Dataset Information

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial.

ABSTRACT:

Rationale

Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome.

Methods

A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria.

Intervention

A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38).

Outcomes

The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others.

Results

Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or non-invasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market.

Conclusion

There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering.

Trial registration

Nederlands Trial Register ISRCTN 52566874.

SUBMITTER: Cornet AD

PROVIDER: S-EPMC3954619 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial.

Cornet Alexander D AD Groeneveld A B Johan AB Hofstra Jorrit J JJ Vlaar Alexander P AP Tuinman Pieter R PR van Lingen Arthur A Levi Marcel M Girbes Armand R J AR Schultz Marcus J MJ Beishuizen Albertus A

PloS one 20140314 3

<h4>Rationale</h4>Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome.<h4>Methods</h4>A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included ...[more]

PMID: 24632673

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Project description:BackgroundRenin-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.MethodsWe 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.ResultsDose 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.ConclusionsGSK2586881 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.Trial registrationClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

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Dataset Information

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial.

Rationale

Methods

Intervention

Outcomes

Results

Conclusion

Trial registration

Publications

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial.

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