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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00094887

Enrollment

150

Registered

2004-10-28

Start date

2004-10-31

Completion date

2008-12-31

Last updated

2020-02-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anemia, Sickle Cell

Keywords

Blood Flow, Nitric Oxide, Pain Crisis, Sickle Cell Anemia, Vaso-Occlusive Crisis, Sickle Cell Disease, SCD

Brief summary

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.

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.

Interventions

DRUGNitric 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.

DRUGPlacebo

Nitrogen gas will be delivered in the same manor as the experimental drug.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

10 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Time to Vaso-occlusive Pain Crisis (VOC) Resolution	within 30 days	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.

Secondary

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

Countries

United States

Participant flow

Recruitment details

Participants were recruited from 11 study centers in the United States

Pre-assignment details

Of the 150 participants recruited, 150 were randomized (1:1) into treatment groups.

Participants by arm

Arm	Count
Inhaled Nitric Oxide Inhaled Nitric Oxide INO	75
Placebo Nitrogen gas	75
Total	150

Baseline characteristics

Characteristic	Total	Placebo	Inhaled Nitric Oxide
Age, Continuous	26.3 years STANDARD_DEVIATION 10.75	26.0 years STANDARD_DEVIATION 10.49	26.6 years STANDARD_DEVIATION 11.06
Age, Customized < 16 years	26 participants	14 participants	12 participants
Age, Customized >=16 years	124 participants	61 participants	63 participants
Region of Enrollment United States	150 participants	75 participants	75 participants
Sex: Female, Male Female	75 Participants	37 Participants	38 Participants
Sex: Female, Male Male	75 Participants	38 Participants	37 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	35 / 75	33 / 75
serious Total, serious adverse events	7 / 75	6 / 75

Outcome results

Primary

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.

Time frame: within 30 days

Population: Primary efficacy analysis set, defined as intent to treat population with VOC resolution

Arm	Measure	Value (MEDIAN)
Inhaled Nitric Oxide	Time to Vaso-occlusive Pain Crisis (VOC) Resolution	61.83 Hours
Placebo	Time to Vaso-occlusive Pain Crisis (VOC) Resolution	55.16 Hours

p-value: =0.8085Wilcoxon (Mann-Whitney)

Secondary