Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS)

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Early Vasopressors; Other: Early Fluids

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)

   • 2 liter infusion upon enrollment (may forego second liter if MAP/SBP and heart rate are normalized and clinical assessment if patient is fluid replete after the first liter).
   • 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
• Enrollment (Actual): 1563
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Fresno, California, United States, 93701
      • UCSF Fresno
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA
    • San Francisco, California, United States, 94143
      • UCSF San Francisco
    • Stanford, California, United States, 94305
      • Stanford University Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
    • Denver, Colorado, United States, 80218
      • St. Joseph Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale New Haven Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Methodist Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center (LSU)
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Medical Center
    • Boston, Massachusetts, United States, 02445
      • Brigham and Women's Hospital
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
    • Worcester, Massachusetts, United States, 01608
      • St. Vincent Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55414
      • University of Minnesota Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New York
    • New York, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10029
      • Mt. Sinai Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 30033
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University OHSU
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15261
      • UPMC Mercy
    • Pittsburgh, Pennsylvania, United States, 15261
      • UPMC Presbyterian
    • Pittsburgh, Pennsylvania, United States, 15261
      • UPMC Shadyside
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37221
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Ogden, Utah, United States, 84403
      • McKay-Dee Hospital
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University Virginia Medical Center
    • Richmond, Virginia, United States, 23298
      • VCU Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98122
      • Swedish Hospital First Hill
    • Seattle, Washington, United States, 98104
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.; Other Names: Norepinephrine
Other: Liberal Fluids; The general approach is to use fluid boluses to treat hypotension.	Other: Early Fluids; Additional 2 liter intravenous fluid infusion upon enrollment (may forego second liter if MAP/SBP and heart rate are normalized and clinical assessment if patient is fluid replete after the first liter). 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.; Other Names: Balanced crystalloid solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death Before Discharge Home by Day 90	The primary outcome was death from any cause before discharge home by day 90. Point estimates were from Kaplan-Meier curves. There were 109 deaths and 5 patients with censored data the restrictive fluid group and 116 deaths and 4 patients with censored data in the liberal group. We defined home as the same setting or a setting similar to the one where the patient resided before becoming ill. Thus, if a patient originated from a private residence and was discharged from the hospital to a rehabilitation setting, we assessed for vital status until return to the private residence.Vital status was 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).	From randomization to discharge home up to and including day 90.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of ARDS	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.	7 days after randomization
Organ Support Free Days	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.	28 days after randomization
Ventilator Free Days (VFD)	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.	28 days after randomization
Renal Replacement Free Days	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.	28 days after randomization
Vasopressor Free Days	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.	From study day 2 through day 28
ICU Free Days	Defined as the number of days spent alive out of the ICU to day 28.	28 days after randomization
Hospital Free Days to Discharge Home	Days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.	28 days after randomization
New Intubation With Invasive Mechanical Ventilation by 28 Days	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.	28 days after randomization
Initiation of Renal Replacement Therapy	Patients receiving (new) renal replacement therapy through day 28. Patients with chronic renal replacement therapy initiated prior to the current sepsis illness were not eligible to meet this endpoint.	28 days after randomization
Kidney Disease: Change in Creatinine-based Global Outcomes (KIDGO) Score Between Baseline and 72 Hours	Assessment of renal function using the KDIGO staging system (using serum creatinine criteria only) between baseline and 72 hours post randomization 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 were not eligible for this endpoint determination. Scoring of 1-3 (using serum creatinine levels; a higher score indicates worsening kidney function): creatinine level 1.5-1.9 times baseline OR >/= 0.3 mg/dl (>/= 25.5 umol/l) increase; creatinine level 2.0-2.9 times baseline; creatinine level 3.0 times baseline OR increase in serum creatinine to >/=4.0mg/dl (>/= 353 umol/l) OR initiation of renal replacement therapy	72 hours after randomization
Change in SOFA (Sepsis Related Organ Failure Assessment) Score	SOFA score was calculated at enrollment and at 72 hours using clinically available data.Total score: 0-4 points; 4 = worst outcome. Values not available at baseline were assumed normal. 72 hours assessment: Closest previously known value was carried forward for missing values. SOFA Scoring Breakout (lower scores mean a better outcome; clinically significant organ failure for CLOVERS was defined as a SOFA score 2 or more points higher than baseline): Coagulation( Platelets, ×10³/µL): Score = 0: >150; 1: </= 150; 2: </= 100; 3: </= 50; 4: </= 2; Liver (Bilirubin, mg/dL): Score: 0: <1.2; 1: 1.2-1.9; 2: 2.0-5.9; 3: 6.0-11.9; 4: >11.9; Cardiovascular(Hypotension): Score: 0: no hypotension; 1: Mean arterial pressure <70 mmHg; 2: Dopamine</=5 OR any dobutamine; 3: Dopanime >5, epinephrine </=0, or Norepi </=0.1; 4: Dop >15, epi >0.1, or norepi >0.1; Renal (Creatinine, mg/dL or urine output, ml/d): Score: 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	72 hours after randomization
New Onset Atrial or Ventricular Arrhythmia	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.	28 days after randomization
Death From Any Cause at Any Location by Day 90	Subjects were contacted at day 90 to ascertain their survival status via telephone contact with the patient or family members or by a review of medical records and publicly available data sources.	From randomization to and including day 90

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: David Alan Schoenfeld, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW, Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI; CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018 Oct;72(4):457-466. doi: 10.1016/j.annemergmed.2018.03.039. Epub 2018 May 10.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2018
• Primary Completion (Actual): May 10, 2022
• Study Completion (Actual): August 24, 2022

Study Registration Dates

• First Submitted: February 9, 2018
• First Submitted That Met QC Criteria: February 9, 2018
• First Posted (Actual): February 15, 2018

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Fluid management; vasopressors; Sepsis-induced hypotension
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Norepinephrine; Vasoconstrictor Agents
• Other Study ID Numbers: PETAL03 CLOVERS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No