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 No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO.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.
Bibliographical noteFunding Information:
The trial was sponsored by the National Institutes of Health (UM1HL113203-01 to J. A. K.) and by an investigator-initiated grant from Ikaria Pharmaceuticals, who manufactured the INOvent device in 2013. Ikaria was acquired by Mallinckrodt Pharmaceuticals in 2015. Additional funding and the COBAS device for high-sensitivity troponin T measurements were obtained through an investigator-initiated contract with Roche. The sponsors had no role in the protocol design, and have had and will have no role in data analysis presentation or manuscript writing.
© 2017 Elsevier Inc.