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.
Brief Title
Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
Detailed Description
Hypothesis 1A: Acetaminophen (APAP) or Vitamin C infusion will increase the days alive and free of organ support to day 28.
Hypothesis 1B: APAP or Vitamin C will have a favorable effect on other secondary outcomes including pulmonary and non-pulmonary organ dysfunction and biomarkers of inflammation and endothelial injury
The investigators plan to carry out two multi-center phase 2b randomized double-blinded placebo-controlled trials of two different pharmacologic therapies within a single platform trial.
1. One trial will assess the efficacy of Acetaminophen (1 gram intravenously every 6 hours) for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.
2. A second trial will assess the efficacy of Vitamin C (50 mg/kg every 6 hours) infused intravenously for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.
A total of 900 participants who meet all of the inclusion criteria and none of the exclusion criteria, were planned be randomized in a 2:1:2:1 fashion (APAP-Active: APAP-Placebo: Vit C-Active: Vit C-Placebo). The APAP and Vitamin C trials were planned to be resulted separately. With the closure of the Vitamin C arm in June 2022; the study proceeded with the APAP and Placebo arms with a 1:1 randomization scheme. The total sample size for the APAP trial was 447 participants (227 in the active arm and 220 in the placebo arm). The total sample size for the Vitamin C trial was 79 (40 in the active arm and 39 in the placebo arm). The total combined number in the 4 arms of the ASTER trial was 526 (227 APAP active, 220 APAP placebo, 40 Vit C active, 39 Vit C placebo), although a total of only 487 patients were actually randomized (this is due to the 39 pooled placebo patients that appear in both trials).
Hypothesis 1B: APAP or Vitamin C will have a favorable effect on other secondary outcomes including pulmonary and non-pulmonary organ dysfunction and biomarkers of inflammation and endothelial injury
The investigators plan to carry out two multi-center phase 2b randomized double-blinded placebo-controlled trials of two different pharmacologic therapies within a single platform trial.
1. One trial will assess the efficacy of Acetaminophen (1 gram intravenously every 6 hours) for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.
2. A second trial will assess the efficacy of Vitamin C (50 mg/kg every 6 hours) infused intravenously for 120 hours in patients with sepsis who have evidence of either hemodynamic or respiratory organ failure.
A total of 900 participants who meet all of the inclusion criteria and none of the exclusion criteria, were planned be randomized in a 2:1:2:1 fashion (APAP-Active: APAP-Placebo: Vit C-Active: Vit C-Placebo). The APAP and Vitamin C trials were planned to be resulted separately. With the closure of the Vitamin C arm in June 2022; the study proceeded with the APAP and Placebo arms with a 1:1 randomization scheme. The total sample size for the APAP trial was 447 participants (227 in the active arm and 220 in the placebo arm). The total sample size for the Vitamin C trial was 79 (40 in the active arm and 39 in the placebo arm). The total combined number in the 4 arms of the ASTER trial was 526 (227 APAP active, 220 APAP placebo, 40 Vit C active, 39 Vit C placebo), although a total of only 487 patients were actually randomized (this is due to the 39 pooled placebo patients that appear in both trials).
Categories
Completion Date
Completion Date Type
Actual
Conditions
Acute Respiratory Distress Syndrome
Critical Illness
Respiratory Failure
Sepsis
Eligibility Criteria
Inclusion Criteria:
1. Age ≥ 18 years
2. Sepsis defined as:
1. Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND
2. Hypotension as defined by the need for any vasopressor (and 1 liter of fluid already administered intravenously for resuscitation) OR respiratory failure defined by mechanical ventilation, BIPAP or CPAP at any level, or greater than or equal to 6 liters/minute of supplemental oxygen (criterion b must be met at time of enrollment)
3. Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital
Exclusion Criteria:
1. No consent/inability to obtain consent from the participant or a legally authorized representative
2. Patient unable to be randomized within 36 hours of presentation to the ED or within 36 hours of presentation to any acute care hospital
3. Diagnosis of cirrhosis by medical chart review
4. Liver transplant recipient
5. AST or ALT greater than five times upper limit of normal
6. Diagnosis of ongoing chronic alcohol use disorder/abuse by chart review; if medical record unclear, use Appendix F
7. Clinical diagnosis of diabetic ketoacidosis or other condition such as profound hypoglycemia that requires hourly blood glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
8. Hypersensitivity to Acetaminophen or Vitamin C
9. Patient, surrogate or physician not committed to full support (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)
10. Home assisted ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing
11. Chronic dialysis
12. Current active kidney stone (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
13. Multiple (\>1) episodes of prior kidney stones, known history of oxalate kidney stones, or history of oxalate nephropathy. (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
14. Kidney transplant recipient (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
15. Use of home oxygen \>3L/minute via nasal cannula for chronic cardiopulmonary disease
16. Moribund patient not expected to survive 24 hours
17. Underlying malignancy or other condition with estimated life expectancy of less than 1 month
18. Pregnant woman, woman of childbearing potential without a documented negative urine or serum pregnancy test during the current hospitalization, or woman who is breast feeding
19. Prisoner
20. Treating team unwilling to enroll because of intended use of Acetaminophen or Vitamin C
21. Treating team unwilling to use plasma (as opposed to point of care testing) for glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial).
1. Age ≥ 18 years
2. Sepsis defined as:
1. Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND
2. Hypotension as defined by the need for any vasopressor (and 1 liter of fluid already administered intravenously for resuscitation) OR respiratory failure defined by mechanical ventilation, BIPAP or CPAP at any level, or greater than or equal to 6 liters/minute of supplemental oxygen (criterion b must be met at time of enrollment)
3. Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital
Exclusion Criteria:
1. No consent/inability to obtain consent from the participant or a legally authorized representative
2. Patient unable to be randomized within 36 hours of presentation to the ED or within 36 hours of presentation to any acute care hospital
3. Diagnosis of cirrhosis by medical chart review
4. Liver transplant recipient
5. AST or ALT greater than five times upper limit of normal
6. Diagnosis of ongoing chronic alcohol use disorder/abuse by chart review; if medical record unclear, use Appendix F
7. Clinical diagnosis of diabetic ketoacidosis or other condition such as profound hypoglycemia that requires hourly blood glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
8. Hypersensitivity to Acetaminophen or Vitamin C
9. Patient, surrogate or physician not committed to full support (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)
10. Home assisted ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing
11. Chronic dialysis
12. Current active kidney stone (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
13. Multiple (\>1) episodes of prior kidney stones, known history of oxalate kidney stones, or history of oxalate nephropathy. (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
14. Kidney transplant recipient (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial)
15. Use of home oxygen \>3L/minute via nasal cannula for chronic cardiopulmonary disease
16. Moribund patient not expected to survive 24 hours
17. Underlying malignancy or other condition with estimated life expectancy of less than 1 month
18. Pregnant woman, woman of childbearing potential without a documented negative urine or serum pregnancy test during the current hospitalization, or woman who is breast feeding
19. Prisoner
20. Treating team unwilling to enroll because of intended use of Acetaminophen or Vitamin C
21. Treating team unwilling to use plasma (as opposed to point of care testing) for glucose monitoring (applicable to the 4 arm (Vitamin C/placebo vs. Acetaminophen/placebo) phase of the trial).
Inclusion Criteria
Inclusion Criteria:
1. Age ≥ 18 years
2. Sepsis defined as:
1. Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND
2. Hypotension as defined by the need for any vasopressor (and 1 liter of fluid already administered intravenously for resuscitation) OR respiratory failure defined by mechanical ventilation, BIPAP or CPAP at any level, or greater than or equal to 6 liters/minute of supplemental oxygen (criterion b must be met at time of enrollment)
3. Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital
1. Age ≥ 18 years
2. Sepsis defined as:
1. Clinical evidence of a known or suspected infection and orders written to administer antibiotics AND
2. Hypotension as defined by the need for any vasopressor (and 1 liter of fluid already administered intravenously for resuscitation) OR respiratory failure defined by mechanical ventilation, BIPAP or CPAP at any level, or greater than or equal to 6 liters/minute of supplemental oxygen (criterion b must be met at time of enrollment)
3. Admitted to a study site ICU (or intent for the patient to be admitted to a study site ICU) within 36 hours of presentation to the ED or admitted to the study site ICU within 36 hours of presentation to any acute care hospital
Gender
All
Gender Based
false
Keywords
ARDS
Acetaminophen
Vitamin C
Sepsis
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04291508
Org Class
Other
Org Full Name
Massachusetts General Hospital
Org Study Id
PETAL04ASTER
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
Primary Outcomes
Outcome Description
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.
Outcome Measure
Days Alive and Free of Organ Support to Day 28
Outcome Time Frame
28 days after randomization
Outcome Description
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 Measure
28-day All Cause Mortality
Outcome Time Frame
28 days after randomization
Outcome Description
The number of days alive and without assisted ventilation (midnight to midnight) in the overall cohort. No penalty for death.
Outcome Measure
Days Free of Assisted Ventilation to Day 28
Outcome Time Frame
28 days after randomization
Outcome Description
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 Measure
Days Free of Renal Replacement Therapy to Day 28 in Overall Cohort
Outcome Time Frame
28 days after randomization
Outcome Description
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 Measure
Days Free of Vasopressors to Day 28 in Overall Cohort
Outcome Time Frame
28 days after randomization
Secondary Outcomes
Outcome Description
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 Time Frame
28 days after randomization
Outcome Measure
Ventilator-free Days (VFD)
Outcome Description
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 Time Frame
28 days after randomization
Outcome Measure
Vasopressor-free Days
Outcome Description
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 Time Frame
28 days after randomization
Outcome Measure
Renal Replacement-free Days
Outcome Description
All deaths occuring in the study hospital until study day 28.
Outcome Time Frame
28 days after randomization
Outcome Measure
28 Day Hospital Mortality
Outcome Description
The number of days spent alive out of the ICU to day 28.
Outcome Time Frame
28 days after randomization
Outcome Measure
ICU Free Days
Outcome Description
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 Time Frame
Up to day 28
Outcome Measure
Hospital Free Days to Discharge Home
Outcome Description
Any patient who received assisted ventilation during the study hospitalization to study day 28 days meets this endpoint.
Outcome Time Frame
Up to day 28
Outcome Measure
Number of Subjects With Initiation of Assisted Ventilation
Outcome Description
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 Time Frame
Up to day 28
Outcome Measure
Number of Subjects With Initiation of Renal Replacement Therapy
Outcome Description
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 Time Frame
Day 0-Day 7
Outcome Measure
Change in Organ-specific Sepsis-related Organ Failure Assessment (SOFA) Scores Between Enrollment and Study Day 7
Outcome Description
Renal calculi diagnosed between randomization and study day 90 in patients in the Vitamin C-Active/Vitamin C-Placebo group.
Outcome Time Frame
Up to day 90
Outcome Measure
Renal Calculi to Day 90
Outcome Description
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 Time Frame
90 days after randomization
Outcome Measure
90-day All-cause Mortality
Outcome Description
Vital status prior to discharge home before day 90.
Outcome Time Frame
90 days after randomization
Outcome Measure
90-day Hospital Mortality
Outcome Description
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 Time Frame
Up to day 7
Outcome Measure
Number of Subjects Who Developed ARDS Within 7 Days of Randomization
Outcome Description
We will measure the change in serum creatinine from enrollment to discharge, death, initiation of dialysis or 28 days, whichever occurs first
Outcome Time Frame
Up to day 28
Outcome Measure
Change in Serum Creatinine Concentration
Outcome Description
Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death
Outcome Time Frame
28 days after randomization
Outcome Measure
Number of Subjects With Major Adverse Kidney Events at 28 Days (MAKE28)
Outcome Description
ICU free days to day 28 are defined as the number of days spent alive and out of the ICU to day 28.
Outcome Time Frame
To day 28
Outcome Measure
ICU Days to Day 28
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Michelle Gong
Investigator Email
mgong@montefiore.org
Investigator Phone
718-920-5464
Categories Mesh Debug
Lung & Chest Cancers --- LUNG DISEASES
COVID-19 --- LUNG DISEASES
Lung --- LUNG DISEASES
Asthma and Other Respiratory Diseases --- RESPIRATORY TRACT DISEASES
Lung & Chest Cancers --- RESPIRATORY TRACT DISEASES
COVID-19 --- RESPIRATORY TRACT DISEASES
Lung --- RESPIRATORY TRACT DISEASES
COVID-19 --- INFECTIONS
Infectious Disease --- INFECTIONS
Diabetes & Endocrine System --- INFLAMMATION
MeSH Terms
RESPIRATORY DISTRESS SYNDROME
CRITICAL ILLNESS
RESPIRATORY INSUFFICIENCY
SEPSIS
LUNG DISEASES
RESPIRATORY TRACT DISEASES
RESPIRATION DISORDERS
DISEASE ATTRIBUTES
PATHOLOGIC PROCESSES
PATHOLOGICAL CONDITIONS, SIGNS AND SYMPTOMS
INFECTIONS
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
INFLAMMATION
GLUCOSE
HEXOSES
MONOSACCHARIDES
SUGARS
CARBOHYDRATES