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Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS)

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ClinicalTrials.gov Identifier: NCT03434028
Recruitment Status : Recruiting
First Posted : February 15, 2018
Last Update Posted : May 28, 2018
Sponsor:
Information provided by (Responsible Party):
David Alan Schoenfeld, Massachusetts General Hospital

Brief Summary:
Multicenter, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for patients with sepsis-induced hypotension. The aim of the study is to determine the impact of a restrictive fluids strategy (vasopressors first followed by rescue fluids) as compared to a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with sepsis-induced hypotension.

Condition or disease Intervention/treatment Phase
Septic Shock Drug: Early Vasopressors Drug: Early Fluids Phase 3

Detailed Description:

Primary Hypothesis: Restrictive (vs liberal) fluid treatment strategy during the first 24 hours of resuscitation for sepsis-induced hypotension will reduce 90-day in-hospital mortality.

  1. We will emphasize early screening and protocol initiation, and enroll a maximum of 2320 patients with suspected sepsis-induced hypotension.

    • All patients will receive at least 1 liter of fluids prior to meeting study inclusion criteria (and no more than 3 liters prior to randomization).
    • Patients will be enrolled within 4 hours of meeting study inclusion criteria
    • Any type of isotonic crystalloid (normal saline, ringers lactate, or a balanced solution such as plasmalyte) is permitted.
  2. Restrictive Fluids (Early Vasopressors) Group

    • Norepinephrine will be used as preferred vasopressor and titrated to achieve mean arterial pressure (MAP) between 65 mmHg and 75 mmHg
    • "Rescue fluids" may be administered as 500ml boluses if predefined rescue criteria are met
  3. Liberal Fluids (Fluids First) Group

    • Additional 2 liter intravenous fluid bolus upon enrollment
    • Administer 500ml fluid boluses for fluid triggers until 5 liters administered or development of clinical signs of acute volume overload develop
    • "Rescue vasopressors" may be administered after 5 liters of fluid, for development of acute volume overload, or if other predefined rescue criteria are met

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
Actual Study Start Date : March 7, 2018
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
Restrictive Fluids
The general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used.
Drug: Early Vasopressors
Norepinephrine will be used as preferred vasopressor and titrated to achieve mean arterial pressure (MAP) between 65 mmHg and 75 mmHg. "Rescue fluids" may be administered as 500ml boluses if predefined rescue criteria are met.

Liberal Fluids
The general approach is to use fluid boluses to treat hypotension.
Drug: Early Fluids
Additional 2 liter intravenous fluid bolus upon enrollment. Administer 500ml fluid boluses for fluid triggers until 5 liters administered or development of clinical signs of acute volume overload develop. "Rescue vasopressors" may be administered after 5 liters of fluid, for development of acute volume overload, or if other predefined rescue criteria are met. Any type of isotonic crystalloid (normal saline, ringers lactate, balanced solution such as plasmalyte) is permitted.




Primary Outcome Measures :
  1. All-cause mortality prior to discharge home [ 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).


Secondary Outcome Measures :
  1. Organ support free days [ Time Frame: 28 days after randomization ]
    Defined as a patient being alive and without assisted breathing, new renal replacement therapy, or vasopressors (excluding vasopressor use prior to 48 hours). Any day that a patient is alive and without organ support will represent days alive and free of organ support.

  2. 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.

  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 renal replacement therapy. Patients who died prior to day 28 are assigned zero renal replacement free days.

  4. Vasopressor free days [ Time Frame: 28 days after randomization ]
    The number of calendar days between day 2 (eligibility starting 48 hours post randomization) and 26 days later that the patient is alive and without the use of vasopressor therapy. Patients who died prior to day 28 are assigned zero vasopressor free days.

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

  6. Hospital free days to discharge home [ Time Frame: 28 days after randomization ]
    Days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.

  7. Initiation of mechanical ventilation [ Time Frame: 28 days after randomization ]
    Patients who receive invasive mechanical ventilation via endotracheal or tracheostomy tube, except those intubated solely for a procedure and extubated within 24 hours, through to study day 28 meet this endpoint. Non-invasive mechanical ventilation will not be included as an outcome. This is a binary outcome.

  8. Initiation of renal replacement therapy [ Time Frame: 28 days after randomization ]
    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.

  9. Change in creatinine-based KDIGO stage [ Time Frame: 72 hours after randomization ]
    Renal function will be assessed using the KDIGO staging system (serum creatinine criteria only; not urine output) between baseline and 72 hours to assess for de novo acute kidney injury (AKI) (e.g., meeting criteria for AKI by KDIGO criteria) or worsening AKI (e.g., increasing severity). Patients on chronic renal replacement therapy will not be eligible for this endpoint determination.

  10. Change in SOFA score [ Time Frame: 72 hours after randomization ]
    We will calculate the SOFA score upon enrollment and at 72 hours using clinically available data. If a value is not available at baseline, it will be assumed to be normal. At the 72 hours assessment, if a value is missing then we will carry forward the closet previously known value. If a patient is intubated or heavily sedated at either 0 or 72 hours, 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. Development of ARDS [ Time Frame: 7 days after randomization ]
    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.

  12. New onset atrial or ventricular arrhythmia [ Time Frame: 28 days after randomization ]
    The occurrence of one or more episodes (sustained for more than 1 minute for SVT and AF, > 15 seconds for VT) during through day 28 will be recorded.



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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:

  • Age ≥ 18 years
  • A suspected or confirmed infection (broadly defined by administration or planned administration of antibiotics)
  • Sepsis-induced hypotension defined as systolic blood pressure < 100 mmHg or MAP < 65 mmHg after a minimum of at least 1 liter of fluid (*Fluids inclusive of pre-hospital fluids; blood pressure must be below any known or reported pre-morbid baseline).

Exclusion Criteria:

  • More than 4 hours elapsed since meeting inclusion criteria or 24 hours elapsed since admission to the hospital
  • Patient already received 3 liters of intravenous fluid (includes prehospital volumes)
  • Unable to obtain informed consent
  • Known pregnancy
  • Hypotension suspected to be due to non-sepsis cause (e.g. hemorrhagic shock)
  • Blood pressure is at known or reported baseline level
  • Severe Volume Depletion from an acute condition other than sepsis. In the judgment of the treating physician, the patient has an acute condition other than sepsis causing (or indicative) of *severe volume depletion; Examples include: Diabetic ketoacidosis, high volume vomiting or diarrhea, hyperosmolar hyperglycemic state, and nonexertional hyperthermia (heat stroke); severe is defined by the need for substantial intravenous fluid administration as part of routine clinical care
  • Pulmonary edema or clinical signs of new fluid overload (e.g. bilateral crackles, new oxygen requirement, new peripheral edema, fluid overload on chest x-ray)
  • Treating physician unwilling to give additional fluids as directed by the liberal protocol
  • Treating physician unwilling to use vasopressors as directed by the restrictive protocol.
  • Current or imminent decision to withhold most/all life-sustaining treatment; this does not exclude those patients committed to full support except cardiopulmonary resuscitation
  • Immediate surgical intervention planned such that study procedures could not be followed
  • Prior enrollment in this study

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): NCT03434028


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

  Hide Study Locations
Locations
United States, California
UCSF Fresno Recruiting
Fresno, California, United States, 93701
Ronald Reagan UCLA Recruiting
Los Angeles, California, United States, 90095
UCSF San Francisco Recruiting
San Francisco, California, United States, 94143
Stanford University Hospital Not yet recruiting
Stanford, California, United States, 94305
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Denver Health Medical Center Recruiting
Denver, Colorado, United States, 80204
St. Joseph Hospital Not yet recruiting
Denver, Colorado, United States, 80218
United States, Illinois
Northwestern University Not yet recruiting
Evanston, Illinois, United States, 60208
United States, Indiana
Indiana University Health Methodist Hospital Recruiting
Indianapolis, Indiana, United States, 46202
United States, Kentucky
University of Kentucky Not yet recruiting
Lexington, Kentucky, United States, 40506
United States, Louisiana
University Medical Center (LSU) Not yet recruiting
New Orleans, Louisiana, United States, 70112
United States, Maine
Maine Medical Center Not yet recruiting
Portland, Maine, United States, 04102
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Beth Israel Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Baystate Medical Center Recruiting
Springfield, Massachusetts, United States, 01199
St. Vincent Hospital Not yet recruiting
Worcester, Massachusetts, United States, 01608
United States, Michigan
University of Michigan Medical Center Not yet recruiting
Ann Arbor, Michigan, United States, 48109
Henry Ford Medical Center Not yet recruiting
Detroit, Michigan, United States, 48025
United States, Mississippi
University of Mississippi Medical Center Not yet recruiting
Jackson, Mississippi, United States, 39216
United States, New York
Mt. Sinai Hospital Not yet recruiting
New York, New York, United States, 10029
Montefiore Medical Center Recruiting
New York, New York, United States, 10467
United States, North Carolina
University of North Carolina at Chapel Hill Not yet recruiting
Chapel Hill, North Carolina, United States, 30033
Duke University Medical Center Not yet recruiting
Durham, North Carolina, United States, 27710
Wake Forest Baptist Health Recruiting
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
University of Cincinnati Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45219
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Health and Science University OHSU Not yet recruiting
Portland, Oregon, United States, 97239
United States, Pennsylvania
Penn State Hershey Medical Center Not yet recruiting
Hershey, Pennsylvania, United States, 17033
UPMC Mercy Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15261
UPMC Presbyterian Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15261
UPMC Shadyside Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15261
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37221
United States, Utah
Intermountain Medical Center Recruiting
Murray, Utah, United States, 84107
McKay-Dee Hospital Not yet recruiting
Ogden, Utah, United States, 84403
Utah Valley Regional Medical Center Not yet recruiting
Provo, Utah, United States, 84604
University of Utah Health Sciences Center Not yet recruiting
Salt Lake City, Utah, United States, 84132
LDS Hospital Not yet recruiting
Salt Lake City, Utah, United States, 84143
United States, Virginia
University Virginia Medical Center Not yet recruiting
Charlottesville, Virginia, United States, 22903
VCU Medical Center Not yet recruiting
Richmond, Virginia, United States, 23298
United States, Washington
Harborview Medical Center Recruiting
Seattle, Washington, United States, 98104
University of Washington Medical Center Not yet recruiting
Seattle, Washington, United States, 98104
Swedish Hospital First Hill Not yet recruiting
Seattle, Washington, United States, 98122
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: David Alan Schoenfeld, PhD Massachusetts General Hospital

Responsible Party: David Alan Schoenfeld, PETAL CCC Prinicipal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03434028     History of Changes
Other Study ID Numbers: PETAL03 CLOVERS
First Posted: February 15, 2018    Key Record Dates
Last Update Posted: May 28, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by David Alan Schoenfeld, Massachusetts General Hospital:
Fluid management
Sepsis-induced hypotension
vasopressors

Additional relevant MeSH terms:
Sepsis
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock
Vasoconstrictor Agents