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

Abstract

Background: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock.

Methods: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events.

Discussion: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial.

Trial registration: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

Keywords: Angiotensin II; Biomarker; DPP3; Dipeptidyl-peptidase 3; Renin; Septic shock; Vasopressor.

Fig. 1

Schedule of enrollment, interventions, and assessments. *Time zero is defined as 2 h after randomization in the standard of care arm and as time of angiotensin II initiation in the intervention arm. †Post-discontinuation biomarker levels will be obtained only in the angiotensin II arm. ‡See Data Collection Form for a full list of baseline characteristics/comorbidities/medical history, laboratory values, and adverse events being collected. §Acute kidney injury will be defined and staged using creatinine-based 2012 KDIGO (Kidney Disease Improving Global Outcomes) criteria [30]. ‖Diagnosis of ARDS will be ascertained via screening of clinical notes and corroborated by the investigators using the 2012 Berlin Criteria [31]. Abbreviations: DPP3, dipeptidyl-peptidase 3; ICU, intensive care unit; IMV, invasive mechanical ventilation; LOS, length of stay; KRT, kidney replacement therapy; SOFA, sequential organ failure assessment