Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
- Conditions
- Critical IllnessAcute Respiratory Distress SyndromeRespiratory FailureSepsis
- Interventions
- Drug: 5% Dextrose (room temperature)Drug: 5% Dextrose refrigeratedDrug: Intravenous Vitamin C (refrigerated)
- Registration Number
- NCT04291508
- Lead Sponsor
- Massachusetts General Hospital
- 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 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 488
-
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
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Acetaminophen-Placebo 5% Dextrose (room temperature) 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). Vitamin C-Placebo 5% Dextrose refrigerated 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. IV Acetaminophen-Active Intravenous Acetaminophen (room temperature) 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). IV Vitamin C-Active Intravenous Vitamin C (refrigerated) 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
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 Assisted Ventilation Up to day 28 Any patient who received assisted ventilation during the study hospitalization to study day 28 days meets this endpoint.
Number of Subjects With Initiation of Renal Replacement Therapy Up to day 28 Patients who receive (new) renal replacement therapy through day 28 will meet this endpoint. Patients with chronic renal replacement therapy initiated prior to the current sepsis illness will not be eligible to meet this endpoint.
Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7 Day 0-Day 7 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.
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.
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).
90-day Hospital Mortality 90 days after randomization Vital status prior to discharge home before day 90.
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.
Trial Locations
- Locations (41)
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University of Texas Health Science Center
🇺🇸Houston, Texas, United States
Hennepin County Medical Center
🇺🇸Minneapolis, Minnesota, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
University of Utah Hospital
🇺🇸Salt Lake City, Utah, United States
University Medical Center
🇺🇸New Orleans, Louisiana, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
University of Arizona
🇺🇸Tucson, Arizona, United States
Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
UPMC Presbyterian/Mercy/Shadyside/Magee
🇺🇸Pittsburgh, Pennsylvania, United States
Mt. Sinai Hospital
🇺🇸New York, New York, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Wake Forest Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
VCU Medical Center
🇺🇸Richmond, Virginia, United States
Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Montefiore Medical Center-Moses
🇺🇸Bronx, New York, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Maine Medical Center
🇺🇸Portland, Maine, United States
Harborview Medical Center
🇺🇸Seattle, Washington, United States
Swedish Hospital First Hill
🇺🇸Seattle, Washington, United States
Baystate Medical Center
🇺🇸Springfield, Massachusetts, United States
University of Michigan Medical Center
🇺🇸Ann Arbor, Michigan, United States
Henry Ford Medical Center
🇺🇸Detroit, Michigan, United States
Fairview Southdale Hospital
🇺🇸Edina, Minnesota, United States
Montefiore Medical Center-Weiler
🇺🇸Bronx, New York, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Sentara/EVMS
🇺🇸Norfolk, Virginia, United States
University of Alabama Medical Center
🇺🇸Birmingham, Alabama, United States
UCSF Fresno
🇺🇸Fresno, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Ronald Reagan UCLA Medical Center
🇺🇸Los Angeles, California, United States
UC Davis Medical Center
🇺🇸Sacramento, California, United States
UCSF Medical Center
🇺🇸San Francisco, California, United States
Stanford University
🇺🇸Stanford, California, United States
Denver Health Medical Center
🇺🇸Denver, Colorado, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States