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Table 4 Secondary outcomes

From: The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock

Key secondary clinical outcomes:

• Days free from KRT (up to 28 days)

• Days free from mechanical ventilation (up to 28 days)

• ICU mortality

• Hospital mortality

Additional secondary clinical outcomes:

• Vasopressor response, as quantified by decrease in NED of background vasopressor(s) in the AT2 arm and total vasopressor requirement in NED in the control arm (i.e., primary proximate endpoint), will be re-assessed at multiple additional time points:

o 1 h

o 6 h

o 12 h

o 24 h

o 48 h

o 72 h

• Time to sustained shock reversal (as defined by vasopressor independence)

• Change in SOFA [36] scores and organ-specific SOFA sub-scores at 24 h, 48 h, and 72 h

• Frequency of acute kidney injury (as defined by KDIGO criteria [30])

• ICU length of stay

• Hospital length of stay

Exploratory analyses of biomarker kinetics:

• Repeating the primary analysis (i.e., the ability of baseline biomarker levels to predict change in total NED at 3 h, adjusted for baseline SOFA score and treatment arm) using pre-baseline biomarker levels obtained immediately upon patient entry into the study (instead of baseline biomarker levels, obtained with initiation of AT2 therapy in the AT2 arm or 2 h after randomization in the control arm)

• Correlations between changes in biomarker levels and change in total NED or ICU mortality

• In the AT2 arm, we will assess for presence of rebound effect by measuring biomarker levels 24 (± 8) h post-drug discontinuation and, if present, will assess for correlation of rebound effect with ICU mortality

Prespecified safety endpoints/adverse events (AEs):a

• New venous thromboembolism or arterial thrombosis diagnosed during hospital stay

• Atrial fibrillation

• Tachycardia (heart rate > 100/min sustained for ≥ 1 h)

• Lactic acidosis

• Peripheral limb/digital ischemia

• Intestinal ischemia

• Thrombocytopenia

• Hyperglycemia

• Confirmed infection (with infecting organism confirmed by culture or other identification method; administration of appropriate antimicrobial therapy; and clinical documentation of infection)

• Any other potentially related AEs will be recorded

  1. aFor these to be considered AEs, they must be new hospital-acquired events which developed after randomization. Additional Abbreviations: AT2 angiotensin II, ICU intensive care unit, KRT kidney replacement therapy, NED norepinephrine equivalent dose, SOFA Sequential Organ Failure Assessment
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ISSN: 1745-6215