unit | 128 Participants | 280 Participants | 13 Participants | 123 Participants | 16 Participants |
| Screening hospital location no. (%) Other | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants |
| Screening hospital location no. (%) stepdown/intermediate unit | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 112 Participants | 247 Participants | 12 Participants | 102 Participants | 21 Participants |
| Sex: Female, Male Male | 115 Participants | 240 Participants | 9 Participants | 97 Participants | 19 Participants |
| Site of infection no. (%) Central nervous system infection | 3 Participants | 9 Participants | 0 Participants | 4 Participants | 2 Participants |
| Site of infection no. (%) Endocarditis or endovascular infection | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Site of infection no. (%) Flu/other virus confirmed by testing | 8 Participants | 12 Participants | 0 Participants | 3 Participants | 1 Participants |
| Site of infection no. (%) Intra-abdominal infection | 24 Participants | 47 Participants | 1 Participants | 18 Participants | 4 Participants |
| Site of infection no. (%) Other source of infection | 15 Participants | 22 Participants | 0 Participants | 6 Participants | 1 Participants |
| Site of infection no. (%) Pneumonia | 100 Participants | 213 Participants | 11 Participants | 85 Participants | 17 Participants |
| Site of infection no. (%) Skin or soft-tissue infection | 17 Participants | 36 Participants | 2 Participants | 14 Participants | 3 Participants |
| Site of infection no. (%) Unknown to providers | 22 Participants | 45 Participants | 1 Participants | 20 Participants | 2 Participants |
| Site of infection no. (%) Urinary tract infection | 37 Participants | 97 Participants | 5 Participants | 47 Participants | 8 Participants |
| Site of infection no. (%) Vascular catheter-related infection | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Time from inclusion to randomization (hour), median (q1-q3) | 9.6 hours | 9.8 hours | 12.9 hours | 9.2 hours | 13.2 hours |
| Vasopressors at baseline no. (%) | 174 Participants | 370 Participants | 14 Participants | 152 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 58 / 223 | 6 / 40 | 60 / 197 | 9 / 21 |
| other Total, other adverse events | 12 / 227 | 2 / 40 | 7 / 199 | 2 / 21 |
| serious Total, serious adverse events | 20 / 227 | 4 / 40 | 18 / 199 | 4 / 21 |
Outcome results
Primary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | 28-day All Cause Mortality | 39 Participants |
| IV Vitamin C-Active | 28-day All Cause Mortality | 6 Participants |
| Acetaminophen-Placebo | 28-day All Cause Mortality | 43 Participants |
| Vitamin C-Placebo | 28-day All Cause Mortality | 6 Participants |
p-value: 0.2695% CI: [-12, 3.3]Chi-squared
p-value: 0.3195% CI: [-35.8, 8.7]Fisher Exact
Primary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Days Alive and Free of Organ Support to Day 28 | 20.2 days | Standard Deviation 10.6 |
| IV Vitamin C-Active | Days Alive and Free of Organ Support to Day 28 | 20.5 days | Standard Deviation 9.5 |
| Acetaminophen-Placebo | Days Alive and Free of Organ Support to Day 28 | 19.7 days | Standard Deviation 10.5 |
| Vitamin C-Placebo | Days Alive and Free of Organ Support to Day 28 | 18.4 days | Standard Deviation 11.7 |
p-value: 0.6595% CI: [-1.6, 2.5]t-test, 2 sided
p-value: 0.46495% CI: [-3.5, 7.6]t-test, 2 sided
Primary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Days Free of Assisted Ventilation to Day 28 | 21.5 days | Standard Deviation 10.2 |
| IV Vitamin C-Active | Days Free of Assisted Ventilation to Day 28 | 21.6 days | Standard Deviation 9.4 |
| Acetaminophen-Placebo | Days Free of Assisted Ventilation to Day 28 | 20.6 days | Standard Deviation 10.5 |
| Vitamin C-Placebo | Days Free of Assisted Ventilation to Day 28 | 19.5 days | Standard Deviation 11.7 |
p-value: 0.3595% CI: [-1, 2.9]t-test, 2 sided
p-value: 0.4595% CI: [-3.4, 7.6]t-test, 2 sided
Primary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort | 23.7 days | Standard Deviation 9 |
| IV Vitamin C-Active | Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort | 24.8 days | Standard Deviation 7.8 |
| Acetaminophen-Placebo | Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort | 23.9 days | Standard Deviation 8.4 |
| Vitamin C-Placebo | Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort | 20.8 days | Standard Deviation 10.9 |
p-value: 0.8395% CI: [-1.9, 1.5]t-test, 2 sided
p-value: 0.195% CI: [-0.8, 8.9]t-test, 2 sided
Primary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Days Free of Vasopressors to Day 28 in Overall Cohort | 22.2 days | Standard Deviation 9.4 |
| IV Vitamin C-Active | Days Free of Vasopressors to Day 28 in Overall Cohort | 22.6 days | Standard Deviation 8.6 |
| Acetaminophen-Placebo | Days Free of Vasopressors to Day 28 in Overall Cohort | 23.9 days | Standard Deviation 8.4 |
| Vitamin C-Placebo | Days Free of Vasopressors to Day 28 in Overall Cohort | 19.1 days | Standard Deviation 11.3 |
p-value: 0.5595% CI: [-1.2, 2.4]t-test, 2 sided
p-value: 0.1895% CI: [-1.6, 8.7]t-test, 2 sided
Secondary
28 Day Hospital Mortality
All deaths occuring in the study hospital until study day 28.
Time frame: 28 days after randomization
Population: Data needed to determine this outcome was missing in 3 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | 28 Day Hospital Mortality | 37 Participants |
| IV Vitamin C-Active | 28 Day Hospital Mortality | 6 Participants |
| Acetaminophen-Placebo | 28 Day Hospital Mortality | 41 Participants |
| Vitamin C-Placebo | 28 Day Hospital Mortality | 6 Participants |
p-value: 0.2695% CI: [-11.8, 3.2]Chi-squared
p-value: 0.3195% CI: [-35.8, 8.7]Fisher Exact
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).
Time frame: 90 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | 90-day All-cause Mortality | 58 Participants |
| IV Vitamin C-Active | 90-day All-cause Mortality | 6 Participants |
| Acetaminophen-Placebo | 90-day All-cause Mortality | 60 Participants |
| Vitamin C-Placebo | 90-day All-cause Mortality | 9 Participants |
p-value: 0.3195% CI: [-13.1, 4.2]Chi-squared
p-value: 0.0295% CI: [-51.7, -4]Chi-squared
Secondary
90-day Hospital Mortality
Vital status prior to discharge home before day 90.
Time frame: 90 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | 90-day Hospital Mortality | 50 Participants |
| IV Vitamin C-Active | 90-day Hospital Mortality | 6 Participants |
| Acetaminophen-Placebo | 90-day Hospital Mortality | 45 Participants |
| Vitamin C-Placebo | 90-day Hospital Mortality | 9 Participants |
p-value: 0.995% CI: [-8.5, 7.5]Chi-squared
p-value: 0.0295% CI: [-51.7, -4]Chi-squared
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7 | -3.2 score on a scale | Standard Deviation 3.3 |
| IV Vitamin C-Active | Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7 | -2.2 score on a scale | Standard Deviation 4.6 |
| Acetaminophen-Placebo | Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7 | -3.0 score on a scale | Standard Deviation 3.2 |
| Vitamin C-Placebo | Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7 | -2.1 score on a scale | Standard Deviation 2.1 |
p-value: 0.795% CI: [-0.9, 0.6]t-test, 2 sided
p-value: 0.9695% CI: [-2.7, 2.5]t-test, 2 sided
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
Time frame: Up to day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Change in Serum Creatinine Concentration | -0.3 mg/dL | Standard Deviation 1 |
| IV Vitamin C-Active | Change in Serum Creatinine Concentration | -0.2 mg/dL | Standard Deviation 1.2 |
| Acetaminophen-Placebo | Change in Serum Creatinine Concentration | -0.2 mg/dL | Standard Deviation 1 |
| Vitamin C-Placebo | Change in Serum Creatinine Concentration | -0.1 mg/dL | Standard Deviation 0.3 |
p-value: 0.6895% CI: [-0.2, 0.2]t-test, 2 sided
p-value: 0.6295% CI: [-0.7, 0.4]Fisher Exact
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.
Time frame: Up to day 28
Population: Data needed to determine this outcome was missing in 3 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Hospital Free Days to Discharge Home | 11.3 days | Standard Deviation 10.9 |
| IV Vitamin C-Active | Hospital Free Days to Discharge Home | 11.5 days | Standard Deviation 10 |
| Acetaminophen-Placebo | Hospital Free Days to Discharge Home | 11.5 days | Standard Deviation 10.8 |
| Vitamin C-Placebo | Hospital Free Days to Discharge Home | 7.0 days | Standard Deviation 10.4 |
p-value: 0.8495% CI: [-2.3, 1.9]t-test, 2 sided
p-value: 0.195% CI: [-0.9, 10]t-test, 2 sided
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | ICU Days to Day 28 | 5.3 days | Standard Deviation 6.2 |
| IV Vitamin C-Active | ICU Days to Day 28 | 6.9 days | Standard Deviation 6.9 |
| Acetaminophen-Placebo | ICU Days to Day 28 | 5.2 days | Standard Deviation 6.2 |
| Vitamin C-Placebo | ICU Days to Day 28 | 3.8 days | Standard Deviation 6.2 |
p-value: 0.8895% CI: [-1.1, 1.3]t-test, 2 sided
p-value: 0.195% CI: [-0.6, 6.6]t-test, 2 sided
Secondary
ICU Free Days
The number of days spent alive out of the ICU to day 28.
Time frame: 28 days after randomization
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | ICU Free Days | 19.3 days | Standard Deviation 9.9 |
| IV Vitamin C-Active | ICU Free Days | 18.7 days | Standard Deviation 9.7 |
| Acetaminophen-Placebo | ICU Free Days | 19.1 days | Standard Deviation 10 |
| Vitamin C-Placebo | ICU Free Days | 17.9 days | Standard Deviation 12 |
p-value: 0.7695% CI: [-1.6, 2.2]t-test, 2 sided
p-value: 0.7895% CI: [-4.9, 6.5]t-test, 2 sided
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | Number of Subjects Who Developed ARDS Within 7 Days of Randomization | 4 Participants |
| IV Vitamin C-Active | Number of Subjects Who Developed ARDS Within 7 Days of Randomization | 2 Participants |
| Acetaminophen-Placebo | Number of Subjects Who Developed ARDS Within 7 Days of Randomization | 16 Participants |
| Vitamin C-Placebo | Number of Subjects Who Developed ARDS Within 7 Days of Randomization | 0 Participants |
p-value: 0.00395% CI: [-12.2, -2.4]Chi-squared
p-value: 0.5295% CI: [-2.3, 15.6]Fisher Exact
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | Number of Subjects With Initiation of Assisted Ventilation | 21 Participants |
| IV Vitamin C-Active | Number of Subjects With Initiation of Assisted Ventilation | 4 Participants |
| Acetaminophen-Placebo | Number of Subjects With Initiation of Assisted Ventilation | 21 Participants |
| Vitamin C-Placebo | Number of Subjects With Initiation of Assisted Ventilation | 2 Participants |
p-value: 0.7995% CI: [-10.9, 8.3]Chi-squared
p-value: 195% CI: [-17.5, 27.3]Fisher Exact
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.
Time frame: Up to day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | Number of Subjects With Initiation of Renal Replacement Therapy | 22 Participants |
| IV Vitamin C-Active | Number of Subjects With Initiation of Renal Replacement Therapy | 3 Participants |
| Acetaminophen-Placebo | Number of Subjects With Initiation of Renal Replacement Therapy | 16 Participants |
| Vitamin C-Placebo | Number of Subjects With Initiation of Renal Replacement Therapy | 2 Participants |
p-value: 0.5395% CI: [-3.7, 7.2]Chi-squared
p-value: 195% CI: [-17, 13]Fisher Exact
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
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28) | 55 Participants |
| IV Vitamin C-Active | Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28) | 9 Participants |
| Acetaminophen-Placebo | Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28) | 48 Participants |
| Vitamin C-Placebo | Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28) | 8 Participants |
p-value: 0.995% CI: [-7.8, 8.8]Chi-squared
p-value: 0.295% CI: [-40.1, 8.9]Chi-squared
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.
Time frame: Up to day 90
Population: Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Acetaminophen-Active | Renal Calculi to Day 90 | 0 Participants |
| IV Vitamin C-Active | Renal Calculi to Day 90 | 1 Participants |
| Acetaminophen-Placebo | Renal Calculi to Day 90 | 0 Participants |
| Vitamin C-Placebo | Renal Calculi to Day 90 | 0 Participants |
p-value: 195% CI: [-2.3, 7.3]Fisher Exact
Secondary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Renal Replacement-free Days | 22.4 days | Standard Deviation 11 |
| IV Vitamin C-Active | Renal Replacement-free Days | 23.7 days | Standard Deviation 10.1 |
| Acetaminophen-Placebo | Renal Replacement-free Days | 21.8 days | Standard Deviation 11.6 |
| Vitamin C-Placebo | Renal Replacement-free Days | 19.1 days | Standard Deviation 12.8 |
p-value: 0.5895% CI: [-1.6, 2.8]t-test, 2 sided
p-value: 0.1395% CI: [-1.4, 10.5]t-test, 2 sided
Secondary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Vasopressor-free Days | 21.4 days | Standard Deviation 10.4 |
| IV Vitamin C-Active | Vasopressor-free Days | 21.8 days | Standard Deviation 10 |
| Acetaminophen-Placebo | Vasopressor-free Days | 20.2 days | Standard Deviation 11.3 |
| Vitamin C-Placebo | Vasopressor-free Days | 18.2 days | Standard Deviation 12.3 |
p-value: 0.2395% CI: [-0.8, 3.4]t-test, 2 sided
p-value: 0.2295% CI: [-2.2, 9.4]t-test, 2 sided
Secondary
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
Population: Data needed to determine this outcome was missing in 4 patients in the Acetaminophen active arm and 2 patients in the Acetaminophen placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Acetaminophen-Active | Ventilator-free Days (VFD) | 20.9 days | Standard Deviation 11 |
| IV Vitamin C-Active | Ventilator-free Days (VFD) | 21.3 days | Standard Deviation 10.1 |
| Acetaminophen-Placebo | Ventilator-free Days (VFD) | 19.5 days | Standard Deviation 11.8 |
| Vitamin C-Placebo | Ventilator-free Days (VFD) | 18.8 days | Standard Deviation 12.7 |
p-value: 0.2195% CI: [-0.8, 3.6]t-test, 2 sided
p-value: 0.495% CI: [-3.4, 8.5]t-test, 2 sided