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

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ClinicalTrials.gov Identifier: NCT04291508
Recruitment Status : Not yet recruiting
First Posted : March 2, 2020
Last Update Posted : March 12, 2020
Sponsor:
Information provided by (Responsible Party):
Boyd Taylor Thompson, 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.

Condition or disease Intervention/treatment Phase
Acute Respiratory Distress Syndrome Critical Illness Respiratory Failure Sepsis Drug: Intravenous Acetaminophen (room temperature) Drug: Intravenous Vitamin C (refrigerated) Drug: 5% Dextrose (room temperature) Drug: 5% Dextrose refrigerated Phase 2

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.

For efficiency, both the Acetaminophen and the Vitamin C groups will use a shared placebo control group. All arms will have the same inclusion and exclusion criteria. All efficacy comparisons will use a pooled placebo group. All safety comparisons will use matching placebo group.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomized to at a ratio of 2:1 active versus placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Vitamin C or Vitamin C-placebo will be refrigerated. Acetaminophen or acetaminophen-placebo will be stored at room temperature and the volume will be reduced for patients less than 50 kg. Investigators will be informed of which of the two placebo controlled groups the patient was randomized to.
Primary Purpose: Treatment
Official Title: Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery
Estimated Study Start Date : May 1, 2020
Estimated Primary Completion Date : May 30, 2021
Estimated Study Completion Date : May 30, 2021


Arm Intervention/treatment
Active Comparator: 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).
Drug: 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)

Active Comparator: 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)
Drug: Intravenous Vitamin C (refrigerated)
Vitamin C given intravenously at the dose of 50 mg/kg every six hours for 5 days (20 doses)
Other Name: Ascor

Placebo Comparator: 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).
Drug: 5% Dextrose (room temperature)
Placebo (identical appearing room temperature 5% dextrose solution) infused every six hours for 5 days (20 doses)

Placebo Comparator: Vitamin C-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).
Drug: 5% Dextrose refrigerated
Placebo (identical appearing refrigerated 5% dextrose solution) infused every six hours for 5 days (20 doses)




Primary Outcome Measures :
  1. Days alive and free of organ support to day 28 [ Time Frame: 28 days after randomization ]
    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.


Secondary Outcome Measures :
  1. Ventilator-free days (VFD) [ Time Frame: 28 days after randomization ]
    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.

  2. Vasopressor-free days [ Time Frame: 28 days after randomization ]
    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.

  3. Renal replacement-free days [ Time Frame: 28 days after randomization ]
    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.

  4. 28-day hospital mortality [ Time Frame: 28 days after randomization ]

    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.


  5. ICU free days [ Time Frame: 28 days after randomization ]
    The number of days spent alive out of the ICU to day 28.

  6. Hospital free days to discharge home [ Time Frame: 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.

  7. Days in ICU among survivors and non-survivors [ Time Frame: Up to day 28 ]
    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

  8. Number of subjects with initiation of assisted ventilation [ Time Frame: Up to day 28 ]
    Any patient who received assisted ventilation during the study hospitalization in the first 28 days meets this endpoint.

  9. Number of subjects with initiation of renal replacement therapy [ Time Frame: 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.

  10. Change in organ-specific Sepsis-related Organ Failure Assessment (SOFA) scores between enrollment and study day 7 [ Time Frame: Day 0-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

  11. 90-day hospital mortality [ Time Frame: 90 days after randomization ]
    Vital status prior to discharge home before day 90.

  12. Number of subjects who developed ARDS [ Time Frame: Up to day 7 ]
    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.

  13. Change in serum creatinine concentration [ Time Frame: 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

  14. Number of subjects with Major Adverse Kidney Events at 28 days (MAKE28) [ Time Frame: 28 days after randomization ]
    Defined as persistent increase in serum creatinine by 200% from baseline, need for new renal replacement therapy, or death

  15. Change in Radiographic Assessment of Lung Edema (RALE) score [ Time Frame: Up to 72 hours after randomization ]
    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

  16. 90-day all-cause mortality [ Time Frame: 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).

  17. Number of subjects with renal stones to day 90 [ Time Frame: Up to day 90 ]
    Incident of renal (kidney) stones determined by chart review at the end of hospitalization and by self-report at day 90 phone call in those discharged from the hospital prior to day 90.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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) OR respiratory failure defined by assisted ventilation (includes mechanical ventilation and BIPAP), CPAP, 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 an order written from the ED 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
  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. Current active kidney stone
  12. Known history of oxalate kidney stones or history of oxalate nephropathy
  13. Kidney transplant recipient
  14. Use of home oxygen for chronic cardiopulmonary disease
  15. Moribund patient not expected to survive 24 hours
  16. Underlying malignancy or other condition with estimated life expectancy of less than 1 month
  17. 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
  18. Prisoner
  19. Enrollment in another critical care based pharmacologic interventional trial
  20. Treating team unwilling to enroll because of intended use of Acetaminophen or Vitamin C

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04291508


Contacts
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Contact: Katie Oldmixon, RN 617-726-4777 coldmixon@mgh.harvard.edu
Contact: Nancy Ringwood, BSN 617-724-9836 nringwood@mgh.harvard.edu

Locations
Show Show 44 study locations
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
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Principal Investigator: Boyd Taylor Thompson, MD Massachusetts General Hospital
Additional Information:
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Responsible Party: Boyd Taylor Thompson, PETAL CCC Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04291508    
Other Study ID Numbers: PETAL04ASTER
First Posted: March 2, 2020    Key Record Dates
Last Update Posted: March 12, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Boyd Taylor Thompson, Massachusetts General Hospital:
ARDS
Acetaminophen
Vitamin C
Sepsis
Additional relevant MeSH terms:
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Sepsis
Toxemia
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Respiratory Insufficiency
Acute Lung Injury
Critical Illness
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Disease Attributes
Lung Injury
Acetaminophen
Ascorbic Acid
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antipyretics