Nitric Oxide Inhalation to Treat Sickle Cell Pain Crises

A Prospective, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis

This study will examine whether nitric oxide (NO) gas can reduce the time it takes for pain to go away in patients who are in sickle cell crisis. NO is important in regulating blood vessel dilation, and consequently, blood flow. The gas is continuously produced by cells that line the blood vessels. It is also transported from the lungs by hemoglobin in red blood cells.

Patients 10 years of age or older with sickle cell disease (known SS, S-beta-thalassemia or other blood problems causing sickle cell disease) may be eligible for this study. Patients whose disease is due to hemoglobin (Hgb) SC are excluded. Candidates are screened with blood tests and a chest x-ray to look at the lungs and heart.

Participants are admitted to the hospital in a pain crisis. They are evaluated and then randomly assigned to receive one of two treatments: 1) standard treatment plus NO, or 2) standard treatment plus placebo. The placebo used in this study is nitrogen, a gas that makes up most of the air we breathe and is not known to help in sickle cell disease.

For the first 8 hours of the study, patients receive placebo or NO through a facemask. The mask may be taken off for 5 minutes every hour and for not more than 20 minutes to eat a meal. After the first 8 hours, the gas is delivered through a nasal cannula (small plastic tubing that rests under the nose) that may be taken off only while showering or using the restroom. Patients are questioned about the severity of their pain when they start the study and then every few hours while they are in the hospital. Their vital signs (temperature, breathing rate, and blood pressure) and medicines are checked. Patients will breathe the gas for a maximum of 3 days, but will stay hospitalized until the patient feels well enough to go home. Patients are followed up about 1 month after starting the study by a return visit to the hospital or by a phone call.

Study Overview

• Status: Completed
• Conditions: Anemia, Sickle Cell
• Intervention / Treatment: Drug: Nitric Oxide; Drug: Placebo

Detailed Description

The object of this study is to determine the safety and efficacy of nitric oxide for inhalation in the treatment of vaso-occlusive pain crisis (VOC) in patients with sickle cell disease. The study population will include patients with sickle cell disease (SS, S-beta-Thalassemia) presenting with vaso-occlusive pain crisis. Patients will be administered either placebo or inhaled nitric oxide to see if the experimental agent, inhaled nitric oxide, can reduce the time it takes for resolution of the vaso-occlusive crisis.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • California
    • Oakland, California, United States, 94609-1809
      • Children's Hospital Oakland
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Colorado Sickle Cell Treatement and Research Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard University Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02115
      • Childrens Hospital, Boston
  • Ohio
    • Cleveland, Ohio, United States, 44106-2602
      • Case Western Reserve University Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15213-2583
      • Childrens Hospital, Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Each subject must meet all of the following inclusion criteria during the screening process in order to participate in the study:

• Patient must have a diagnosis of SCD (known SS, S-Beta-thalassemia or other hemoglobinopathies causing sickle cell disease). Patients with disease due to Hgb SC are not permitted.
• Must present to the ED/EC or other appropriate unit in VOC.
• Greater than or equal to 10 years old.
• Written informed consent/assent has been obtained.

Exclusion Criteria:

Subjects meeting any of the following criteria during baseline evaluation will be excluded from entry into the study:

• Exposure to therapeutic nitric oxide within the past 12 hours.
• Patient has received sildenafil or other phosphodiesterase 5 inhibitors, therapeutic L-arginine, nitroprusside or nitroglycerine within the past 12 hours.
• Patient has received previous ED/EC or other appropriate unit treatment for a vaso-occlusive crisis less than 48 hours or hospitalization less than 14 days ago (patients transferred directly from another ED or clinic may be enrolled).
• Patient has visited the ED/EC or other appropriate unit greater than 10 times in the past year having a vaso-occlusive crisis.
• Patients presenting with clinically diagnosed bacterial infection (e.g., osteomyelitis, pneumonia, sepsis or meningitis).
• Patients who are currently enrolled in any other investigational drug study except for hydroxyurea studies.
• Pregnant women (urine HCG + )/ nursing mothers.
• Patients who have received an exchange transfusion (not simple transfusion) in the last 30 days or are on a chronic simple or exchange transfusion program.
• Suspected splenic sequestration.
• Acute chest syndrome or pneumonia: Abnormal new pulmonary infiltrate (alveolar infiltration and not atelectasis) and one or more pulmonary signs and/or symptoms (fever, rales, wheezing, cough, shortness of breath, retractions).
• Previous participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inhaled Nitric Oxide; Participants receive Inhaled nitric oxide (INO)	Drug: Nitric Oxide; Nitric oxide will be delivered for 4 hours at 80 ppm through a face mask. The dose will then be reduced to 40 ppm for 4 hours. After a total of 8 hours of treatment through face mask, the patient will get 6 mL/puls/breath of NO at 800 ppm or 3 m//pulse/breath, depending on patient weight.; Other Names: INOmax
Placebo Comparator: Placebo; Participants receive Nitrogen gas	Drug: Placebo; Nitrogen gas will be delivered in the same manor as the experimental drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Vaso-occlusive Pain Crisis (VOC) Resolution	VOC resolution was defined by all of the following conditions: Pain relief - Visual Analog Scale (VAS) pain scores of 6 or less, (6 as worst and 0 as best); Freedom from parenteral narcotic use,; Ability to walk unless the subject was not able to walk for any reason other than acute VOC prior to the onset of crisis,; Subject and/or family's belief that the painful crisis could be managed at home with or without oral analgesic use, and the physician concurred with that assessment.	within 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Hospitalization	Length of hospitalization is defined as the length of time from admission to discharge order	within 40 days
Number of Participants Discharged to Home Within the First 24 Hours		within 24 hours
Total Dose of Opioids Received	The total dose (mg) of opioid medications received during the trial	within 8 hours and within 40 days
Number of Participants With Acute Chest Syndrome/Pneumonia Requiring Blood Transfusion	Number of participants who required a blood transfusion before discharge because of acute chest syndrome/pneumonia	within 40 days
Number of Participants Readmitted to Hospital Within 30 Days After Discharge	The number of participants readmitted to the hospital for any reason within 30 days after discharge	during first 24 hours and during 30 day follow-up

Collaborators and Investigators

• Sponsor: Mallinckrodt
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Study Director: James Baldassarre, MD, Mallinckrodt

Publications and helpful links

General Publications

• Sanders DY, Severance HW, Pollack CV Jr. Sickle cell vaso-occlusive pain crisis in adults: alternative strategies for management in the emergency department. South Med J. 1992 Aug;85(8):808-11. doi: 10.1097/00007611-199208000-00005.
• Gladwin MT, Kato GJ, Weiner D, Onyekwere OC, Dampier C, Hsu L, Hagar RW, Howard T, Nuss R, Okam MM, Tremonti CK, Berman B, Villella A, Krishnamurti L, Lanzkron S, Castro O, Gordeuk VR, Coles WA, Peters-Lawrence M, Nichols J, Hall MK, Hildesheim M, Blackwelder WC, Baldassarre J, Casella JF; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011 Mar 2;305(9):893-902. doi: 10.1001/jama.2011.235.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: October 1, 2004
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: October 28, 2004
• First Submitted That Met QC Criteria: October 27, 2004
• First Posted (Estimate): October 28, 2004

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: January 17, 2020
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; SCD; Nitric Oxide; Sickle Cell Anemia; Blood Flow; Pain Crisis; Vaso-Occlusive Crisis
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: INOT 36; 05-H-0019 (Registry Identifier: NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO