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Randomized Controlled Trial
. 2011 Mar 2;305(9):893-902.
doi: 10.1001/jama.2011.235.

Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial

Mark T Gladwin  1 , Gregory J Kato, Debra Weiner, Onyinye C Onyekwere, Carlton Dampier, Lewis Hsu, R Ward Hagar, Thomas Howard, Rachelle Nuss, Maureen M Okam, Carole K Tremonti, Brian Berman, Anthony Villella, Lakshmanan Krishnamurti, Sophie Lanzkron, Oswaldo Castro, Victor R Gordeuk, Wynona A Coles, Marlene Peters-Lawrence, James Nichols, Mary K Hall, Mariana Hildesheim, William C Blackwelder, James Baldassarre, James F Casella; DeNOVO Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial

Mark T Gladwin et al. JAMA. .

Abstract

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.

Trial registration: clinicaltrials.gov Identifier: NCT00094887.

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Conflict of interest statement

Conflict of Interest and Financial Disclosure:

Mark T. Gladwin has received research support in the form of a Collaborative Research and Development Agreement between the US Government and Ikaria/INO Therapeutics and is listed as a co-inventor on a US Government Patent for the use of nitrite salts for cardiovascular indications. Dr. Gladwin receives grant support from the Institute of Transfusion Medicine, the Hemophilia Center of Western Pennsylvania and Federal funding by the NHLBI, NIDDK and NIAMS of the National Institutes of health (NIH grants R01HL098032, RO1HL096973, RC1DK085852, P30AR058910).

Gregory J. Kato has received research grant support from a cooperative research and development agreement between the National Institutes of Health and Ikaria INO Therapeutics and from the Division of Intramural Research of the National Institutes of Health. Victor R. Gordeuk has received research support from Biomarin and TRF-Pharma, and Emmaus Pharmaceuticals.

Lakshmanan Krishnamurti has received research support from the National Heart Lung and Blood Institute (NHLBI HB-06-06).

James F. Casella has received research support from the National Institutes of Health, NHLBI, NINDS, NCRR, MCHB, Maryland DHMH. Dr. Casella received 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 (ref). No ongoing relationship exists.

James Baldassarre is an employee of Ikaria.

Debra Weiner, MD, PhD has received research support from the FDA Orphan Product Development Grant Program.

Onyinye Onyekwere, MD, has received research support from Novartis Pharmaceuticals, Eli Lilly and Company, Icagen/McNeil, NIH/NHLBI and Anthera Pharmaceuticals, Inc

Carlton Dampier MD received research grant support during the period of this study from Icagen, Inc, BioMarin Pharmaceuticals, Inc, and the National Institutes of Health (U54HL070585, U10HL083705, R21HD049244, N01HB07159). Dr Dampier also had consulting relationships with Anthera Pharmaceuticals Inc, GlycoMimetics Inc, and Wyeth Pharmaceuticals Inc

Lewis Hsu, MD, R. Ward Hagar, MD, Thomas Howard, MD, Brigitta G. Mueller, MD, Rachelle Nuss, MD, Maureen Okam, MD, Lakshmanan Krishnamurti, MD; Brian Berman, M.D., Oswaldo Castro, MD, Victor R. Gordeuk, MD,; Wynona Coles, RT, Mariana Hildesheim, MS, Mary K. Hall, CIP, William C. Blackwelder, PhD, James Baldassarre, MD, Deborah Weiner, MD, James Casella, MD, Carlton Dampier, MD report no relevant conflict of interest related to the participant of this manuscript.

Figures

Figure 1
Figure 1. Patient Enrollment and Randomization
The patient population consisted of 150 patients presenting with VOC who were enrolled and randomized in a prospective, placebo-controlled, double-blind clinical trial of inhaled NO versus placebo at sites in the United States. Four patients withdrew in each group, and the numbers resolving pain crisis were 65 and 64 for the iNO and placebo groups, respectively. All 150 participants were evaluated by intention to treat. The large number of patients assessed for eligibility (1,078) reflects the pre-enrollment of out-patients at many of the sites.
Figure 2
Figure 2. Efficacy of Inhaled NO Gas Versus Placebo on VOC
There was no significant effect of inhaled NO on time to VOC resolution by Kaplan-Meier analysis (A), p=.87, log-rank test.
Figure 3
Figure 3. Effect of Inhaled NO Gas on methemoglobin
Methemoglobin concentrations were significantly higher for participants on inhaled NO gas than for participants in the placebo group (A; p < .0001). Blood samples for nitrate and nitrite testing were taken before crisis when possible (labeled baseline), on Day 1 before treatment started (labeled Pre-Tx), and on each subsequent day until discharge.
Figure 4
Figure 4. Kaplan-Meier Analysis of VOC Resolution by Study Site, Gender and Pain at Baseline
Shorter times to VOC resolution were observed for participants at NIH and JHU (A; p<.001, log-rank test), males (B; p=.04, log-rank test), and participants with baseline VAS scores less than 7.7 cm (C; p<.001, log-rank test). No significant differences in time to resolution were observed in participants on hydroxyurea therapy (D; p=.4, log-rank test).
Figure 4
Figure 4. Kaplan-Meier Analysis of VOC Resolution by Study Site, Gender and Pain at Baseline
Shorter times to VOC resolution were observed for participants at NIH and JHU (A; p<.001, log-rank test), males (B; p=.04, log-rank test), and participants with baseline VAS scores less than 7.7 cm (C; p<.001, log-rank test). No significant differences in time to resolution were observed in participants on hydroxyurea therapy (D; p=.4, log-rank test).
Figure 4
Figure 4. Kaplan-Meier Analysis of VOC Resolution by Study Site, Gender and Pain at Baseline
Shorter times to VOC resolution were observed for participants at NIH and JHU (A; p<.001, log-rank test), males (B; p=.04, log-rank test), and participants with baseline VAS scores less than 7.7 cm (C; p<.001, log-rank test). No significant differences in time to resolution were observed in participants on hydroxyurea therapy (D; p=.4, log-rank test).
Figure 4
Figure 4. Kaplan-Meier Analysis of VOC Resolution by Study Site, Gender and Pain at Baseline
Shorter times to VOC resolution were observed for participants at NIH and JHU (A; p<.001, log-rank test), males (B; p=.04, log-rank test), and participants with baseline VAS scores less than 7.7 cm (C; p<.001, log-rank test). No significant differences in time to resolution were observed in participants on hydroxyurea therapy (D; p=.4, log-rank test).
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References

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