Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

Study Overview
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Brief Summary
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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
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Hypothesis 1A: Acetaminophen (APAP) or Vitamin C infusion will increase the days alive and free of organ support to day 28. Hypothesis 1B: APAP or Vitamin C will have a favorable effect on other secondary outcomes including pulmonary and non-pulmonary organ dysfunction and biomarkers of inflammation and endothelial injury The investigators plan to carry out two multi-center phase 2b randomized double-blinded placebo-controlled trials of two different pharmacologic therapies within a single platform trial. One trial will assess the efficacy of Acetaminophen (1 gram intravenously every 6 hours) for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure. A second trial will assess the efficacy of Vitamin C (50 mg/kg every 6 hours) infused intravenously for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure. A total of 900 participants who meet all of the inclusion criteria and none of the exclusion criteria will be randomized in a 2:1:2:1 fashion (APAP-Active: APAP-Placebo: Vit C-Active: Vit C-Placebo). With the closure of the Vitamin C arm in June 2022; the study is proceeding with the APAP and Placebo arms with a 1:1 randomization scheme. The total sample size is 450 participants (225 in the active arm and 225 in the placebo arm).

Official Title
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Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery

Conditions
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Acute Respiratory Distress Syndrome, Critical Illness, Respiratory Failure, Sepsis

Intervention / Treatment
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* Drug: Intravenous Acetaminophen (room temperature)
* Drug: Intravenous Vitamin C (refrigerated)
* Drug: 5% Dextrose (room temperature)
* Drug: 5% Dextrose refrigerated


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Sepsis defined as: Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND Hypotension as defined by the need for any vasopressor (and 1 liter of fluid already administered intravenously for resuscitation) OR respiratory failure defined by mechanical ventilation, BIPAP or CPAP at any level, or greater than or equal to 6 liters/minute of supplemental oxygen (criterion b must be met at time of enrollment) Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital Exclusion Criteria: No consent/inability to obtain consent from the participant or a legally authorized representative Patient unable to be randomized within 36 hours of presentation to the ED or within 36 hours of presentation to any acute care hospital Diagnosis of cirrhosis by medical chart review Liver transplant recipient AST or ALT greater than five times upper limit of normal Diagnosis of ongoing chronic alcohol use disorder/abuse by chart review; if medical record unclear, use Appendix F Clinical diagnosis of diabetic ketoacidosis or other condition such as profound hypoglycemia that requires hourly blood glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial) Hypersensitivity to Acetaminophen or Vitamin C Patient, surrogate or physician not committed to full support (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest) Home assisted ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing Chronic dialysis Current active kidney stone (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial) 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) Kidney transplant recipient (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial) Use of home oxygen >3L/minute via nasal cannula for chronic cardiopulmonary disease Moribund patient not expected to survive 24 hours Underlying malignancy or other condition with estimated life expectancy of less than 1 month Pregnant woman, woman of childbearing potential without a documented negative urine or serum pregnancy test during the current hospitalization, or woman who is breast feeding Prisoner Treating team unwilling to enroll because of intended use of Acetaminophen or Vitamin C Treating team unwilling to use plasma (as opposed to point of care testing) for glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized to at a ratio of 2:1 active versus placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IV Acetaminophen-Active<br>Patients randomized to the Acetaminophen arm will receive Acetaminophen at the dose of 1 gram (or 15 mg/kg if actual body weight < 50kg) in 100 ml 5% dextrose in water every 6 hours intravenously for 5 days (20 doses). | Drug: Intravenous Acetaminophen (room temperature)<br>* 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)<br>|
| Active Comparator: IV Vitamin C-Active<br>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. | Drug: Intravenous Vitamin C (refrigerated)<br>* Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)<br>* Other names: Ascor;|
| Placebo Comparator: Acetaminophen-Placebo<br>Patients randomized to placebo will receive an identical-appearing intravenous infusion of 100 ml of 5% dextrose in water every 6 hours for 5 days (20 doses). | Drug: 5% Dextrose (room temperature)<br>* Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)<br>|
| Placebo Comparator: Vitamin C-Placebo<br>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. | Drug: 5% Dextrose refrigerated<br>* Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive and free of organ support to day 28 | Defined as alive and free of organ support (dialysis, assisted ventilation, and vasopressors) to day 28. Participants will need to be free of all three components (assisted ventilation, vasopressors, new renal replacement therapy) to qualify for a day alive and free from organ failures. Patients on chronic dialysis will not be scored for the new renal failure free component of this outcome. | 28 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free days (VFD) | Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. | 28 days after randomization | 
| Vasopressor-free days | The number of calendar days between randomization and 28 days later that the patient is alive and without the use of vasopressor therapy. Patients who die prior to day 28 are assigned zero vasopressor free days. | 28 days after randomization | 
| Renal replacement-free days | The number of calendar days between randomization and 28 days later that the patient is alive and without new renal replacement therapy. Patients who died prior to day 28 are assigned zero renal replacement free days. | 28 days after randomization | 
| 28-day hospital mortality | Vital status prior to discharge home before day 28. Home is defined as a patient's place of residence prior to enrollment. Thus, if a patient is discharged to a location that is different from the place of residence prior to enrollment (e.g. rehabilitation facility or hospice) then the patient will be followed until they return to their original location, 90 days, or death, whichever comes first. | 28 days after randomization | 
| ICU free days | The number of days spent alive out of the ICU to day 28. | 28 days after randomization | 
| Hospital free days to discharge home | Defined as 28 days minus the number of days from randomization to discharge home. If a patient has not been discharged home prior to study day 28 or dies prior to day 28, hospital free days will be zero. Patients transferred to another hospital or other health care facility will be followed to day 28 to assess this endpoint. | Up to day 28 | 
| Days in ICU among survivors and non-survivors | The total number of days spent in the ICU until hospital discharge or death during the first 28 days. If a patient is discharged alive from the study hospital we assume they are no longer in the ICU | Up to day 28 | 
| Number of subjects with initiation of assisted ventilation | Any patient who received assisted ventilation during the study hospitalization in the first 28 days meets this endpoint. | Up to day 28 | 
| Number of subjects with initiation of renal replacement therapy | Patients who receive (new) renal replacement therapy through day 28 will meet this endpoint. Patients with chronic renal replacement therapy initiated prior to the current sepsis illness will not be eligible to meet this endpoint. | Up to day 28 | 
| Change in organ-specific Sepsis-related Organ Failure Assessment (SOFA) scores between enrollment and study day 7 | We will calculate the SOFA score upon enrollment and at day 7 using clinically available data. If a value is not available at baseline, it will be assumed to be normal. At the day 7 assessment, if a value is missing then we will carry forward the closest previously known value. If a patient is intubated or heavily sedated at either 0 or day 7, the GCS will be omitted when calculating the change in score. If a patient was on renal replacement therapy prior to presentation, then the renal dysfunction component to the SOFA score will be omitted as well | Day 0-Day 7 | 
| 90-day hospital mortality | Vital status prior to discharge home before day 90. | 90 days after randomization | 
| Number of subjects who developed ARDS | Presence and severity of ARDS is determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and confirmation of ARDS through chest x-ray reviews. | Up to day 7 | 
| Change in serum creatinine concentration | We will measure the change in serum creatinine from enrollment to discharge, death, initiation of dialysis or 28 days, whichever occurs first | Up to day 28 | 
| Number of subjects with Major Adverse Kidney Events at 28 days (MAKE28) | Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death | 28 days after randomization | 
| Change in Radiographic Assessment of Lung Edema (RALE) score | We will determine the change in Radiographic Assessment of Lung Edema (RALE) score from enrollment to 72 hours in patients who are receiving assisted ventilation or high flow nasal oxygen at the time of study randomization | Up to 72 hours after randomization | 
| 90-day all-cause mortality | Vital status of the patient at day 90 will be determined using any of the following methods: medical record review, phone calls to patient, proxy or healthcare facility, review of obituaries, or information from the Centers for Disease Control and Prevention's National Death Index (NDI). | 90 days after randomization | 
| Renal calculi to day 90 | Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group. | Up to day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, Acetaminophen, Vitamin C, Sepsis