The NIH was one of eleven centers nationwide in this prospective, multi-center, double-blind, randomized, placebo-controlled study of 150 patients with SCD presenting with vaso-occlusive pain crisis. The objective was to determine the safety and efficacy of nitric oxide for inhalation in the treatment of vaso-occlusive pain crisis in patients with sickle cell disease and to validate an approved device for transcutaneous measurement of methemoglobin in a population of patients with sickle cell anemia.. The study population included patients with sickle cell disease (SS, S-beta-Thalassemia) presenting with vaso-occlusive pain crisis. Patients with known SCD were identified and consented prior to their presentation to the Emergency Department/Emergency Clinic (ED/EC) or other appropriate unit. Entry into the trial began when the patient presented to the ED/EC or other appropriate unit in pain crisis, met all inclusion criteria and signed an informed consent confirming their willingness to participate. Participants were 10 years of age or above and were administred either placebo or inhaled nitric oxide to see if the experimental agent, inhaled nitric oxide, could reduce the time it takes for resolution of the vaso-occlusive crisis. We, at the NIH, began pre-enrolling in January 2005 and pre-enrolled 116 subjects. Of these 116 subjects, 51 actually enrolled and were randomized to either placebo or nitric oxide and an additional 13 more subjects who were not pre-enrolled also were randomized in the study, bringing the total number of subjects at the NIH randomized to the study to 64. Of these 64 subjects, 5 were children. Some of the other participating sites also pre-enrolled subjects. The total number of subjects randomized in the treatment study was 150. As of December 22, 2008 the protocol was closed to recruitment and enrollment. The trial lasted for approximately 45 months and all participating sites have completed enrollment and follow up. The primary results are summarized from the 2011 publication in JAMA: CONTEXT: Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). OBJECTIVE: To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. MAIN OUTCOME MEASURES: The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours;(2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale);(3) ability to walk;and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home. RESULTS: There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval CI, 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. CONCLUSION: Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. The study remains open for data analysis and manuscript preparation. Additional analysis of secondary outcome variables is proceeding.
|Gladwin, Mark T; Kato, Gregory J; Weiner, Debra et al. (2011) Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 305:893-902|