Table 2.

Examples of pre-pandemic explanatory and pragmatic acute care trials

	Study population and enrolment	Interventions and study type	Sample size	Duration	Outcomes	Findings
Explanatory acute care trials
Trial of 12 mL/kg vs 6 mL/kg tidal volume positive-pressure ventilation for treatment of acute lung injury and ARDS (ARMA)41	Highly selected population of patients (≥18 years) with ARDS recruited by a dedicated research team at multiple sites in the USA	Traditional ventilator management (an initial tidal volume of 12 mL/kg ideal bodyweight) versus ventilation with a lower tidal volume (6 mL/kg ideal bodyweight); protocol specified tight control of all ventilator management and co-interventions such as ventilator weaning; multicentre, randomised controlled trial	861 patients randomly assigned (1:1) to traditional ventilator management (n=429) or ventilation with a lower tidal volume (n=432)	3 years (287 patients per year)	Primary outcomes: death before discharge home and number of ventilator-free days from day 1 to day 28; additional outcomes included extensive physiological data and biomarkers	Ventilation with lower tidal volumes reduced mortality
Efficacy and safety of drotrecogin alfa (activated) in adult patients with septic shock (PROWESS-SHOCK) trial42	Highly selected population of patients (≥18 years) with sepsis, shock, and clinical evidence of hypoperfusion recruited by a dedicated research team at multiple sites in several countries	Human activated protein C drotrecogin alfa (activated; 24 μg/kg per h for 96 h) versus placebo; multicentre, randomised, double-blind, placebo-controlled trial	1696 patients randomly assigned (1:1) to drotrecogin alfa (n=851) or placebo (n=845)	3·5 years (565 patients per year)	Primary outcome: mortality at 28 days; plasma protein C levels and SOFA score obtained daily for 7 days	Drotrecogin alfa (activated) did not significantly reduce mortality
Fluids And Catheters Treatment Trial (FACTT)43	Highly selected population of patients (≥13 years) with ARDS recruited by a dedicated research team at multiple sites in North America	Fluid-management with lower (conservative use of fluids) versus higher (liberal use of fluids) intravascular pressure guided by a pulmonary artery catheter or a central venous catheter; protocol specified tight control of fluid management in both groups; multicentre, randomised trial with a two-by-two factorial design	1000 patients randomly assigned (1:1) to conservative fluid management (n=503) or liberal fluid management (n=497)	5·5 years (182 patients per year)	Primary outcome: death before discharge home within the first 60 days	Conservative use of fluids did not reduce mortality but was associated with more ventilator-free days; pulmonary artery catheter-guided management did not improve survival and was associated with more complications
Pragmatic acute care trials
Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE) trial38	Patients (≥18 years) with STEMI at 31 centres enrolled within the existing Swedish Coronary Angiography and Angioplasty Registry with broad eligibility criteria; enrolment embedded into routine clinical care	Manual thrombus aspiration followed by PCI versus PCI only; intervention delivery embedded into routine clinical care; multicentre, open-label, randomised controlled trial	7244 patients randomly assigned (1:1) to manual thrombus aspiration and PCI (n=3621) or PCI only (n=3623)	3 years (2414 patients per year)	Primary outcome: all-cause 30-day mortality; all outcomes from a pre-existing registry	Thrombus aspiration before PCI reduced mortality among patients with STEMI
Corticosteroid Randomisation After Significant Head injury (CRASH) trial44	Patients (judged to be ≥16 years) with head injury and coma enrolled within 8 hours of injury at 239 hospitals from 49 countries with broad eligibility criteria; enrolment embedded into routine clinical care	48-h infusion of methylprednisolone or placebo; treatment embedded into routine clinical care; multicentre, randomised, double-blind, placebo-controlled trial	10 008 patients randomly assigned (1:1) to high-dose corticosteroids (n=5007) or placebo (n=5001)	5 years (2002 patients per year)	Primary outcomes: death at 2 weeks and death or disability at 6 months	Corticosteroid use after head injury increased mortality
Isotonic Solutions and Major Adverse Renal events Trial (SMART)33	All patients (≥18 years) admitted to one of five ICUs at an academic medical centre during the study period; enrolment, intervention delivery, and outcome assessment using electronic health records	Physiologically balanced isotonic crystalloids (lactated Ringer's solution or Plasma-Lyte A, according to treating clinician's preference) versus 0·9% saline; intervention delivery embedded into routine clinical care; open-label, cluster-randomised, multiple-crossover trial	15 802 patients randomly assigned (according to randomisation unit) to balanced crystalloids (n=7942) or saline (n=7860)	2 years (7901 patients per year)	Primary outcome: major adverse kidney event within 30 days (composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction)	Use of balanced crystalloids reduced the rate of death from any cause, new renal-replacement therapy, or persistent renal dysfunction

ARDS=acute respiratory distress syndrome. ICU=intensive care unit. PCI=percutaneous coronary intervention. SOFA=Sequential Organ Failure Assessment. STEMI=ST-segment elevation myocardial infarction.