Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery (ASTER)

Mass General Brigham

Status and phase: Completed; Phase 2

Conditions: Respiratory Failure; Critical Illness; Acute Respiratory Distress Syndrome; Sepsis

Treatments: Drug: 5% Dextrose refrigerated; Drug: Intravenous Acetaminophen (room temperature); Drug: Intravenous Vitamin C (refrigerated); Drug: 5% Dextrose (room temperature)

Study type: Interventional

Funder types: Other

Identifiers

NCT04291508

PETAL04ASTER

Details and patient eligibility

About

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.

Full 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).

Enrollment: 488 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

488 participants in 4 patient groups, including a placebo group

IV Acetaminophen-Active

Active Comparator group

Description:

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).

Treatment:

Drug: Intravenous Acetaminophen (room temperature)

IV Vitamin C-Active

Active Comparator group

Description:

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.

Treatment:

Drug: Intravenous Vitamin C (refrigerated)

Acetaminophen-Placebo

Placebo Comparator group

Description:

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).

Treatment:

Drug: 5% Dextrose (room temperature)

Vitamin C-Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: 5% Dextrose refrigerated