Septic ShockPhase 3CLOVERSNCT03434028
Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
A Phase 3 study testing Early Vasopressors and Early Fluids in people with Septic Shock, run by Massachusetts General Hospital at 50 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock
- What is being tested?
- Early Vasopressors and Early Fluids
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,563 participants
- Where
- 50 sitesUnited States
- Study dates
- 7 Mar 2018to 24 Aug 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
50 sites in 1 country.
50 sites in 1 country
United States50 sites
University of Michigan Medical Center
Ann Arbor, Michigan, 48109
University of Colorado Hospital
Aurora, Colorado, 80045
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Beth Israel Medical Center
Boston, Massachusetts, 02215
Brigham and Women's Hospital
Boston, Massachusetts, 02445
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 30033
Medical University of South Carolina
Charleston, South Carolina, 29425
University Virginia Medical Center
Charlottesville, Virginia, 22903
University of Cincinnati Medical Center
Cincinnati, Ohio, 45219
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Ohio State University Wexner Medical Center
Columbus, Ohio, 43210
Denver Health Medical Center
Denver, Colorado, 80204
St. Joseph Hospital
Denver, Colorado, 80218
Duke University Medical Center
Durham, North Carolina, 27710
UCSF Fresno
Fresno, California, 93701
Penn State Hershey Medical Center
Hershey, Pennsylvania, 17033
University of Texas Health Science Center
Houston, Texas, 77030
Indiana University Health Methodist Hospital
Indianapolis, Indiana, 46202
University of Mississippi Medical Center
Jackson, Mississippi, 39216
University of Kentucky
Lexington, Kentucky, 40506
Ronald Reagan UCLA
Los Angeles, California, 90095
University of Minnesota Medical Center
Minneapolis, Minnesota, 55414
Hennepin County Medical Center
Minneapolis, Minnesota, 55415
Intermountain Medical Center
Murray, Utah, 84107
Vanderbilt University Medical Center
Nashville, Tennessee, 37221
Yale New Haven Hospital
New Haven, Connecticut, 06519
University Medical Center (LSU)
New Orleans, Louisiana, 70112
Mt. Sinai Hospital
New York, New York, 10029
Montefiore Medical Center
New York, New York, 10467
McKay-Dee Hospital
Ogden, Utah, 84403
Temple University Hospital
Philadelphia, Pennsylvania, 19140
UPMC Mercy
Pittsburgh, Pennsylvania, 15261
UPMC Presbyterian
Pittsburgh, Pennsylvania, 15261
UPMC Shadyside
Pittsburgh, Pennsylvania, 15261
Maine Medical Center
Portland, Maine, 04102
Oregon Health and Science University OHSU
Portland, Oregon, 97239
Utah Valley Regional Medical Center
Provo, Utah, 84604
VCU Medical Center
Richmond, Virginia, 23298
University of Utah Health Sciences Center
Salt Lake City, Utah, 84132
LDS Hospital
Salt Lake City, Utah, 84143
UCSF San Francisco
San Francisco, California, 94143
Harborview Medical Center
Seattle, Washington, 98104
University of Washington Medical Center
Seattle, Washington, 98104
Swedish Hospital First Hill
Seattle, Washington, 98122
Baystate Medical Center
Springfield, Massachusetts, 01199
Stanford University Hospital
Stanford, California, 94305
University of Arizona
Tucson, Arizona, 85724
Wake Forest Baptist Health
Winston-Salem, North Carolina, 27157
St. Vincent Hospital
Worcester, Massachusetts, 01608
About this study
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.
Read the 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.
- 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.
- 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
- 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
- Conditions
- Septic Shock
- Being tested
- Early Vasopressors, Early Fluids
- Keywords
- Fluid management, Sepsis-induced hypotension, vasopressors
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Early VasopressorsDrug
Also called Norepinephrine
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.
Early FluidsOther
Also called Balanced crystalloid solution
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.
| Study group | Role | What they receive |
|---|---|---|
| Restrictive Fluids | Other | The general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used. Receives: Drug: Early Vasopressors |
| Liberal Fluids | Other | The general approach is to use fluid boluses to treat hypotension. Receives: Other: Early Fluids |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: From randomization to discharge home up to and including day 90.
Secondary outcomes (13)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 72 hours after randomization
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.
Measured: 7 days 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.
Measured: 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.
Measured: From randomization to and including day 90
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2018
- Study start7 Mar 2018
- Primary completion10 May 2022
- Study completion24 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 1,563 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Boyd Taylor Thompson, Massachusetts General Hospital
- Investigators
- David Alan Schoenfeld, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03434028
- Sponsor's protocol ID
- PETAL03 CLOVERS
- Acronym
- CLOVERS
- Status last verified
- Jun 2023
- First submitted
- 9 Feb 2018
- Last updated
- 6 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Jorda A, Gelbenegger G, Shapiro NI, Douglas IS, Whitman C, Chen Z, Hippensteel JA, Kamphuis LA, Flick RJ, Harhay MO, Caldwell E, Zeitlinger M, Jilma B, Iwashyna TJ, Hough CL, Auriemma CL. Effects of an early restrictive versus liberal fluid strategy on long-term patient-centered outcomes in sepsis-induced hypotension: an open-label, randomized controlled trial. Am J Respir Crit Care Med. 2026 Jul 1;212(7):1510-1521. doi: 10.1093/ajrccm/aamag154.
PubMed 42093058Oshima 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;136(7):e202480. doi: 10.1172/JCI202480. eCollection 2026 Apr 1.
PubMed 41632536Oshima 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.
PubMed 40315385Jorda 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.
PubMed 38992663National 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.
PubMed 36688507Self 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.
PubMed 29753517
Study at a glance
From the registry record, last updated by the sponsor on 6 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
- ClinicalTrials.gov ID
- NCT03434028
- Acronym / sponsor ID
- CLOVERS / PETAL03 CLOVERS
- Conditions
- Septic Shock
- Keywords
- Fluid management, Sepsis-induced hypotension, vasopressors
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,563 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- 7 Mar 2018 (actual)
- Primary completion
- 10 May 2022 (actual)
- Study completion
- 24 Aug 2022 (actual)
- First posted
- 15 Feb 2018 (actual)
- Results
- Posted 6 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
- 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.
- 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
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Restrictive Fluids | Other | Drug: Early VasopressorsThe general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used. |
| Liberal Fluids | Other | Other: Early FluidsThe general approach is to use fluid boluses to treat hypotension. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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).
Key exclusion criteria (13 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Early VasopressorsAlso: NorepinephrineNorepinephrine 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. | Drug | Restrictive Fluids |
| Early FluidsAlso: Balanced crystalloid solutionAdditional 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 | Liberal Fluids |
Primary outcome
Death Before Discharge Home by Day 90
Time frame: From randomization to discharge home up to and including 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).
13 secondary outcomes
Organ Support Free Days
Time frame: 28 days after randomization
Ventilator Free Days (VFD)
Time frame: 28 days after randomization
Renal Replacement Free Days
Time frame: 28 days after randomization
Vasopressor Free Days
Time frame: From study day 2 through day 28
ICU Free Days
Time frame: 28 days after randomization
Hospital Free Days to Discharge Home
Time frame: 28 days after randomization
New Intubation With Invasive Mechanical Ventilation by 28 Days
Time frame: 28 days after randomization
Initiation of Renal Replacement Therapy
Time frame: 28 days after randomization
Kidney Disease: Change in Creatinine-based Global Outcomes (KIDGO) Score Between Baseline and 72 Hours
Time frame: 72 hours after randomization
Change in SOFA (Sepsis Related Organ Failure Assessment) Score
Time frame: 72 hours after randomization
Development of ARDS
Time frame: 7 days after randomization
New Onset Atrial or Ventricular Arrhythmia
Time frame: 28 days after randomization
Death From Any Cause at Any Location by Day 90
Time frame: From randomization to and including day 90
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42093058Jorda A, Gelbenegger G, Shapiro NI, Douglas IS, Whitman C, Chen Z, Hippensteel JA, Kamphuis LA, Flick RJ, Harhay MO, Caldwell E, Zeitlinger M, Jilma B, Iwashyna TJ, Hough CL, Auriemma CL. Effects of an early restrictive versus liberal fluid strategy on long-term patient-centered outcomes in sepsis-induced hypotension: an open-label, randomized controlled trial. Am J Respir Crit Care Med. 2026 Jul 1;212(7):1510-1521. doi: 10.1093/ajrccm/aamag154.
- Derived from this study: PubMed 41632536Oshima 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;136(7):e202480. doi: 10.1172/JCI202480. eCollection 2026 Apr 1.
- Derived from this study: PubMed 40315385Oshima 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.
- Derived from this study: PubMed 38992663Jorda 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.
- Derived from this study: PubMed 36688507National 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.
- Derived from this study: PubMed 29753517Self 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Alan Schoenfeld, PhD principal investigator
Massachusetts General Hospital
50 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Early Vasopressors and Early Fluids in people with Septic Shock, run by Massachusetts General Hospital at 50 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 50 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Death Before Discharge Home by Day 90 (time frame: From randomization to discharge home up to and including day 90.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03434028, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jul 2023.