Author Contributions: Dr Gladwin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gladwin, Kato, Weiner, Dampier, Howard, Hall, Blackwelder, Baldassarre, Casella.
Acquisition of data: Gladwin, Kato, Weiner, Onyekwere, Dampier, Hsu, Hagar, Howard, Nuss, Okam, Tremonti, Berman, Villella, Krishnamurti, Lanzkron, Castro, Gordeuk, Coles, Peters-Lawrence, Nichols, Baldassarre, Casella.
Analysis and interpretation of data: Gladwin, Kato, Weiner, Dampier, Hsu, Nuss, Krishnamurti, Gordeuk, Hildesheim, Casella.
Drafting of the manuscript: Gladwin, Kato, Weiner, Howard, Tremonti, Villella, Krishnamurti, Gordeuk, Coles, Peters-Lawrence, Nichols, Blackwelder, Baldassarre, Casella.
Critical revision of the manuscript for important intellectual content: Gladwin, Kato, Weiner, Onyekwere, Dampier, Hsu, Hagar, Nuss, Okam, Tremonti, Berman, Krishnamurti, Lanzkron, Castro, Hall, Hildesheim, Casella.
Statistical analysis: Gladwin, Kato, Gordeuk, Hildesheim, Blackwelder.
Obtained funding: Gladwin, Weiner, Baldassarre.
Administrative, technical, or material support: Gladwin, Onyekwere, Howard, Nuss, Tremonti, Villella, Castro, Coles, Peters-Lawrence, Nichols, Hall.
Study supervision: Gladwin, Kato, Weiner, Onyekwere, Dampier, Hsu, Howard, Villella, Krishnamurti, Baldassarre, Casella.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Gladwin reported having received research support in the form of a collaborative research and development agreement between the US government and Ikaria/INO Therapeutics and being listed as a co-inventor on a US patent for the use of nitrite salts for cardiovascular indications. Dr Gladwin reported receiving grant support from the Institute of Transfusion Medicine and the Hemophilia Center of Western Pennsylvania and federal funding from the National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (R01HL098032, RO1HL096973, RC1DK085852, P30AR058910). Dr Kato reported having received research grant support from a cooperative research and development agreement between the NIH and Ikaria/INO Therapeutics and from the Division of Intramural Research of the NIH. Dr Weiner reported having received research support from the Food and Drug Administration Orphan Product Development Grant Program. Dr Onyekwere reported having received research support from Novartis Pharmaceuticals, Eli Lilly, Icagen/McNeil, NIH/NHLBI, and Anthera Pharmaceuticals. Dr Dampier reported having received research grant support during the period of this study from Icagen, BioMarin Pharmaceuticals, and the NIH (U54HL070585, U10HL083705, R21HD049244, N01HB07159). Dr Dampier reported having had consulting relationships with Anthera Pharmaceuticals, GlycoMimetics, and Wyeth Pharmaceuticals. Dr Krishnamurti reported having received research support from the NHLBI (HB-06-06). Dr Gordeuk reported having received research support from Biomarin, TRF Pharma, and Emmaus Pharmaceuticals. Dr Baldassarre reported being an employee of Ikaria. Dr Casella reported having received research support from the NIH, NHLBI, National Institute of Neurological Disorders and Stroke, National Center for Research Resources (NCRR), Maternal and Child Health Bureau, and Maryland Department of Health and Mental Hygiene. Dr Casella reported receiving past research support from Cytrex Corporation for the investigation of a drug (poloxamer 188) for use in vaso-occlusive crisis. The results of these studies have been reported. No ongoing relationship exists. No other conflicts were reported.
Funding/Support: This project was collaboratively supported and funded by Ikaria and the Intramural Research Division of the NHLBI, NIH, US Department of Health and Human Services (DHHS). The data and safety monitoring board was assembled and supported by the Intramural Research Division of the NHLBI, NIH, US DHHS. Statistical analysis was supported and independently conducted by the investigators using funds from the Vascular Medicine Institute, Hemophilia Center of Western Pennsylvania, and the Institute for Transfusion Medicine (M.T.G.). This study also received support from grant UL1RR025005 to JHU from the NCRR, a component of the NIH and the NIH Roadmap for Medical Research.
Role of the Sponsors: Study drug, placebo, and delivery devices were provided by Ikaria. Ikaria, formerly INO Therapeutics, provided the Data Coordinating Center, so it was involved in the conduct of the study, collection of data, and management of the site data collection. Dr Baldassarre is an employee of Ikaria and contributed to the analysis of data as an author. Ikaria and Dr Baldassarre reviewed the manuscript but did not have rights to approve the manuscript. The study design and statistical analysis were performed independently by study investigators and performed under the auspices of an NIH government collaborative research and development agreement. The blinded statistical reviewer was employed by the NIH and not Ikaria.
DeNOVO Clinical Site Support Teams (subinvestigators, study coordinators, and respiratory therapists): NIH: Catarina Minniti, MD; Kevin Coles, RRT; Howard University Hospital: Abiodun Akintilo, MS; Alice Ukaegbu, MSN, FNP; George Tandongfuet, RRT; JHU School of Medicine: Phillip Seaman, PA; Gary Oldenburg, RRT; St Christopher's Hospital for Children: Maureen Meier (Rockstein), RN, CCRC; Marylou MacDermott, MSN, CRNP; Steven Johnson, CRTT, MEd; Annette Horton, RRT; Alta Bates Medical Center: Vickie Nolan; Terri Nielsen, RN, BSN; Lou Schroel; Children's Hospital Boston: Eric Fleegler, MD; Matthew Heeney, MD; Pam Boardman, MPH; Nancy Craig, RTT; University of Colorado Health Science Center: Julie McAfee, BA; Laura Cole; Donna Parker, RRT; Brigham and Women's Hospital: Ronald McCaffrey, MD; Ainsley Ross, BA; Case Western Reserve University: Philip Toltzis, MD; University of Alabama at Birmingham: Roy McDonald; Lindley Webb, CPNP; Mary Jones; Craig Wooten, RT; Children's Hospital of Pittsburgh: Maria Schmucker; Al Saville, RRT; Mike Simpson, RRT.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the opinions of the NIH or US government.