A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

被引：461

作者：

Khan, Akram ^{[1
]}

Benthin, Cody ^{[1
]}

Zeno, Brian ^{[2
]}

Albertson, Timothy E. ^{[3
]}

Boyd, John ^{[4
]}

Christie, Jason D. ^{[5
]}

Hall, Richard ^{[6
,7
]}

Poirier, Germain ^{[8
]}

Ronco, Juan J. ^{[9
]}

Tidswell, Mark ^{[10
]}

Hardes, Kelly ^{[11
]}

Powley, William M. ^{[12
]}

Wright, Tracey J. ^{[12
]}

Siederer, Sarah K. ^{[12
]}

Fairman, David A. ^{[12
]}

Lipson, David A. ^{[5
,13
]}

Bayliffe, Andrew I. ^{[12
]}

Lazaar, Aili L. ^{[5
,13
]}

机构：

[1] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA

[2] Riverside Methodist Hosp, Columbus, OH 43214 USA

[3] Univ Calif Davis, Sch Med, Sacramento, CA 95616 USA

[4] St Pauls Hosp, Vancouver, BC, Canada

[5] Univ Penn, Sch Med, Div Pulm Allergy & Crit Care Med, Philadelphia, PA 19104 USA

[6] Nova Scotia Hlth Author, Halifax, NS, Canada

[7] Dalhousie Univ, Halifax, NS, Canada

[8] Sherbrooke Univ, Charles LeMoyne Hosp, Greenfield Pk, PQ, Canada

[9] Univ British Columbia, Vancouver Gen Hosp, Crit Care Med, Vancouver, BC, Canada

[10] Baystate Med Ctr, Dept Med, Div Pulm & Crit Care, Springfield, MA 01199 USA

[11] GlaxoSmithKline R&D, Stockley Pk, England

[12] GlaxoSmithKline R&D, Stevenage, Herts, England

[13] GlaxoSmithKline R&D, King Of Prussia, PA USA

来源：

CRITICAL CARE | 2017年 / 21卷

关键词：

Angiotensin-converting enzyme 2; Acute lung injury; Respiratory distress syndrome; Adult; Acute respiratory failure; Renin-angiotensin system; Humans; Interleukin-6; SURFACTANT-PROTEIN-D; LUNG INJURY; OXIDATIVE STRESS; BLOOD-PRESSURE; II FORMATION; POLYMORPHISM; SYSTEM; DYSFUNCTION; ACTIVATION; ARDS;

D O I：

10.1186/s13054-017-1823-x

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Background: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.

引用

页数：9

共 37 条

[21] Angiotensin converting enzyme insertion /deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome [J].