Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial

Abstract

Background: The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone.

Methods: This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (<14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and β=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy.

Results: We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO.

Conclusions: We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE.

Conflict of interest statement

Conflicts of interest: No other authors have a conflict to report

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1

Diagram of study hypothesis and integration of the clinical study and the basic science study. PE causes intracardiac hemolysis which disrupts NO signaling by scavenging NO and releasing arginase which depletes L-arginine, producing a negative feedback cycle of increased pulmonary VSM constriction, increased PVR, higher RV pressures and more hemolysis. Inhaled NO (iNO*) will break this cycle.

Figure 2

Timeline and key measurements of the clinical study. Echo #1was optional. O2 delivery by nasal cannula can vary depending upon patient comfort.

Figure 3

Protocol for administering and weaning study drug. Relative endpoints included persistent symptoms or signs, that in the judgment of the investigator, appeared to be worsened by increasing the inhaled NO ppm and improved by decreasing the inhaled NO ppm. Absolute endpoints included: respiratory distress prompting the clinical care team to plan for mechanical or noninvasive ventilatory support, hypoxemia (SaO2 10% for more than one hour, or persistent vomiting). The rapid wean protocol was an immediate halving of the inspired concentration and assessment of clinical status; if the patient were improved, the NO was reduced to 0 ppm.

Figure 4

Power estimates assuming two effect sizes of 0.25 and 0.30 each with two different assumptions for p1 and p2