Nitric Oxide Inhalation to Treat Sickle Cell Pain Crises
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
| 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:
|
| Placebo Comparator: Placebo Participants receive Nitrogen gas |
Drug: Placebo
Nitrogen gas will be delivered in the same manor as the experimental drug.
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama | Birmingham | Alabama | United States | 35294 |
| 2 | Children's Hospital Oakland | Oakland | California | United States | 94609-1809 |
| 3 | Colorado Sickle Cell Treatement and Research Center | Aurora | Colorado | United States | 80045 |
| 4 | Howard University Hospital | Washington | District of Columbia | United States | 20060 |
| 5 | Johns Hopkins University | Baltimore | Maryland | United States | 21205 |
| 6 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
| 7 | Brigham and Women's Hospital | Boston | Massachusetts | United States | 02115 |
| 8 | Childrens Hospital, Boston | Boston | Massachusetts | United States | 02115 |
| 9 | Case Western Reserve University Hospital | Cleveland | Ohio | United States | 44106-2602 |
| 10 | St. Christopher's Hospital for Children | Philadelphia | Pennsylvania | United States | 19134 |
| 11 | Childrens Hospital, Pittsburgh | Pittsburgh | Pennsylvania | United States | 15213-2583 |
Sponsors and Collaborators
- Mallinckrodt
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Study Director: James Baldassarre, MD, Mallinckrodt
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- INOT 36
- 05-H-0019
- NCT00652535
Study Results
Participant Flow
| Recruitment Details | Participants were recruited from 11 study centers in the United States |
|---|---|
| Pre-assignment Detail | Of the 150 participants recruited, 150 were randomized (1:1) into treatment groups. |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Period Title: Overall Study | ||
| STARTED | 75 | 75 |
| Safety Population | 75 | 75 |
| Intent to Treat Population | 75 | 75 |
| Per Protocol Analysis Set | 71 | 71 |
| Primary Efficacy Population | 65 | 64 |
| COMPLETED | 71 | 71 |
| NOT COMPLETED | 4 | 4 |
Baseline Characteristics
| Arm/Group Title | Inhaled Nitric Oxide | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Inhaled Nitric Oxide INO | Nitrogen gas | Total of all reporting groups |
| Overall Participants | 75 | 75 | 150 |
| Age, Customized (participants) [Number] | |||
| < 16 years |
12
16%
|
14
18.7%
|
26
17.3%
|
| >=16 years |
63
84%
|
61
81.3%
|
124
82.7%
|
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
26.6
(11.06)
|
26.0
(10.49)
|
26.3
(10.75)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
38
50.7%
|
37
49.3%
|
75
50%
|
| Male |
37
49.3%
|
38
50.7%
|
75
50%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
75
100%
|
75
100%
|
150
100%
|
Outcome Measures
| Title | Time to Vaso-occlusive Pain Crisis (VOC) Resolution |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Primary efficacy analysis set, defined as intent to treat population with VOC resolution |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Measure Participants | 65 | 64 |
| Median (Full Range) [Hours] |
61.83
|
55.16
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Inhaled Nitric Oxide, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | = 0.8085 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Title | Length of Hospitalization |
|---|---|
| Description | Length of hospitalization is defined as the length of time from admission to discharge order |
| Time Frame | within 40 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intention to treat |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Measure Participants | 75 | 75 |
| Median (Full Range) [Days] |
4.06
|
3.11
|
| Title | Number of Participants Discharged to Home Within the First 24 Hours |
|---|---|
| Description | |
| Time Frame | within 24 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intention to treat |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Measure Participants | 75 | 75 |
| Count of Participants [Participants] |
5
6.7%
|
7
9.3%
|
| Title | Total Dose of Opioids Received |
|---|---|
| Description | The total dose (mg) of opioid medications received during the trial |
| Time Frame | within 8 hours and within 40 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intention to treat |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Measure Participants | 75 | 75 |
| within 8 hours |
16.25
|
17.25
|
| within 40 days |
153.75
|
211.37
|
| Title | Number of Participants With Acute Chest Syndrome/Pneumonia Requiring Blood Transfusion |
|---|---|
| Description | Number of participants who required a blood transfusion before discharge because of acute chest syndrome/pneumonia |
| Time Frame | within 40 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intention to treat |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Measure Participants | 75 | 75 |
| Count of Participants [Participants] |
8
10.7%
|
7
9.3%
|
| Title | Number of Participants Readmitted to Hospital Within 30 Days After Discharge |
|---|---|
| Description | The number of participants readmitted to the hospital for any reason within 30 days after discharge |
| Time Frame | during first 24 hours and during 30 day follow-up |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intention to treat |
| Arm/Group Title | Inhaled Nitric Oxide | Placebo |
|---|---|---|
| Arm/Group Description | Participants receive Inhaled Nitric Oxide (INO) | Participants receive Nitrogen gas |
| Measure Participants | 75 | 75 |
| during first 24 hours |
0
0%
|
0
0%
|
| during 30-day follow-up |
9
12%
|
17
22.7%
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | 75 subjects were assigned to treatment with iNO and 75 subjects were assigned to treatment with placebo; all subjects were included in the ITT and Safety Populations. 142 subjects completed the study according to the protocol and 8 subjects (4 in each treatment group) did not complete the study according to protocol. | |||
| Arm/Group Title | Inhaled Nitric Oxide | Placebo | ||
| Arm/Group Description | Inhaled Nitric Oxide INO | Nitrogen gas | ||
All Cause Mortality |
||||
| Inhaled Nitric Oxide | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Inhaled Nitric Oxide | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/75 (9.3%) | 6/75 (8%) | ||
| Blood and lymphatic system disorders | ||||
| Acute Chest Syndrome | 5/75 (6.7%) | 5 | 5/75 (6.7%) | 5 |
| Gastrointestinal disorders | ||||
| Dysphagia | 1/75 (1.3%) | 1 | 0/75 (0%) | 0 |
| General disorders | ||||
| Pyrexia | 1/75 (1.3%) | 1 | 1/75 (1.3%) | 1 |
| Sensation of Foreign Body | 1/75 (1.3%) | 1 | 0/75 (0%) | 0 |
| Investigations | ||||
| Hemoglobin Decrease | 1/75 (1.3%) | 1 | 0/75 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Inhaled Nitric Oxide | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 35/75 (46.7%) | 33/75 (44%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 5/75 (6.7%) | 5 | 4/75 (5.3%) | 4 |
| Gastrointestinal disorders | ||||
| Constipation | 2/75 (2.7%) | 2 | 4/75 (5.3%) | 4 |
| Nausea | 5/75 (6.7%) | 5 | 4/75 (5.3%) | 4 |
| Vomiting | 5/75 (6.7%) | 5 | 1/75 (1.3%) | 2 |
| General disorders | ||||
| Pyrexia | 12/75 (16%) | 13 | 10/75 (13.3%) | 10 |
| Nervous system disorders | ||||
| Headache | 3/75 (4%) | 3 | 5/75 (6.7%) | 5 |
| Skin and subcutaneous tissue disorders | ||||
| Pruritis | 4/75 (5.3%) | 4 | 6/75 (8%) | 6 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Medical Information Call Center |
|---|---|
| Organization | Mallinckrodt Pharmaceuticals |
| Phone | 800-556-3314 |
| clinicaltrials@mnk.com |
- INOT 36
- 05-H-0019
- NCT00652535