Septic ShockPhase 4CLASSICNCT03668236
The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial
A Phase 4 study testing Isotonic crystalloids in people with Septic Shock, run by Anders Perner, MD, PhD at 31 sites in 8 countries.
Trial summary
The purpose of this trial is to assess patient important benefits and harms of IV fluid restriction vs. standard care fluid therapy in patients with septic shock. 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?
- Isotonic crystalloids
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,554 participants
- Where
- 31 sitesin 8 countries
- Study dates
- 27 Nov 2018to 16 Nov 2022
- Phase
- Phase 4
- 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
- All the following criteria must be fulfilled:
- Aged 18 years or above
- Admitted to the ICU or plan to be admitted to the ICU regardless of trial participation
- Septic shock defined according to the Sepsis-3 criteria:
- Suspected or confirmed site of infection or positive blood culture AND
- Ongoing infusion of vasopressor/inotrope agent to maintain a mean arterial blood pressure of 65 mmHg or above AND
- Lactate of 2 mmol/L or above in any plasma sample performed within the last 3-hours
- Have received at least 1 L of IV fluid (crystalloids, colloids or blood products) in the last 24-hours prior to screening.
Who cannot join
- Patients who fulfil any of the following criteria will be excluded:
- Septic shock for more than 12 hours at the time of screening as these patients are no longer early in their course
- Life-threatening bleeding as these patients need specific fluid/blood product strategies
- Acute burn injury of more than 10% of the body surface area as these patients need a specific fluid strategy
- Known pregnancy
- Consent not obtainable as per the model approved for the specific site
Trial locations and contacts
31 sites in 8 countries.
31 sites in 8 countries
Denmark11 sites
Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.
Aalborg
Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet
Copenhagen, 2100
Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
Copenhagen
Dept. of Anaesthesia and Intensive Care, Herning Hospital
Herning
Dept. of Intensive Care, Hillerød Hospital
Hillerød, 3400
Dept. of Anaesthesia and Intensive Care, Holbæk Hospital
Holbæk
Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Køge
Køge
Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital
Kolding
Dept. of Anaesthesia and Intensive Care, Randers Hospital
Randers
Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde
Roskilde
Dept. of Anaesthesia and Intensive Care, Viborg Hospital
Viborg
Sweden7 sites
Dept. of Intensive Care Medicine, St Göran
Gothenburg
Dept. of intensive care, Huddinge
Huddinge
MIMA Medicinsk intermediärvårdsavdelning
Huddinge
Dept. of Intensive Care, Solna
Solna
Medical ICU, Karolinska, Södersjukhuset
Stockholm
Södersjukhuset
Stockholm
Dept. of Intensive Care Medicine Sundsvall Hospital
Sundsvall
Italy4 sites
Dept. of Intensive Care, Ancona Hospital
Ancona
Humanitas research hospital Bergamo
Bergamo, Milan
Dept. of Intensive Care, Humanitas Research Hospital Castelanza
Castellanza, Milan
Dept. of Intensive Care, Humanitas Research Hospital
Milan
Norway4 sites
Dept. of intensive care, Østfold, Kalnes
Grålum
Dept. of intensive Care, Innlandet Hamar
Hamar
Dept. of Intensive Care, Oslo University Hospital
Oslo, 0450
Dept. of Intensive Care Medicine, Stavanger
Stavanger
Switzerland2 sites
Dept. of intensive care, Basel
Basel
Dept. of Intensive Care, University Hospital Bern
Bern
United Kingdom1 site
Dept. of Intensive Care Unit, Guy's and St. Thomas' Hospital
London
About this study
The purpose of this trial is to assess patient important benefits and harms of IV fluid restriction vs. standard care fluid therapy in patients with septic shock.
Read the detailed description
BACKGROUND:
Septic shock is common, often lethal, costly, and associated with prolonged suffering among survivors and relatives. Traditionally, intravenous (IV) fluids are used to optimise the circulation, and the use of higher volumes is recommended by international guidelines. There is, however, no high-quality evidence to support this. In contrast, data from cohort studies, small trials and systematic reviews in sepsis and large trials in other settings and patient groups suggest potential benefits from restriction of IV fluids in patients with septic shock.
OBJECTIVES:
The aim of the CLASSIC trial is to assess the benefits and harms of IV fluid restriction vs. standard care on patient-important outcome measures in adult intensive care unit (ICU) patients with septic shock.
DESIGN:
CLASSIC is an international, multicentre, parallel-grouped, open-labelled, centrally randomised, stratified, outcome assessor- and analyst-blinded trial.
POPULATION:
Adult ICU patients who have septic shock and have received at least 1 L of IV fluid in the last 24-hours.
EXPERIMENTAL INTERVENTION:
In the IV fluid restriction group no IV fluids should be given in the ICU unless extenuating circumstances occur, including signs of severe hypoperfusion, overt fluid loss or a failing GI tract with a total fluid input of less than 1 L per day. In these circumstances, IV fluid may be given in measured amounts.
CONTROL INTERVENTION:
In the standard care group there will be no upper limit for the use of IV fluids.
OUTCOMES:
The primary outcome is 90-day mortality; secondary outcomes are serious adverse events in the ICU (ischemic events or severe acute kidney injury); serious adverse reactions in the ICU; days alive without life support at day 90; days alive and out of hospital at day 90 and mortality, health-related quality of life and cognitive function at 1-year.
TRIAL SIZE:
A total of 1554 participants will be randomised to allow the detection of a 15% relative risk reduction (7% absolute) in the restrictive vs. standard care group in 90-day mortality with a power of 80%.
- Conditions
- Septic Shock
- Being tested
- Isotonic crystalloids
- Keywords
- Fluid resuscitation, Critical care, Intensive care, Crystalloid, IV fluid therapy
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Isotonic crystalloidsDrug
Types of fluid to be used in both intervention groups:
- IV fluids given for circulatory impairment: Only isotonic crystalloids are to be used as per the Scandinavian guideline for fluid resuscitation
- Fluids given to substitute overt loss: Isotonic crystalloids are to be used. If large amounts of ascites are tapped, then human albumin may be used
- Fluids used for dehydration: Water or isotonic glucose should be used
- Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency, including water in the case of severe hypernatremia
- Blood products are only to be used on specific indications including severe bleeding, severe anaemia and prophylactic in case of severe coagulopathy
| Study group | Role | What they receive |
|---|---|---|
| Fluid restriction group | Experimental | No IV fluids unless one of the extenuating circumstances occur; then, IV fluid may be given in measured amounts:
1. In case of severe hypoperfusion or severe circulatory impairment defined by either:
* Lactate≥4 mmol/L
* MAP<50 mmHg (with or without vasopressor/inotrope)
* Mottling beyond the kneecap (mottling score >2) OR
* Urinary output<0.1 mL/kg bodyweight/h, but only in the first 2hrs after randomisation
A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation
2. In case of overt fluid losses (e.g. vomiting, large aspirates,…) IV fluid may be given to correct for the loss, but not above the volume lost.
3. In case the oral/enteral route for water or electrolyte solutions is contraindicated or has failed, IV fluids may be given to:
* Correct dehydration or electrolyte deficiencies
* Ensure a total fluid input of 1L per 24hrs
IV fluids may be given as carrier for medication, but the volume should be reduced to the lowest possible Receives: Drug: Isotonic crystalloids |
| Standard-care | Active comparator | There will be no upper limit for the use of either IV or oral/enteral fluids. In particular:
1. IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. These criteria are based on the Surviving Sepsis Campaign guideline.
2. IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid
3. IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements Receives: Drug: Isotonic crystalloids |
What is being measured
The primary outcome is the main question the study is designed to answer.
90-day Mortality
Al cause mortality at 90 days
Measured: Day 90 after randomisation
Secondary outcomes (7)
Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU
SAEs were defined as ischaemic events (cerebral, cardiac, intestinal or limb ischaemia) or as a new episode of severe acute kidney injury (modified KDIGO-3)
Measured: Until ICU discharge, maximum 90 days
Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU.
The pre-specified SARs to IV crystalloids were: Generalized tonic-clonic seizures, anaphylactic reactions, central pontine myelinolysis, severe hypernatremia, severe hyperchloremic acidosis, and severe metabolic alkalosis. Data on the outcome measures, including SARs, were obtained from patient medical records by the trial investigators or their delegates.
Measured: Until ICU discharge, maximum 90 days
Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy)
Measured: Until ICU discharge, maximum 90 days
Days Alive and Out of Hospital at Day 90
Measured: Day 90 after randomisation
All-cause Mortality at 1-year After Randomisation
Measured: 1-year after randomisation
Health-related Quality of Life 1 Year After Randomisation
Measured using the EuroQoL EQ-5D-5L questionnaire (comprising 5 questions with a score from 1 to 5 each and a visual analogue scale from 0 to 100). Participants who have died will be assigned the lowest possible scores.
Measured: 1 year after randomisation
Cognitive Function 1-year After Randomisation
Assessed by the Montreal Cognitive Assessment (MoCa) MINI score validated for telephone use. Mini MoCA consists of 4 cognitive dimensions: attention (immediate recall of 5 words), executive functions and language (1-min verbal fluency), orientation (6 items on date and geographic orientation), and memory (delayed recall and recognition of 5 previously learned words). The total score ranges from 0 to 30, with lower values indicating worse cognitive function. To correct for any educational effect on the cognitive test, 1 point is added for participants with 12 years of education or less (scores were truncated at the maximum upper value of 30 points) Participants who had died were assigned the value 0.
Measured: 1-year after randomisation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Sep 2018
- Study start27 Nov 2018
- Primary completion14 Feb 2022
- Study completion16 Nov 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 (8)Papers the sponsor has linked to this study.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 1,554 participants (actual)
Sponsor and investigators
- Lead sponsor
- Anders Perner, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- Copenhagen University Hospital, Rigshospitalet, Centre for Research in Intensive Care (CRIC), Scandinavian Critical Care Trials Group
- Responsible party
- Sponsor-investigator, Anders Perner, MD, PhD, Scandinavian Critical Care Trials Group
- Investigators
- Tine Sylvest Meyhoff, MD, Principal investigator, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03668236
- Sponsor's protocol ID
- RH-ITA-007
- Acronym
- CLASSIC
- Status last verified
- Feb 2025
- First submitted
- 6 Sep 2018
- Last updated
- 24 Feb 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A; CLASSIC Trial Group; Scandinavian Critical Care Trials Group. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016 Nov;42(11):1695-1705. doi: 10.1007/s00134-016-4500-7. Epub 2016 Sep 30.
PubMed 27686349Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettila V, Moller MH, Kjaer MN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortso CJS, Meier N, Jensen TS, Engstrom J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herlov LS, Solling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schonemann-Lund M, Brochner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Adnoy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Radej J, Kriz M, Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17.
PubMed 35709019Meyhoff TS, Hjortrup PB, Moller MH, Wetterslev J, Lange T, Kjaer MN, Jonsson AB, Hjortso CJS, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst I, Ostermann M, Mouncey P, Rowan K, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Nebrich L, Russell L, Vang M, Rasmussen ML, Solling C, Rasmussen BS, Brochner AC, Perner A. Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan. Acta Anaesthesiol Scand. 2019 Oct;63(9):1262-1271. doi: 10.1111/aas.13434. Epub 2019 Jul 24.
PubMed 31276193Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV Fluid Restriction According to Standard Fluid Treatment Intensity Across Conservative Versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial Sites. Crit Care Med. 2025 Aug 1;53(8):e1590-e1600. doi: 10.1097/CCM.0000000000006679. Epub 2025 Apr 24.
PubMed 40272936Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV fluid restriction according to site-specific intensity of standard fluid treatment-protocol. Acta Anaesthesiol Scand. 2024 Aug;68(7):975-982. doi: 10.1111/aas.14423. Epub 2024 Apr 4.
PubMed 38576165Kjaer MN, Meyhoff TS, Sivapalan P, Granholm A, Hjortrup PB, Madsen MB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Ostermann M, Gould D, Cecconi M, Malbrain MLNG, Ahlstedt C, Kiel LB, Bestle MH, Nebrich L, Hildebrandt T, Russell L, Vang M, Rasmussen ML, Solling C, Brochner AC, Krag M, Pfortmueller C, Kriz M, Siegemund M, Albano G, Aagaard SR, Bundgaard H, Crone V, Wichmann S, Johnstad B, Martin YK, Seidel P, Martensson J, Hollenberg J, Wistrand M, Donati A, Barbara E, Karvunidis T, Hollinger A, Carsetti A, Lumlertgul N, Joelsson-Alm E, Lambiris N, Aslam TN, Friberg FF, Vesterlund GK, Mortensen CB, Vestergaard SR, Caspersen SF, Jensen DB, Borup M, Rasmussen BS, Perner A. Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock. Intensive Care Med. 2023 Jul;49(7):820-830. doi: 10.1007/s00134-023-07114-8. Epub 2023 Jun 18.
PubMed 37330928Meyhoff TS, Moller MH, Hjortrup PB, Cronhjort M, Perner A, Wetterslev J. Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest. 2020 Jun;157(6):1478-1496. doi: 10.1016/j.chest.2019.11.050. Epub 2020 Jan 23.
PubMed 31982391Kjaer MN, Meyhoff TS, Madsen MB, Hjortrup PB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst ICC, Ostermann M, Mouncey P, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Gyldensted L, Nebrich L, Russell L, Vang M, Solling C, Brochner AC, Rasmussen BS, Perner A. Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial. Acta Anaesthesiol Scand. 2020 Mar;64(3):410-416. doi: 10.1111/aas.13519. Epub 2019 Dec 26.
PubMed 31828753
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial
- ClinicalTrials.gov ID
- NCT03668236
- Acronym / sponsor ID
- CLASSIC / RH-ITA-007
- Conditions
- Septic Shock
- Keywords
- Fluid resuscitation, Critical care, Intensive care, Crystalloid, IV fluid therapy
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,554 participants (actual)
- Lead sponsor
- Anders Perner, MD, PhDUniversity, hospital or other
- Collaborators
- Copenhagen University Hospital, Rigshospitalet, Centre for Research in Intensive Care (CRIC), Scandinavian Critical Care Trials Group
- Study start
- 27 Nov 2018 (actual)
- Primary completion
- 14 Feb 2022 (actual)
- Study completion
- 16 Nov 2022 (actual)
- First posted
- 12 Sep 2018 (actual)
- Results
- Posted 24 Feb 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this trial is to assess patient important benefits and harms of IV fluid restriction vs. standard care fluid therapy in patients with septic shock.
Detailed description
BACKGROUND:
Septic shock is common, often lethal, costly, and associated with prolonged suffering among survivors and relatives. Traditionally, intravenous (IV) fluids are used to optimise the circulation, and the use of higher volumes is recommended by international guidelines. There is, however, no high-quality evidence to support this. In contrast, data from cohort studies, small trials and systematic reviews in sepsis and large trials in other settings and patient groups suggest potential benefits from restriction of IV fluids in patients with septic shock.
OBJECTIVES:
The aim of the CLASSIC trial is to assess the benefits and harms of IV fluid restriction vs. standard care on patient-important outcome measures in adult intensive care unit (ICU) patients with septic shock.
DESIGN:
CLASSIC is an international, multicentre, parallel-grouped, open-labelled, centrally randomised, stratified, outcome assessor- and analyst-blinded trial.
POPULATION:
Adult ICU patients who have septic shock and have received at least 1 L of IV fluid in the last 24-hours.
EXPERIMENTAL INTERVENTION:
In the IV fluid restriction group no IV fluids should be given in the ICU unless extenuating circumstances occur, including signs of severe hypoperfusion, overt fluid loss or a failing GI tract with a total fluid input of less than 1 L per day. In these circumstances, IV fluid may be given in measured amounts.
CONTROL INTERVENTION:
In the standard care group there will be no upper limit for the use of IV fluids.
OUTCOMES:
The primary outcome is 90-day mortality; secondary outcomes are serious adverse events in the ICU (ischemic events or severe acute kidney injury); serious adverse reactions in the ICU; days alive without life support at day 90; days alive and out of hospital at day 90 and mortality, health-related quality of life and cognitive function at 1-year.
TRIAL SIZE:
A total of 1554 participants will be randomised to allow the detection of a 15% relative risk reduction (7% absolute) in the restrictive vs. standard care group in 90-day mortality with a power of 80%.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Fluid restriction group | Experimental | Drug: Isotonic crystalloidsNo IV fluids unless one of the extenuating circumstances occur; then, IV fluid may be given in measured amounts: 1. In case of severe hypoperfusion or severe circulatory impairment defined by either: * Lactate≥4 mmol/L * MAP<50 mmHg (with or without vasopressor/inotrope) * Mottling beyond the kneecap (mottling score >2) OR * Urinary output<0.1 mL/kg bodyweight/h, but only in the first 2hrs after randomisation A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation 2. In case of overt fluid losses (e.g. vomiting, large aspirates,…) IV fluid may be given to correct for the loss, but not above the volume lost. 3. In case the oral/enteral route for water or electrolyte solutions is contraindicated or has failed, IV fluids may be given to: * Correct dehydration or electrolyte deficiencies * Ensure a total fluid input of 1L per 24hrs IV fluids may be given as carrier for medication, but the volume should be reduced to the lowest possible |
| Standard-care | Active comparator | Drug: Isotonic crystalloidsThere will be no upper limit for the use of either IV or oral/enteral fluids. In particular: 1. IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. These criteria are based on the Surviving Sepsis Campaign guideline. 2. IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3. IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Aged 18 years or above
- Admitted to the ICU or plan to be admitted to the ICU regardless of trial participation
- Septic shock defined according to the Sepsis-3 criteria:
- Have received at least 1 L of IV fluid (crystalloids, colloids or blood products) in the last 24-hours prior to screening.
Key exclusion criteria (6 listed)
- Septic shock for more than 12 hours at the time of screening as these patients are no longer early in their course
- Life-threatening bleeding as these patients need specific fluid/blood product strategies
- Acute burn injury of more than 10% of the body surface area as these patients need a specific fluid strategy
- Known pregnancy
- Consent not obtainable as per the model approved for the specific site
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 |
|---|---|---|
| Isotonic crystalloidsTypes of fluid to be used in both intervention groups: * IV fluids given for circulatory impairment: Only isotonic crystalloids are to be used as per the Scandinavian guideline for fluid resuscitation * Fluids given to substitute overt loss: Isotonic crystalloids are to be used. If large amounts of ascites are tapped, then human albumin may be used * Fluids used for dehydration: Water or isotonic glucose should be used * Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency, including water in the case of severe hypernatremia * Blood products are only to be used on specific indications including severe bleeding, severe anaemia and prophylactic in case of severe coagulopathy | Drug | Fluid restriction group, Standard-care |
Primary outcome
90-day Mortality
Time frame: Day 90 after randomisation
Al cause mortality at 90 days
7 secondary outcomes
Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU
Time frame: Until ICU discharge, maximum 90 days
Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU.
Time frame: Until ICU discharge, maximum 90 days
Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy)
Time frame: Until ICU discharge, maximum 90 days
Days Alive and Out of Hospital at Day 90
Time frame: Day 90 after randomisation
All-cause Mortality at 1-year After Randomisation
Time frame: 1-year after randomisation
Health-related Quality of Life 1 Year After Randomisation
Time frame: 1 year after randomisation
Cognitive Function 1-year After Randomisation
Time frame: 1-year after randomisation
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 27686349Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A; CLASSIC Trial Group; Scandinavian Critical Care Trials Group. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016 Nov;42(11):1695-1705. doi: 10.1007/s00134-016-4500-7. Epub 2016 Sep 30.
- Background: PubMed 35709019Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettila V, Moller MH, Kjaer MN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortso CJS, Meier N, Jensen TS, Engstrom J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herlov LS, Solling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schonemann-Lund M, Brochner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Adnoy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Radej J, Kriz M, Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17.
- Background: PubMed 31276193Meyhoff TS, Hjortrup PB, Moller MH, Wetterslev J, Lange T, Kjaer MN, Jonsson AB, Hjortso CJS, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst I, Ostermann M, Mouncey P, Rowan K, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Nebrich L, Russell L, Vang M, Rasmussen ML, Solling C, Rasmussen BS, Brochner AC, Perner A. Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan. Acta Anaesthesiol Scand. 2019 Oct;63(9):1262-1271. doi: 10.1111/aas.13434. Epub 2019 Jul 24.
- Derived from this study: PubMed 40272936Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV Fluid Restriction According to Standard Fluid Treatment Intensity Across Conservative Versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial Sites. Crit Care Med. 2025 Aug 1;53(8):e1590-e1600. doi: 10.1097/CCM.0000000000006679. Epub 2025 Apr 24.
- Derived from this study: PubMed 38576165Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV fluid restriction according to site-specific intensity of standard fluid treatment-protocol. Acta Anaesthesiol Scand. 2024 Aug;68(7):975-982. doi: 10.1111/aas.14423. Epub 2024 Apr 4.
- Derived from this study: PubMed 37330928Kjaer MN, Meyhoff TS, Sivapalan P, Granholm A, Hjortrup PB, Madsen MB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Ostermann M, Gould D, Cecconi M, Malbrain MLNG, Ahlstedt C, Kiel LB, Bestle MH, Nebrich L, Hildebrandt T, Russell L, Vang M, Rasmussen ML, Solling C, Brochner AC, Krag M, Pfortmueller C, Kriz M, Siegemund M, Albano G, Aagaard SR, Bundgaard H, Crone V, Wichmann S, Johnstad B, Martin YK, Seidel P, Martensson J, Hollenberg J, Wistrand M, Donati A, Barbara E, Karvunidis T, Hollinger A, Carsetti A, Lumlertgul N, Joelsson-Alm E, Lambiris N, Aslam TN, Friberg FF, Vesterlund GK, Mortensen CB, Vestergaard SR, Caspersen SF, Jensen DB, Borup M, Rasmussen BS, Perner A. Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock. Intensive Care Med. 2023 Jul;49(7):820-830. doi: 10.1007/s00134-023-07114-8. Epub 2023 Jun 18.
- Derived from this study: PubMed 31982391Meyhoff TS, Moller MH, Hjortrup PB, Cronhjort M, Perner A, Wetterslev J. Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest. 2020 Jun;157(6):1478-1496. doi: 10.1016/j.chest.2019.11.050. Epub 2020 Jan 23.
- Derived from this study: PubMed 31828753Kjaer MN, Meyhoff TS, Madsen MB, Hjortrup PB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst ICC, Ostermann M, Mouncey P, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Gyldensted L, Nebrich L, Russell L, Vang M, Solling C, Brochner AC, Rasmussen BS, Perner A. Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial. Acta Anaesthesiol Scand. 2020 Mar;64(3):410-416. doi: 10.1111/aas.13519. Epub 2019 Dec 26.
- Official study websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes
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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.
Tine Sylvest Meyhoff, MD principal investigator
Copenhagen University Hospital, Rigshospitalet
31 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Isotonic crystalloids in people with Septic Shock, run by Anders Perner, MD, PhD at 31 sites in 8 countries.
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 8 inclusion and 6 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 24 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 31 sites in Denmark, Sweden, Italy, Norway, Switzerland and 3 more countries. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 24 Feb 2025). 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?
90-day Mortality (time frame: Day 90 after randomisation). 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 NCT03668236, which also lists 8 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 24 Feb 2025.