title: Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial.
abstract: OBJECTIVE
  Catecholamine-resistant hypotension (CRH) is characterised by inadequate response to standard doses of vasopressors, and increased mortality. Our Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) trial compares the efficacy and safety of angiotensin II (ANGII) versus placebo in CRH.
  
  
  METHODS
  A phase III, multicentre, randomised, placebo-controlled trial of LJPC-501 (synthetic ANGII) for CRH in up to 120 intensive care units. We have set a target of 300 critically ill patients with CRH receiving standard-of-care (SOC) vasopressor therapy (ie, catecholamine dose > 0.2 µg/kg/min for 6-48 hours to maintain a mean arterial pressure [MAP] of 55-70 mmHg). Calculation of a norepinephrine-equivalent vasopressor dose is critical to determining patient eligibility, as ANGII will supplement ongoing vasopressor therapy.
  
  
  METHODS
  Stable patients will be randomised 1:1 to SOC vasopressor plus continuous intravenous infusion of ANGII or placebo for 48 hours, with an aim of achieving MAP of 75 mmHg for the first 3 hours. ANGII (initiated at 20 ng/ kg/min) will be titrated according to pre-specified guidelines until 48 hours, with patients followed until Day 7. Frequent vital sign and haemodynamic monitoring will support ANGII titration, safety monitoring and efficacy assessments.
  
  
  METHODS
  The primary efficacy endpoint is MAP ≥ 75 mmHg or an increase of ≥ 10 mmHg at treatment Hour 3. Secondary endpoints include change in total and cardiovascular Sequential Organ Failure Assessment scores over 48 hours, and safety data.
  
  
  CONCLUSIONS
  Our study will investigate the utility of adding ANGII to current SOC vasopressor options to increase the efficacy and safety of CRH therapy.
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, Washington, DC, USA. lchawla@ljpc.com.
authors.forename: Lakhmir S
authors.initials: LS
authors.lastname: Chawla
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.affiliation: Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Bagshaw
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Shaw
authors.affiliation: Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Goldstein
authors.affiliation: Departments of Surgery and Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
authors.affiliation: La Jolla Pharmaceutical Company, San Diego, CA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Tidmarsh
mesh_terms: D000804:Angiotensin II / Q000627:therapeutic use*; D002985:Clinical Protocols; D004311:Double-Blind Method; D006801:Humans; D007022:Hypotension / Q000188:drug therapy*; D012107:Research Design; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*
chemical_list: D014662:Vasoconstrictor Agents; D000804:Angiotensin II