Trial Outcomes & Findings for Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery (NCT NCT04291508)

Last Updated: 2024-09-27

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

488 participants

Primary outcome timeframe

28 days after randomization

Results posted on

2024-09-27

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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)	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)	Acetaminophen-Placebo Patients randomized to APAP matching placebo (initially 2:1, subsequently 1:1 after the Vitamin C arm stopped) 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).	Vitamin C-Placebo Patients randomized to matching Vitamin C placebo (2:1) 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)
Overall Study STARTED	228	40	199	21
Overall Study COMPLETED	223	40	197	21
Overall Study NOT COMPLETED	5	0	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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)	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)	Acetaminophen-Placebo Patients randomized to APAP matching placebo (initially 2:1, subsequently 1:1 after the Vitamin C arm stopped) 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).	Vitamin C-Placebo Patients randomized to matching Vitamin C placebo (2:1) 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)
Overall Study Withdrawal by Subject	1	0	1	0
Overall Study lost to follow up	4	0	1	0

Baseline Characteristics

Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IV Acetaminophen-Active n=227 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=199 Participants 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)	Vitamin C-Placebo n=21 Participants 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)	Total n=487 Participants Total of all reporting groups
Age, Continuous	63.9 years STANDARD_DEVIATION 15.9 • n=227 Participants • Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	62.4 years STANDARD_DEVIATION 17.0 • n=40 Participants • Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	63.8 years STANDARD_DEVIATION 14.7 • n=198 Participants • Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	67.6 years STANDARD_DEVIATION 16.4 • n=21 Participants • Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	63.9 years STANDARD_DEVIATION 15.5 • n=486 Participants • Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.
Age, Customized Yes	57 Participants n=227 Participants • Measure Analysis Population Description: Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	10 Participants n=40 Participants • Measure Analysis Population Description: Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	47 Participants n=198 Participants • Measure Analysis Population Description: Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	8 Participants n=21 Participants • Measure Analysis Population Description: Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.	122 Participants n=486 Participants • Measure Analysis Population Description: Data for age missing for one patient in the APAP placebo arm; as a result the Total column reflects 486 patients total.
Sex: Female, Male Female	112 Participants n=227 Participants	21 Participants n=40 Participants	102 Participants n=199 Participants	12 Participants n=21 Participants	247 Participants n=487 Participants
Sex: Female, Male Male	115 Participants n=227 Participants	19 Participants n=40 Participants	97 Participants n=199 Participants	9 Participants n=21 Participants	240 Participants n=487 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	31 Participants n=227 Participants	3 Participants n=40 Participants	24 Participants n=199 Participants	4 Participants n=21 Participants	62 Participants n=487 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	191 Participants n=227 Participants	37 Participants n=40 Participants	170 Participants n=199 Participants	16 Participants n=21 Participants	414 Participants n=487 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=227 Participants	0 Participants n=40 Participants	5 Participants n=199 Participants	1 Participants n=21 Participants	11 Participants n=487 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=227 Participants	0 Participants n=40 Participants	0 Participants n=199 Participants	0 Participants n=21 Participants	2 Participants n=487 Participants
Race (NIH/OMB) Asian	6 Participants n=227 Participants	2 Participants n=40 Participants	12 Participants n=199 Participants	0 Participants n=21 Participants	20 Participants n=487 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	4 Participants n=227 Participants	1 Participants n=40 Participants	3 Participants n=199 Participants	0 Participants n=21 Participants	8 Participants n=487 Participants
Race (NIH/OMB) Black or African American	45 Participants n=227 Participants	10 Participants n=40 Participants	30 Participants n=199 Participants	2 Participants n=21 Participants	87 Participants n=487 Participants
Race (NIH/OMB) White	153 Participants n=227 Participants	25 Participants n=40 Participants	131 Participants n=199 Participants	17 Participants n=21 Participants	326 Participants n=487 Participants
Race (NIH/OMB) More than one race	0 Participants n=227 Participants	0 Participants n=40 Participants	0 Participants n=199 Participants	0 Participants n=21 Participants	0 Participants n=487 Participants
Race (NIH/OMB) Unknown or Not Reported	17 Participants n=227 Participants	2 Participants n=40 Participants	23 Participants n=199 Participants	2 Participants n=21 Participants	44 Participants n=487 Participants
Region of Enrollment United States	227 Participants n=227 Participants	40 Participants n=40 Participants	199 Participants n=199 Participants	21 Participants n=21 Participants	487 Participants n=487 Participants
Baseline total SOFA score (no-GCS)	5.5 Units on a scale STANDARD_DEVIATION 2.5 • n=227 Participants	5.2 Units on a scale STANDARD_DEVIATION 2.3 • n=40 Participants	5.3 Units on a scale STANDARD_DEVIATION 2.5 • n=199 Participants	4.8 Units on a scale STANDARD_DEVIATION 2.4 • n=21 Participants	5.3 Units on a scale STANDARD_DEVIATION 2.5 • n=487 Participants
Body Mass Index (BMI)	29.3 kg/m^2 STANDARD_DEVIATION 10.2 • n=227 Participants • BMI is missing in one patient in the APAP placebo arm resulting in only 198 patients with this baseline variable; as a result the Total column reflects 486 patients total.	33.9 kg/m^2 STANDARD_DEVIATION 17.3 • n=40 Participants • BMI is missing in one patient in the APAP placebo arm resulting in only 198 patients with this baseline variable; as a result the Total column reflects 486 patients total.	29.1 kg/m^2 STANDARD_DEVIATION 9.6 • n=198 Participants • BMI is missing in one patient in the APAP placebo arm resulting in only 198 patients with this baseline variable; as a result the Total column reflects 486 patients total.	27.5 kg/m^2 STANDARD_DEVIATION 7.4 • n=21 Participants • BMI is missing in one patient in the APAP placebo arm resulting in only 198 patients with this baseline variable; as a result the Total column reflects 486 patients total.	29.5 kg/m^2 STANDARD_DEVIATION 10.7 • n=486 Participants • BMI is missing in one patient in the APAP placebo arm resulting in only 198 patients with this baseline variable; as a result the Total column reflects 486 patients total.
Vasopressors at baseline no. (%)	174 Participants n=227 Participants	30 Participants n=40 Participants	152 Participants n=199 Participants	14 Participants n=21 Participants	370 Participants n=487 Participants
Assisted ventilation at baseline, no. (%)	99 Participants n=226 Participants • Baseline assisted ventilation data missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	17 Participants n=40 Participants • Baseline assisted ventilation data missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	81 Participants n=198 Participants • Baseline assisted ventilation data missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	5 Participants n=21 Participants • Baseline assisted ventilation data missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	202 Participants n=485 Participants • Baseline assisted ventilation data missing for one patient in the APAP active arm and one patient in the APAP placebo arm.
HFNO at baseline no.(%)	33 Participants n=226 Participants • Data for baseline HFNO missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	6 Participants n=40 Participants • Data for baseline HFNO missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	33 Participants n=198 Participants • Data for baseline HFNO missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	6 Participants n=21 Participants • Data for baseline HFNO missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	78 Participants n=485 Participants • Data for baseline HFNO missing for one patient in the APAP active arm and one patient in the APAP placebo arm.
ARDS at baseline no. (%)	41 Participants n=226 Participants • Data for baseline ARDS missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	10 Participants n=40 Participants • Data for baseline ARDS missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	28 Participants n=198 Participants • Data for baseline ARDS missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	2 Participants n=21 Participants • Data for baseline ARDS missing for one patient in the APAP active arm and one patient in the APAP placebo arm.	81 Participants n=485 Participants • Data for baseline ARDS missing for one patient in the APAP active arm and one patient in the APAP placebo arm.
Time from inclusion to randomization (hour), median (q1-q3)	9.6 hours n=224 Participants • Data missing on time to randomization for 3 patients in the APAP active arm and 5 patients in the APAP placebo arm; as a result the Total column reflects 479 patients total.	13.2 hours n=40 Participants • Data missing on time to randomization for 3 patients in the APAP active arm and 5 patients in the APAP placebo arm; as a result the Total column reflects 479 patients total.	9.2 hours n=194 Participants • Data missing on time to randomization for 3 patients in the APAP active arm and 5 patients in the APAP placebo arm; as a result the Total column reflects 479 patients total.	12.9 hours n=21 Participants • Data missing on time to randomization for 3 patients in the APAP active arm and 5 patients in the APAP placebo arm; as a result the Total column reflects 479 patients total.	9.8 hours n=479 Participants • Data missing on time to randomization for 3 patients in the APAP active arm and 5 patients in the APAP placebo arm; as a result the Total column reflects 479 patients total.
Screening hospital location no. (%) Intensive care unit	128 Participants n=227 Participants	16 Participants n=40 Participants	123 Participants n=199 Participants	13 Participants n=21 Participants	280 Participants n=487 Participants
Screening hospital location no. (%) Emergency department	95 Participants n=227 Participants	24 Participants n=40 Participants	74 Participants n=199 Participants	8 Participants n=21 Participants	201 Participants n=487 Participants
Screening hospital location no. (%) Floor	2 Participants n=227 Participants	0 Participants n=40 Participants	0 Participants n=199 Participants	0 Participants n=21 Participants	2 Participants n=487 Participants
Screening hospital location no. (%) Other	2 Participants n=227 Participants	0 Participants n=40 Participants	1 Participants n=199 Participants	0 Participants n=21 Participants	3 Participants n=487 Participants
Screening hospital location no. (%) stepdown/intermediate unit	0 Participants n=227 Participants	0 Participants n=40 Participants	1 Participants n=199 Participants	0 Participants n=21 Participants	1 Participants n=487 Participants
Site of infection no. (%) Pneumonia	100 Participants n=227 Participants	17 Participants n=40 Participants	85 Participants n=199 Participants	11 Participants n=21 Participants	213 Participants n=487 Participants
Site of infection no. (%) Urinary tract infection	37 Participants n=227 Participants	8 Participants n=40 Participants	47 Participants n=199 Participants	5 Participants n=21 Participants	97 Participants n=487 Participants
Site of infection no. (%) Intra-abdominal infection	24 Participants n=227 Participants	4 Participants n=40 Participants	18 Participants n=199 Participants	1 Participants n=21 Participants	47 Participants n=487 Participants
Site of infection no. (%) Skin or soft-tissue infection	17 Participants n=227 Participants	3 Participants n=40 Participants	14 Participants n=199 Participants	2 Participants n=21 Participants	36 Participants n=487 Participants
Site of infection no. (%) Flu/other virus confirmed by testing	8 Participants n=227 Participants	1 Participants n=40 Participants	3 Participants n=199 Participants	0 Participants n=21 Participants	12 Participants n=487 Participants
Site of infection no. (%) Central nervous system infection	3 Participants n=227 Participants	2 Participants n=40 Participants	4 Participants n=199 Participants	0 Participants n=21 Participants	9 Participants n=487 Participants
Site of infection no. (%) Endocarditis or endovascular infection	1 Participants n=227 Participants	1 Participants n=40 Participants	1 Participants n=199 Participants	0 Participants n=21 Participants	3 Participants n=487 Participants
Site of infection no. (%) Vascular catheter-related infection	0 Participants n=227 Participants	1 Participants n=40 Participants	1 Participants n=199 Participants	1 Participants n=21 Participants	3 Participants n=487 Participants
Site of infection no. (%) Other source of infection	15 Participants n=227 Participants	1 Participants n=40 Participants	6 Participants n=199 Participants	0 Participants n=21 Participants	22 Participants n=487 Participants
Site of infection no. (%) Unknown to providers	22 Participants n=227 Participants	2 Participants n=40 Participants	20 Participants n=199 Participants	1 Participants n=21 Participants	45 Participants n=487 Participants
COVID-19 status in 3 weeks prior to admission no. (%) Positive test within 3 weeks prior to admission	17 Participants n=227 Participants	6 Participants n=40 Participants	18 Participants n=199 Participants	4 Participants n=21 Participants	45 Participants n=487 Participants
COVID-19 status in 3 weeks prior to admission no. (%) Negative (only negative tests with 3 weeks prior to admission)	163 Participants n=227 Participants	28 Participants n=40 Participants	154 Participants n=199 Participants	16 Participants n=21 Participants	361 Participants n=487 Participants
COVID-19 status in 3 weeks prior to admission no. (%) Unknown	47 Participants n=227 Participants	6 Participants n=40 Participants	27 Participants n=199 Participants	1 Participants n=21 Participants	81 Participants n=487 Participants
Baseline creatinine (mg/dL)	1.6 mg/dL STANDARD_DEVIATION 1.3 • n=227 Participants	1.8 mg/dL STANDARD_DEVIATION 1.6 • n=40 Participants	1.7 mg/dL STANDARD_DEVIATION 1.3 • n=199 Participants	1.4 mg/dL STANDARD_DEVIATION 1.0 • n=21 Participants	1.6 mg/dL STANDARD_DEVIATION 1.3 • n=487 Participants
Baseline outpatient creatinine in 365 days prior to admission (mg/dL)	1.1 mg/dL STANDARD_DEVIATION 0.8 • n=164 Participants • Numbers in analyzed rows differs from overall because baseline outpatient creatinine was not available for all randomized patients; as a result the Total column reflects 368 patients total.	1.1 mg/dL STANDARD_DEVIATION 1.0 • n=29 Participants • Numbers in analyzed rows differs from overall because baseline outpatient creatinine was not available for all randomized patients; as a result the Total column reflects 368 patients total.	1.3 mg/dL STANDARD_DEVIATION 1.1 • n=157 Participants • Numbers in analyzed rows differs from overall because baseline outpatient creatinine was not available for all randomized patients; as a result the Total column reflects 368 patients total.	0.9 mg/dL STANDARD_DEVIATION 0.5 • n=18 Participants • Numbers in analyzed rows differs from overall because baseline outpatient creatinine was not available for all randomized patients; as a result the Total column reflects 368 patients total.	1.2 mg/dL STANDARD_DEVIATION 0.9 • n=368 Participants • Numbers in analyzed rows differs from overall because baseline outpatient creatinine was not available for all randomized patients; as a result the Total column reflects 368 patients total.
Baseline AST (U/L)	45.5 U/L STANDARD_DEVIATION 35.0 • n=227 Participants	46.9 U/L STANDARD_DEVIATION 35.9 • n=40 Participants	40.4 U/L STANDARD_DEVIATION 37.2 • n=199 Participants	45.3 U/L STANDARD_DEVIATION 27.1 • n=21 Participants	43.5 U/L STANDARD_DEVIATION 35.7 • n=487 Participants
Baseline ALT (U/L)	30.9 U/L STANDARD_DEVIATION 26.6 • n=227 Participants	32.5 U/L STANDARD_DEVIATION 23.6 • n=40 Participants	31.0 U/L STANDARD_DEVIATION 34.2 • n=199 Participants	35.7 U/L STANDARD_DEVIATION 36.2 • n=21 Participants	31.3 U/L STANDARD_DEVIATION 30.1 • n=487 Participants
Baseline bilirubin (mg/dL)	0.9 mg/dL STANDARD_DEVIATION 0.9 • n=225 Participants • Number analyzed in row differs from overall because we collected clinically available bilirubin and bilirubin values were not available for all randomized patients; as a result the Total column reflects 483 patients total.	0.8 mg/dL STANDARD_DEVIATION 0.5 • n=40 Participants • Number analyzed in row differs from overall because we collected clinically available bilirubin and bilirubin values were not available for all randomized patients; as a result the Total column reflects 483 patients total.	0.9 mg/dL STANDARD_DEVIATION 1.0 • n=197 Participants • Number analyzed in row differs from overall because we collected clinically available bilirubin and bilirubin values were not available for all randomized patients; as a result the Total column reflects 483 patients total.	1.1 mg/dL STANDARD_DEVIATION 2.1 • n=21 Participants • Number analyzed in row differs from overall because we collected clinically available bilirubin and bilirubin values were not available for all randomized patients; as a result the Total column reflects 483 patients total.	0.9 mg/dL STANDARD_DEVIATION 1.0 • n=483 Participants • Number analyzed in row differs from overall because we collected clinically available bilirubin and bilirubin values were not available for all randomized patients; as a result the Total column reflects 483 patients total.
Baseline platelets (×1000/mm³)	218.9 (cells*1000/mm^3) STANDARD_DEVIATION 125.9 • n=226 Participants • Baseline platelets was not available for one patient in the APAP active arm resulting in only 226 patients analyzed in that column; as a result the Total column reflects 486 patients total.	208.9 (cells*1000/mm^3) STANDARD_DEVIATION 104.2 • n=40 Participants • Baseline platelets was not available for one patient in the APAP active arm resulting in only 226 patients analyzed in that column; as a result the Total column reflects 486 patients total.	225.3 (cells*1000/mm^3) STANDARD_DEVIATION 135.5 • n=199 Participants • Baseline platelets was not available for one patient in the APAP active arm resulting in only 226 patients analyzed in that column; as a result the Total column reflects 486 patients total.	180.7 (cells*1000/mm^3) STANDARD_DEVIATION 107.6 • n=21 Participants • Baseline platelets was not available for one patient in the APAP active arm resulting in only 226 patients analyzed in that column; as a result the Total column reflects 486 patients total.	219.0 (cells*1000/mm^3) STANDARD_DEVIATION 127.6 • n=486 Participants • Baseline platelets was not available for one patient in the APAP active arm resulting in only 226 patients analyzed in that column; as a result the Total column reflects 486 patients total.
Baseline Plasma cell-free hemoglobin (mg/dL)	24.1 mg/dL STANDARD_DEVIATION 60.3 • n=218 Participants • Baseline Plasma cell-free hemoglobin was missing in 7 APAP active patients and 8 APAP placebo patients resulting in numbers analyzed being different from overall; as a result the Total column reflects 469 patients total.	26.6 mg/dL STANDARD_DEVIATION 31.2 • n=39 Participants • Baseline Plasma cell-free hemoglobin was missing in 7 APAP active patients and 8 APAP placebo patients resulting in numbers analyzed being different from overall; as a result the Total column reflects 469 patients total.	18.9 mg/dL STANDARD_DEVIATION 40.7 • n=192 Participants • Baseline Plasma cell-free hemoglobin was missing in 7 APAP active patients and 8 APAP placebo patients resulting in numbers analyzed being different from overall; as a result the Total column reflects 469 patients total.	64.9 mg/dL STANDARD_DEVIATION 167.7 • n=20 Participants • Baseline Plasma cell-free hemoglobin was missing in 7 APAP active patients and 8 APAP placebo patients resulting in numbers analyzed being different from overall; as a result the Total column reflects 469 patients total.	23.9 mg/dL STANDARD_DEVIATION 60.5 • n=469 Participants • Baseline Plasma cell-free hemoglobin was missing in 7 APAP active patients and 8 APAP placebo patients resulting in numbers analyzed being different from overall; as a result the Total column reflects 469 patients total.
Baseline Acetaminophen no. (%)	106 Participants n=227 Participants	27 Participants n=40 Participants	84 Participants n=199 Participants	7 Participants n=21 Participants	224 Participants n=487 Participants
Baseline plasma cell-free Hemoglobin	8.3 mg/dL n=218 Participants • Data was not available for all patients for this baseline variable. As a result the Total column reflects 469 patients total.	14.2 mg/dL n=39 Participants • Data was not available for all patients for this baseline variable. As a result the Total column reflects 469 patients total.	8.3 mg/dL n=192 Participants • Data was not available for all patients for this baseline variable. As a result the Total column reflects 469 patients total.	15.9 mg/dL n=20 Participants • Data was not available for all patients for this baseline variable. As a result the Total column reflects 469 patients total.	8.6 mg/dL n=469 Participants • Data was not available for all patients for this baseline variable. As a result the Total column reflects 469 patients total.

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Days Alive and Free of Organ Support to Day 28	20.2 days Standard Deviation 10.6	20.5 days Standard Deviation 9.5	19.7 days Standard Deviation 10.5	18.4 days Standard Deviation 11.7

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
28-day All Cause Mortality	39 Participants	6 Participants	43 Participants	6 Participants

PRIMARY outcome

Timeframe: 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.

The number of days alive and without assisted ventilation (midnight to midnight) in the overall cohort. No penalty for death.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Days Free of Assisted Ventilation to Day 28	21.5 days Standard Deviation 10.2	21.6 days Standard Deviation 9.4	20.6 days Standard Deviation 10.5	19.5 days Standard Deviation 11.7

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort	23.7 days Standard Deviation 9.0	24.8 days Standard Deviation 7.8	23.9 days Standard Deviation 8.4	20.8 days Standard Deviation 10.9

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Days Free of Vasopressors to Day 28 in Overall Cohort	22.2 days Standard Deviation 9.4	22.6 days Standard Deviation 8.6	23.9 days Standard Deviation 8.4	19.1 days Standard Deviation 11.3

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Ventilator-free Days (VFD)	20.9 days Standard Deviation 11.0	21.3 days Standard Deviation 10.1	19.5 days Standard Deviation 11.8	18.8 days Standard Deviation 12.7

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Vasopressor-free Days	21.4 days Standard Deviation 10.4	21.8 days Standard Deviation 10.0	20.2 days Standard Deviation 11.3	18.2 days Standard Deviation 12.3

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Renal Replacement-free Days	22.4 days Standard Deviation 11.0	23.7 days Standard Deviation 10.1	21.8 days Standard Deviation 11.6	19.1 days Standard Deviation 12.8

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=224 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
28 Day Hospital Mortality	37 Participants	6 Participants	41 Participants	6 Participants

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
ICU Free Days	19.3 days Standard Deviation 9.9	18.7 days Standard Deviation 9.7	19.1 days Standard Deviation 10.0	17.9 days Standard Deviation 12.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=196 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Hospital Free Days to Discharge Home	11.3 days Standard Deviation 10.9	11.5 days Standard Deviation 10.0	11.5 days Standard Deviation 10.8	7.0 days Standard Deviation 10.4

SECONDARY outcome

Timeframe: Up to day 28

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

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=125 Participants 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)	IV Vitamin C-Active n=23 Participants 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)	Acetaminophen-Placebo n=116 Participants 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)	Vitamin C-Placebo n=16 Participants 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)
Number of Subjects With Initiation of Assisted Ventilation	21 Participants	4 Participants	21 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Number of Subjects With Initiation of Renal Replacement Therapy	22 Participants	3 Participants	16 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=148 Participants 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)	IV Vitamin C-Active n=28 Participants 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)	Acetaminophen-Placebo n=139 Participants 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)	Vitamin C-Placebo n=14 Participants 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)
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	-2.2 score on a scale Standard Deviation 4.6	-3.0 score on a scale Standard Deviation 3.2	-2.1 score on a scale Standard Deviation 2.1

SECONDARY outcome

Timeframe: 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.

Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group.

Outcome measures

Outcome measures
Measure	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)	IV Vitamin C-Active n=40 Participants 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)	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)	Vitamin C-Placebo n=21 Participants 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)
Renal Calculi to Day 90	0 Participants	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=223 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
90-day All-cause Mortality	58 Participants	6 Participants	60 Participants	9 Participants

SECONDARY outcome

Timeframe: 90 days after randomization

Vital status prior to discharge home before day 90.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=224 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
90-day Hospital Mortality	50 Participants	6 Participants	45 Participants	9 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=183 Participants 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)	IV Vitamin C-Active n=30 Participants 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)	Acetaminophen-Placebo n=169 Participants 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)	Vitamin C-Placebo n=19 Participants 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)
Number of Subjects Who Developed ARDS Within 7 Days of Randomization	4 Participants	2 Participants	16 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=198 Participants 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)	IV Vitamin C-Active n=37 Participants 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)	Acetaminophen-Placebo n=181 Participants 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)	Vitamin C-Placebo n=19 Participants 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)
Change in Serum Creatinine Concentration	-0.3 mg/dL Standard Deviation 1.0	-0.2 mg/dL Standard Deviation 1.2	-0.2 mg/dL Standard Deviation 1.0	-0.1 mg/dL Standard Deviation 0.3

SECONDARY outcome

Timeframe: 28 days after randomization

Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=221 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=197 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28)	55 Participants	9 Participants	48 Participants	8 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	IV Acetaminophen-Active n=222 Participants 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)	IV Vitamin C-Active n=40 Participants 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)	Acetaminophen-Placebo n=196 Participants 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)	Vitamin C-Placebo n=21 Participants 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)
ICU Days to Day 28	5.3 days Standard Deviation 6.2	6.9 days Standard Deviation 6.9	5.2 days Standard Deviation 6.2	3.8 days Standard Deviation 6.2

Adverse Events

IV Acetaminophen-Active

Serious events: 20 serious events

Other events: 12 other events

Deaths: 58 deaths

IV Vitamin C-Active

Serious events: 4 serious events

Other events: 2 other events

Deaths: 6 deaths

Acetaminophen-Placebo

Serious events: 18 serious events

Other events: 7 other events

Deaths: 60 deaths

Vitamin C-Placebo

Serious events: 4 serious events

Other events: 2 other events

Deaths: 9 deaths

Serious adverse events

Other adverse events

Additional Information

PETAL Network Coordinatine Center PI, B. Taylor Thompson, MD

Massachsetts General Hospital

Phone: 617 872-2882

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place