A Phase 3 interventional study of Early Vasopressors and Early Fluids in Septic Shock, sponsored by Massachusetts General Hospital. Completed at 50 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-07-06.
Sponsored by Massachusetts General Hospital · Phase 3, Interventional, and Treatment
Among 17 studies testing norepinephrine in Shock, Septic — 4 open to participants now, 4 under way, 1 of them phase 3. Norepinephrine · Shock, Septic.
Among the 17 studies testing norepinephrine in Shock, Septic, this one has the largest enrollment, is one of 2 that started in 2018, is one of 6 in phase 3, and was the 10th registered.
1,078 studies on the registry are indexed under Shock, Septic; 232 are open to participants now.
Browse Shock, Septic studies →4 of the 17 studies testing norepinephrine in Shock, Septic are open now, in 4 countries. Recruiting first, the newest first:
Odense University Hospital · Sites in Denmark, Sweden
Ages 18+
Tunis University · Sites in Tunisia
Ages 18+
Peking Union Medical College Hospital · Sites in China
Ages 18+
Universitas Sumatera Utara
Ages 18+
By country, each count listing its studies:
Norepinephrine: first FDA approval 1950 (LEVOPHED). What it is approved for, and how studies give it, is on its page →
Of the 136 Shock, Septic studies recruiting now, 102 (75%) set no upper age limit and 19 (14%) stop at 75 or younger; 12 take children under 18; 13 take healthy volunteers.
This study: 18 Years and older · all sexes · no healthy volunteers.
The full table on the hub →This tab as a report to print or save as PDF → With an account.
17 studies; the count open now beside each. This study's row is marked.
A study in two phases is counted once above. Listed by phase, each with its combined phases: Phase 2 2 · Phase 3 8 · Phase 4 6
First in 1999; this study’s year is marked. 2 started in 2018.
By drug class, each counting the studies that test any of its medicines:
This study's enrollment of 1,563 is above the median of 79 across 636 interventional studies indexed under Shock, Septic.
Median enrollment 100 across the 17 interventional studies. Of the 11 that completed or were terminated, 3 (27%) have results posted.
This tab as a report to print or save as PDF → With an account.
None of the 17 has an industry lead sponsor. The 10 most frequent:
Massachusetts General Hospital is the lead sponsor of 2,588 studies on the registry; 446 are open to participants now.
Of its 223 completed or terminated interventional studies of FDA-regulated products, 168 (75%) have results posted.
Massachusetts General Hospital has 1 study filed under Shock, Septic — fewer than ten, so there is no comparison to draw.
2 of the studies testing norepinephrine in Shock, Septic that are under way reach primary completion within a year, 1 of them phase 3. Phase 3 first, then by date:
| Study | Primary completion |
|---|---|
| NCT05931601Phase 3Odense University HospitalEarly Initiated Vasopressor Therapy in the Emergency Department | 2026-12-31 |
| NCT07418541Universitas Sumatera UtaraEarly Co-Administration of Crystalloid Fluid and Norepinephrine for Preventing Acute Kidney Injury in Septic Shock | 2026-12 |
Add all 2 to your calendar (.ics) → With an account.
Among the 17 studies testing norepinephrine in Shock, Septic, from their registry updates:
Nothing recorded among them since 2026-09-25.
This tab as a report to print or save as PDF → With an account.
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.
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.
Restrictive Fluids (Early Vasopressors) Group
Liberal Fluids (Fluids First)
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
The general approach is to use fluid boluses to treat hypotension.
Other: Early Fluids
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.
Also known as: Norepinephrine
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.
Also known as: Balanced crystalloid solution
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).
Time frame: From randomization to discharge home up to and including day 90.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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): 1. creatinine level 1.5-1.9 times baseline OR \>/= 0.3 mg/dl (\>/= 25.5 umol/l) increase 2. creatinine level 2.0-2.9 times baseline 3. creatinine level 3.0 times baseline OR increase in serum creatinine to \>/=4.0mg/dl (\>/= 353 umol/l) OR initiation of renal replacement therapy
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From randomization to and including day 90
| Milestone | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Started | 782 | 781 |
| Completed | 782 | 781 |
| Not completed | 0 | 0 |
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).
| percentage of participants | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Death Before Discharge Home by Day 90 | 14 (11.6 to 16.4) | 14.9 (12.4 to 17.4) |
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.
| days | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Organ Support Free Days | 24 (23.4 to 24.6) | 23.6 (23 to 24.3) |
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.
| days | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Ventilator Free Days (VFD) | 23.4 (22.7 to 24.1) | 22.8 (22 to 23.5) |
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.
| days | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Renal Replacement Free Days | 24.1 (23.4 to 24.8) | 23.9 (23.2 to 24.6) |
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.
| days | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Vasopressor Free Days | 22 (21.4 to 22.7) | 21.6 (20.9 to 22.3) |
Defined as the number of days spent alive out of the ICU to day 28.
| days | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| ICU Free Days | 22.8 (22.2 to 23.4) | 22.7 (22 to 23.3) |
Days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.
| days | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Hospital Free Days to Discharge Home | 16.2 (15.4 to 17) | 15.4 (14.6 to 16.2) |
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.
| Participants | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| New Intubation With Invasive Mechanical Ventilation by 28 Days | 77 | 87 |
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.
| Participants | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Initiation of Renal Replacement Therapy | 24 | 24 |
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): 1. creatinine level 1.5-1.9 times baseline OR \>/= 0.3 mg/dl (\>/= 25.5 umol/l) increase 2. creatinine level 2.0-2.9 times baseline 3. creatinine level 3.0 times baseline OR increase in serum creatinine to \>/=4.0mg/dl (\>/= 353 umol/l) OR initiation of renal replacement therapy
| score on a scale | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Kidney Disease: Change in Creatinine-based Global Outcomes (KIDGO) Score Between Baseline and 72 Hours | 0.35 (0.28 to 0.41) | 0.34 (0.28 to 0.41) |
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
| score on a scale | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Change in SOFA (Sepsis Related Organ Failure Assessment) Score | -0.7 (-0.9 to -0.4) | -0.8 (-1 to -0.5) |
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.
| Participants | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Development of ARDS | 19 | 20 |
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.
| Participants | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| New Onset Atrial or Ventricular Arrhythmia | 59 | 67 |
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.
| Participants | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Death From Any Cause at Any Location by Day 90 | 172 | 169 |
Collected over Assessment for adverse events was performed from trial enrollment through study day 6 (five days after completion of the study fluid protocol) or Hospital discharge, whichever occurs first. All-Cause All-Location Mortality was assessed up to 90 days from randomization. Please note that this outcome measure differs from the primary outcome of death before discharge home by day 90 and includes deaths after discharge home before day 90.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Restrictive Fluids | 172/768 (22.4%) | 18/782 (2.3%) | 4/782 (0.5%) |
| Liberal Fluids | 169/773 (21.9%) | 19/781 (2.4%) | 14/781 (1.8%) |
| Event | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| DeathGeneral disorders | 0/782 | 4/781 |
| Fluid OverloadCardiac disorders | 0/782 | 3/781 |
| Cardiac ArrestCardiac disorders | 0/782 | 2/781 |
| Pulmonary EdemaCardiac disorders | 0/782 | 2/781 |
| SepsisInfections and infestations | 0/782 | 2/781 |
| Gastrointestinal BleedingGastrointestinal disorders | 2/782 | 0/781 |
| Peripheral IschemiaVascular disorders | 2/782 | 0/781 |
| Flash Pulmonary EdemaCardiac disorders | 0/782 | 1/781 |
| Myocardial Ischemia, Elevated TroponinCardiac disorders | 0/782 | 1/781 |
| TachycardiaCardiac disorders | 0/782 | 1/781 |
| Event | Restrictive Fluids | Liberal Fluids |
|---|---|---|
| Fluid OverloadCardiac disorders | 0/782 | 3/781 |
| AnemiaBlood and lymphatic system disorders | 0/782 | 2/781 |
| CoagulopathyBlood and lymphatic system disorders | 0/782 | 1/781 |
| BradycardiaCardiac disorders | 0/782 | 1/781 |
| Pulmonary EdemaCardiac disorders | 0/782 | 1/781 |
| Transfusion Associated Circulatory OverloadCardiac disorders | 0/782 | 1/781 |
| Renal CalculusRenal and urinary disorders | 0/782 | 1/781 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 0/782 | 1/781 |
| Respiratory FailureRespiratory, thoracic and mediastinal disorders | 0/782 | 1/781 |
| Shortness Of BreathRespiratory, thoracic and mediastinal disorders | 0/782 | 1/781 |
| Age, Continuous(years) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| Mean | 59.1 ± 16 | 59.9 ± 15.9 | 59.5 ± 15.9 |
| Sex: Female, Male(Participants) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| Female | 371 | 366 | 737 |
| Male | 411 | 415 | 826 |
| Race (NIH/OMB)(Participants) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| American Indian or Alaska Native | 8 | 4 | 12 |
| Asian | 26 | 26 | 52 |
| Native Hawaiian or Other Pacific Islander | 1 | 1 | 2 |
| Black or African American | 134 | 112 | 246 |
| White | 532 | 570 | 1102 |
| More than one race | 3 | 1 | 4 |
| Unknown or Not Reported | 78 | 67 | 145 |
| Region of Enrollment(participants) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| United States | 782 | 781 | 1563 |
| Hispanic or Latino ethnic group(Participants) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| yes | 118 | 108 | 226 |
| no | 628 | 646 | 1274 |
| not reported | 36 | 27 | 63 |
| Sequential Organ Failure Assessment (SOFA) score(units on a scale) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| Mean | 3.4 ± 2.8 | 3.5 ± 2.7 | 3.4 ± 2.7 |
| Systolic Blood Pressure(mm Hg) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| Mean | 93.2 ± 12 | 93.8 ± 12.2 | 93.5 ± 12.1 |
| Time from meeting eligibility to randomization(minutes) | Restrictive Fluids | Liberal Fluids | Total |
|---|---|---|---|
| Median | 61 (26 to 116) | 60 (25 to 117) | 61 (26 to 116) |
3 further baseline measures are reported on the registry.
PDFs hosted by the registry, ClinicalTrials.gov.
Ran from Mar 2018 to primary completion in May 2022, 50 months.
Results were first posted in Jul 2023, 1 year 1 month after primary completion.
Of 45 non-industry phase 3 interventional studies under Shock, Septic, half reached primary completion within 42 months of starting (the median), counting those still running; a quarter within 16 and three quarters within 59. This study's 50 months is above that.
Counting every sponsor, half of 46 studies reached it within 42 months; a quarter within 16 and three quarters within 59.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Jun 2023. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Norepinephrine
Massachusetts General Hospital →