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Table 1 Key features of explanatory versus pragmatic clinical trialsa

From: PRagMatic Pediatric Trial of Balanced vs nOrmaL Saline FlUid in Sepsis: study protocol for the PRoMPT BOLUS randomized interventional trial

Study element Explanatory clinical trial Pragmatic clinical trial Considerations for PRoMPT BOLUS
Objective Mechanism or efficacy Effectiveness Comparative effectiveness of two existing standards of care
Study population Restrictive, homogeneous (“ideal” target population) Heterogeneous (“real-world” clinical practice) Children treated with fluid therapy for suspected septic shock with abnormal perfusion as per treating clinician judgment
Intervention Inflexible, strictly enforced Usual practice #1 Balanced/buffered crystalloid fluid (site/clinician preference to use lactated Ringer’s, PlasmaLyte, or Hartmann’s)
Comparison Inflexible, placebo, or usual practice Usual practice #2 0.9% saline
Data collection Extensive, labor-intensive Targeted, limited Targeted and limited to essential data to ensure balance in key covariates between study groups and to collect all outcomes
Protocol implementation and oversight Dedicated study team assists with enrollment and study procedures Treating clinicians carry out study procures embedded within clinical practice Emergency physicians will be trained to screen, enroll, randomize, and initiate study fluids for bolus and maintenance therapy
Protocol adherence Closely monitored with tight parameters Unobtrusive or none Guidance provided to treating clinicians to use randomized study fluid for bolus and maintenance fluid therapy from randomization through 11:59 PM of the following calendar day; non-study fluids allowed for specific clinical indications at clinicians’ judgment. Final adherence defined as receipt of ≥75% of total crystalloid administered by type assigned in the intervention phase.
Outcome(s) Specialized experts often involved in quantifying study endpoints that are direct consequence of intervention Endpoints are objective, clinically meaningful, and easily measured as part of routine clinical practice MAKE30, mortality, hospital-free days, adverse events, and biomarkers all defined with objective criteria; effectiveness and safety outcomes all patient-centered.
Analysis Intention-to treat with interpretation that intervention improves outcomes under “ideal” conditions Intention-to-treat with interpretation that intervention improves outcomes under “usual” conditions Intention-to-treat analysis will be interpreted as the comparative effectiveness between predominant—rather than exclusive—use of balanced/buffered fluids versus 0.9% saline
Generalizability Variable (though often low) Variable (though typically high) Expected to be highly generalizable
Costs Relatively high Relatively low Relatively low for large clinical trial
  1. aAdapted from Thorpe et al Journal of Clinical Epidemiology 2009