Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
CLOVERS
1 other identifier
interventional
1,563
1 country
50
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Mar 2018
Typical duration for phase_3
50 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 9, 2018
CompletedFirst Posted
Study publicly available on registry
February 15, 2018
CompletedStudy Start
First participant enrolled
March 7, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 10, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
August 24, 2022
CompletedResults Posted
Study results publicly available
July 6, 2023
CompletedJuly 6, 2023
June 1, 2023
4.2 years
February 9, 2018
February 3, 2023
June 15, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (13)
Organ Support Free Days
28 days after randomization
Ventilator Free Days (VFD)
28 days after randomization
Renal Replacement Free Days
28 days after randomization
Vasopressor Free Days
From study day 2 through day 28
ICU Free Days
28 days after randomization
- +8 more secondary outcomes
Study Arms (2)
Restrictive Fluids
OTHERThe general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used.
Liberal Fluids
OTHERThe general approach is to use fluid boluses to treat hypotension.
Interventions
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.
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.
Eligibility Criteria
You may qualify if:
- 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).
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (50)
University of Arizona
Tucson, Arizona, 85724, United States
UCSF Fresno
Fresno, California, 93701, United States
Ronald Reagan UCLA
Los Angeles, California, 90095, United States
UCSF San Francisco
San Francisco, California, 94143, United States
Stanford University Hospital
Stanford, California, 94305, United States
University of Colorado Hospital
Aurora, Colorado, 80045, United States
Denver Health Medical Center
Denver, Colorado, 80204, United States
St. Joseph Hospital
Denver, Colorado, 80218, United States
Yale New Haven Hospital
New Haven, Connecticut, 06519, United States
Indiana University Health Methodist Hospital
Indianapolis, Indiana, 46202, United States
University of Kentucky
Lexington, Kentucky, 40506, United States
University Medical Center (LSU)
New Orleans, Louisiana, 70112, United States
Maine Medical Center
Portland, Maine, 04102, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Brigham and Women's Hospital
Boston, Massachusetts, 02115, United States
Beth Israel Medical Center
Boston, Massachusetts, 02215, United States
Brigham and Women's Hospital
Boston, Massachusetts, 02445, United States
Baystate Medical Center
Springfield, Massachusetts, 01199, United States
St. Vincent Hospital
Worcester, Massachusetts, 01608, United States
University of Michigan Medical Center
Ann Arbor, Michigan, 48109, United States
University of Minnesota Medical Center
Minneapolis, Minnesota, 55414, United States
Hennepin County Medical Center
Minneapolis, Minnesota, 55415, United States
University of Mississippi Medical Center
Jackson, Mississippi, 39216, United States
Mt. Sinai Hospital
New York, New York, 10029, United States
Montefiore Medical Center
New York, New York, 10467, United States
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 30033, United States
Duke University Medical Center
Durham, North Carolina, 27710, United States
Wake Forest Baptist Health
Winston-Salem, North Carolina, 27157, United States
University of Cincinnati Medical Center
Cincinnati, Ohio, 45219, United States
Cleveland Clinic Foundation
Cleveland, Ohio, 44195, United States
Ohio State University Wexner Medical Center
Columbus, Ohio, 43210, United States
Oregon Health and Science University OHSU
Portland, Oregon, 97239, United States
Penn State Hershey Medical Center
Hershey, Pennsylvania, 17033, United States
Temple University Hospital
Philadelphia, Pennsylvania, 19140, United States
UPMC Mercy
Pittsburgh, Pennsylvania, 15261, United States
UPMC Presbyterian
Pittsburgh, Pennsylvania, 15261, United States
UPMC Shadyside
Pittsburgh, Pennsylvania, 15261, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
Vanderbilt University Medical Center
Nashville, Tennessee, 37221, United States
University of Texas Health Science Center
Houston, Texas, 77030, United States
Intermountain Medical Center
Murray, Utah, 84107, United States
McKay-Dee Hospital
Ogden, Utah, 84403, United States
Utah Valley Regional Medical Center
Provo, Utah, 84604, United States
University of Utah Health Sciences Center
Salt Lake City, Utah, 84132, United States
LDS Hospital
Salt Lake City, Utah, 84143, United States
University Virginia Medical Center
Charlottesville, Virginia, 22903, United States
VCU Medical Center
Richmond, Virginia, 23298, United States
Harborview Medical Center
Seattle, Washington, 98104, United States
University of Washington Medical Center
Seattle, Washington, 98104, United States
Swedish Hospital First Hill
Seattle, Washington, 98122, United States
Related Publications (5)
Oshima K, Yan B, Tao R, Amorim G, Di Gravio C, McMurtry SA, Burke RC, Nam Y, Nikolli I, Kravitz MS, Stephenson D, Issaian A, Hansen KC, D'Alessandro A, Douglas IS, Self WH, Lindsell CJ, Leroux C, Ringor A, Matthay MA, Schildcrout JS, Shapiro NI, Schmidt EP. Plasma chondroitin sulfate predicts the effectiveness of fluid resuscitation strategies in patients with sepsis. J Clin Invest. 2026 Feb 3:e202480. doi: 10.1172/JCI202480. Online ahead of print.
PMID: 41632536DERIVEDOshima K, Di Gravio C, Yan B, McMurtry SA, Burke R, Levoir LM, Kravitz MS, Stephenson D, Issaian A, Hansen KC, D'Alessandro A, Douglas IS, Self WH, Lindsell CJ, Schildcrout JS, Schmidt EP, Shapiro NI. Endothelial Glycocalyx Degradation in Sepsis: Analysis of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) Trial, a Multicenter, Phase 3, Randomized Trial. Ann Am Thorac Soc. 2025 Sep;22(9):1382-1393. doi: 10.1513/AnnalsATS.202501-012OC.
PMID: 40315385DERIVEDJorda A, Douglas IS, Staudinger T, Heinz G, Bergmann F, Oberbauer R, Sengolge G, Zeitlinger M, Jilma B, Shapiro NI, Gelbenegger G. Fluid management for sepsis-induced hypotension in patients with advanced chronic kidney disease: a secondary analysis of the CLOVERS trial. Crit Care. 2024 Jul 11;28(1):231. doi: 10.1186/s13054-024-05019-6.
PMID: 38992663DERIVEDNational Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, Brown SM, Exline MC, Ginde AA, Gong MN, Grissom CK, Hayden D, Hough CL, Huang W, Iwashyna TJ, Jones AE, Khan A, Lai P, Liu KD, Miller CD, Oldmixon K, Park PK, Rice TW, Ringwood N, Semler MW, Steingrub JS, Talmor D, Thompson BT, Yealy DM, Self WH. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. doi: 10.1056/NEJMoa2212663. Epub 2023 Jan 21.
PMID: 36688507DERIVEDSelf 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.
PMID: 29753517DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
All cause mortality: To clarify, we did not classify death as anticipated or not anticipated; nor did we collect cause of death for this trial.
Results Point of Contact
- Title
- PETAL Clinical Coordinating Center PI
- Organization
- Massachusetts General Hospital
Study Officials
- PRINCIPAL INVESTIGATOR
David Alan Schoenfeld, PhD
Massachusetts General Hospital
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- PETAL CCC Prinicipal Investigator
Study Record Dates
First Submitted
February 9, 2018
First Posted
February 15, 2018
Study Start
March 7, 2018
Primary Completion
May 10, 2022
Study Completion
August 24, 2022
Last Updated
July 6, 2023
Results First Posted
July 6, 2023
Record last verified: 2023-06