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Crit Care Resusc. 2017 Mar;19(1):43-49.

Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial.

Author information

1
Department of Medicine, Veterans Affairs Medical Center, Washington, DC, USA. lchawla@ljpc.com.
2
Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
3
Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
4
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
5
Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
6
Departments of Surgery and Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
7
La Jolla Pharmaceutical Company, San Diego, CA, USA.

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.

DESIGN, SETTING AND PARTICIPANTS:

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.

INTERVENTIONS:

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.

MAIN OUTCOME MEASURES:

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.

CONCLUSION:

Our study will investigate the utility of adding ANGII to current SOC vasopressor options to increase the efficacy and safety of CRH therapy.

PMID:
28215131
[Indexed for MEDLINE]

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