Table 1 Key features of explanatory versus pragmatic clinical trialsa
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 |