Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan

Tine Sylvest Meyhoff; Peter Buhl Hjortrup; Morten Hylander Møller; Jørn Wetterslev; Theis Lange; Maj-Brit Nørregaard Kjær; Andreas Bender Jonsson; Carl Johan Steensen Hjortsø; Maria Cronhjort; Jon Henrik Laake; Stephan M. Jakob; Marek Nalos; Ville Pettilä; Iwan van der Horst; Marlies Ostermann; Paul Mouncey; Kathy Rowan; Maurizio Cecconi; Ricard Ferrer; Manu L N G Malbrain; Christian Ahlstedt; Søren Hoffmann; Morten Heiberg Bestle; Lars Nebrich; Lene Russell; Marianne Vang; Michael Lindhardt Rasmussen; Christoffer Sølling; Bodil Steen Rasmussen; Anne Craveiro Brøchner; Anders Perner

doi:10.1111/aas.13434

Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan

Tine Sylvest Meyhoff, Peter Buhl Hjortrup, Morten Hylander Møller, Jørn Wetterslev, Theis Lange, Maj-Brit Nørregaard Kjær, Andreas Bender Jonsson, Carl Johan Steensen Hjortsø, Maria Cronhjort, Jon Henrik Laake, Stephan M. Jakob, Marek Nalos, Ville Pettilä, Iwan van der Horst, Marlies Ostermann, Paul Mouncey, Kathy Rowan, Maurizio Cecconi, Ricard Ferrer, Manu L N G MalbrainChristian Ahlstedt, Søren Hoffmann, Morten Heiberg Bestle, Lars Nebrich, Lene Russell, Marianne Vang, Michael Lindhardt Rasmussen, Christoffer Sølling, Bodil Steen Rasmussen, Anne Craveiro Brøchner, Anders Perner

7 Citations (Scopus)

Abstract

Introduction: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. Discussion: The CLASSIC trial results will provide important evidence to guide clinicians’ choice regarding the IV fluid therapy in adults with septic shock.

Original language	English
Journal	Acta Anaesthesiologica Scandinavica
Volume	63
Issue number	9
Pages (from-to)	1262-1271
Number of pages	10
ISSN	0001-5172
DOIs	https://doi.org/10.1111/aas.13434
Publication status	Published - 1 Oct 2019

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Meyhoff, T. S., Hjortrup, P. B., Møller, M. H., Wetterslev, J., Lange, T., Kjær, M.-B. N., Jonsson, A. B., Hjortsø, C. J. S., Cronhjort, M., Laake, J. H., Jakob, S. M., Nalos, M., Pettilä, V., van der Horst, I., Ostermann, M., Mouncey, P., Rowan, K., Cecconi, M., Ferrer, R., ... Perner, A. (2019). Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan. Acta Anaesthesiologica Scandinavica, 63(9), 1262-1271. https://doi.org/10.1111/aas.13434

Meyhoff, TS, Hjortrup, PB, Møller, MH, Wetterslev, J, Lange, T, Kjær, M-BN, Jonsson, AB, Hjortsø, CJS, Cronhjort, M, Laake, JH, Jakob, SM, Nalos, M, Pettilä, 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, Sølling, C, Rasmussen, BS, Brøchner, AC & Perner, A 2019, 'Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan', Acta Anaesthesiologica Scandinavica, vol. 63, no. 9, pp. 1262-1271. https://doi.org/10.1111/aas.13434

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title = "Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan",

abstract = "Introduction: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. Discussion: The CLASSIC trial results will provide important evidence to guide clinicians{\textquoteright} choice regarding the IV fluid therapy in adults with septic shock.",

author = "Meyhoff, {Tine Sylvest} and Hjortrup, {Peter Buhl} and M{\o}ller, {Morten Hylander} and J{\o}rn Wetterslev and Theis Lange and Kj{\ae}r, {Maj-Brit N{\o}rregaard} and Jonsson, {Andreas Bender} and Hjorts{\o}, {Carl Johan Steensen} and Maria Cronhjort and Laake, {Jon Henrik} and Jakob, {Stephan M.} and Marek Nalos and Ville Pettil{\"a} and {van der Horst}, Iwan and Marlies Ostermann and Paul Mouncey and Kathy Rowan and Maurizio Cecconi and Ricard Ferrer and Malbrain, {Manu L N G} and Christian Ahlstedt and S{\o}ren Hoffmann and Bestle, {Morten Heiberg} and Lars Nebrich and Lene Russell and Marianne Vang and Rasmussen, {Michael Lindhardt} and Christoffer S{\o}lling and Rasmussen, {Bodil Steen} and Br{\o}chner, {Anne Craveiro} and Anders Perner",

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volume = "63",

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TY - JOUR

T1 - Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan

AU - Meyhoff, Tine Sylvest

AU - Hjortrup, Peter Buhl

AU - Møller, Morten Hylander

AU - Wetterslev, Jørn

AU - Lange, Theis

AU - Kjær, Maj-Brit Nørregaard

AU - Jonsson, Andreas Bender

AU - Hjortsø, Carl Johan Steensen

AU - Cronhjort, Maria

AU - Laake, Jon Henrik

AU - Jakob, Stephan M.

AU - Nalos, Marek

AU - Pettilä, Ville

AU - van der Horst, Iwan

AU - Ostermann, Marlies

AU - Mouncey, Paul

AU - Rowan, Kathy

AU - Cecconi, Maurizio

AU - Ferrer, Ricard

AU - Malbrain, Manu L N G

AU - Ahlstedt, Christian

AU - Hoffmann, Søren

AU - Bestle, Morten Heiberg

AU - Nebrich, Lars

AU - Russell, Lene

AU - Vang, Marianne

AU - Rasmussen, Michael Lindhardt

AU - Sølling, Christoffer

AU - Rasmussen, Bodil Steen

AU - Brøchner, Anne Craveiro

AU - Perner, Anders

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Introduction: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. Discussion: The CLASSIC trial results will provide important evidence to guide clinicians’ choice regarding the IV fluid therapy in adults with septic shock.

AB - Introduction: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. Discussion: The CLASSIC trial results will provide important evidence to guide clinicians’ choice regarding the IV fluid therapy in adults with septic shock.

U2 - 10.1111/aas.13434

DO - 10.1111/aas.13434

M3 - Journal article

C2 - 31276193

SN - 0001-5172

VL - 63

SP - 1262

EP - 1271

JO - Acta Anaesthesiologica Scandinavica

JF - Acta Anaesthesiologica Scandinavica

IS - 9

ER -

Conservative versus Liberal fluid therapy in Septic Shock (CLASSIC) trial - protocol and statistical analysis plan

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