Sickle Cell AnemiaPhase 1NCT00095472
Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease
A Phase 1 study testing L-NMMA and Sodium Nitrite in people with Sickle Cell Anemia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
This study examines ways in which nitric oxide (NO), an important molecule that controls how blood flows through the body's vessels, might be restored with a compound called sodium nitrite. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sickle Cell Anemia
- What is being tested?
- L-NMMA and Sodium Nitrite
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Nov 2004to 24 Aug 2007
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Must be at least 18 years of age
- Homozygous sickle cell disease or S beta-0-thalassemia/alpha-thalassemia
- Provides informed, written consent for participation
Who cannot join
- Patients with currently uncontrolled hypertension (diastolic blood pressures greater than 95 mmHg)
- Hypercholesterolemia (LDL cholesterol greater than 130 mg/dL)
- Diabetes mellitus (fasting blood glucose greater than 120 mg/dL)
- Smoking within one month
- Dietary ingestions of herbal medications, alcohol or caffeine within 12 hours of the study
- Arteriosclerotic cardiovascular disease
Show all 13Show fewer
- Peripheral arteriosclerotic vascular disease
- Treatment within the last 14 days with sildenafil, vardenafil, tadalafil, inhaled nitric oxide, nitroglycerin or other NO-dependent drugs, such as arginine
- Red cell G6PD activity below normal range (All subjects will be tested for red blood cell G6PD deficiency; levels below the lower limits of normal will result in exclusion from participation in the study)
- Cytochrome B5 deficiency
- History of reaction to a medication or other substance characterized by dyspnea and cyanosis
- Lactating females (Lactating females will not participate since nitrites cross into breast milk and could cause methemoglobinemia in the infant)
- Pregnancy testing (urine or blood) will be required of all women of reproductive age to exclude current pregnancy
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
This study examines ways in which nitric oxide (NO), an important molecule that controls how blood flows through the body's vessels, might be restored with a compound called sodium nitrite. It is hoped that the result will reverse the effect of decreased flow of blood due to sickled cells-that is, cells that have changed into the shape of a crescent or sickle. Sickle cell disease is the most common genetic disease affecting African Americans. About 8% of that population has the sickle cell trait. The changed cells can become attached to blood vessels, decreasing blood flow to vital organs. There can be the loss of needed proteins, including hemoglobin, that deliver oxygen throughout the body.
Adults at least 18 years of age who have the SS form of sickle cell disease or S-beta-thalassemia, are in either a steady state or crisis, give informed and written consent for participation, and have had a negative pregnancy test may be eligible for this study. Adults with any other disease that puts them at risk for reduced circulation are not eligible. Women who are breastfeeding are not eligible.
Read more
Participants will undergo a medical history, including family medical history, and a detailed physical evaluation, to take about 1 hour. There will be a collection of blood; echocardiogram, which involves taking a picture of the heart and its four chambers; and measurement of exhaled carbon monoxide, carbon dioxide, and NO. A procedure called orthogonal polarization spectral imaging will be performed. A small object the size of a Popsicle stick will be placed under the tongue or on a fingertip. This procedure presents a picture of blood flow and how the red blood cells appear as they circulate through blood vessels. The study will be conducted in the Vascular Laboratory/Cardiovascular Floor or Intensive Care and will last about 4 hours.
During the study, patients will lie in an adjustable reclining bed and chair. Small tubes will be placed in the artery and vein of the forearm at the inside of the elbow. A small pressure cuff will be applied to the wrist and a larger one to the upper arm. Both cuffs will be inflated with air. A strain gauge, resembling a rubber band, will go around the widest part of the forearm. When the pressure cuffs fill with air, blood will flow into the arm, and information from the strain gauge will be recorded. Between administrations of each medicine, there will be 30-minute rests. Normal saline will be put into the small tube in the artery. Measurements of the blood flow in the forearm will be taken, and a small blood sample will be taken to measure blood counts, proteins, and other natural body chemicals. Then a medicine called sodium nitroprusside, which causes blood vessels to expand and increase blood flow, will be placed into the forearm. It will be given at three different doses for 3 minutes each, with measurements recorded after each dose. Then a medicine called L-NMMA will be placed into the forearm. L-NMMA generally decreases local blood flow by preventing nitric oxide from being produced in the cells lining the blood vessels. It will be given at two different doses for 5 minutes each, with blood flow measured after each dose. Next, nitrite will be placed in the forearm at three different doses for 5 minutes each. Before and after nitrite is given, the researchers will measure the amount of the NO, carbon monoxide, and carbon dioxide that the patients breathe out. Then the procedure for administering normal saline, sodium nitroprusside, and L-NMMA will be repeated, as will a blood test.
This study will not have a direct benefit for participants. However, it is hoped that the information gained from the study will help to develop treatment options for patients with sickle cell disease.
Read the detailed description
Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, microvascular obstruction, inflammation, and end-organ ischemia-reperfusion injury and infarction. Our published data indicate that up to 50% of sickle cell patients have endothelial dysfunction due to impaired bioavailability of endogenous nitric oxide due in large part to scavenging of nitric oxide by cell-free plasma hemoglobin. These data suggest that therapies directed at restoring NO bioavailability might prove beneficial. We have recently discovered that the nitrite anion, available currently for human use as a component of the cyanide antidote kit, is a vasodilator in vivo by generating nitric oxide (NO) in tissues with lower oxygen tension and pH. The mechanism involves a novel physiological function of human hemoglobin as an oxygen- and pH dependent nitrite reductase. To date we have observed that nitrite infusions in animal models significantly reduce liver and cardiac ischemia-reperfusion injury and infarction in mouse models, prevent cerebral vasospasm after subarachnoid hemorrhage in primates, and decrease pulmonary hypertension in newborn hypoxic sheep. The current protocol is designed as a phase I/II trial to address the hypothesis that nitrite infusions will vasodilate the circulation in patients with sickle cell disease at rest and during vaso-occlusive pain crisis, inactivate circulating cell-free plasma hemoglobin, reduce pulmonary artery pressures and reduce ischemia-reperfusion injury (measured by circulating markers of oxidant stress).
- Conditions
- Sickle Cell Anemia
- Being tested
- L-NMMA, Sodium Nitrite
- Keywords
- Blood Flow, Nitric Oxide, Vascular Function, Vasodilation, Vaso-Occlusive Pain Crisis, Sickle Cell Disease
- Medical subject headings
- Anemia, Sickle Cell, Aneurysm
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-NMMADrug
Sodium NitriteDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
Determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent regional blood flow in patients with sickle cell disease.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2004 (estimated)
- Study start1 Nov 2004
- Primary completion24 Aug 2007
- Study completion24 Aug 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell AnemiaStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Investigators
- John F Tisdale, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00095472
- Sponsor's protocol ID
- 050016
- Other IDs
- 05-H-0016
- Status last verified
- 7 Dec 2015
- First submitted
- 4 Nov 2004
- Last updated
- 5 Nov 2019
- Results posted
- No
Publications
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
PubMed 6253831Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987 Dec;61(6):866-79. doi: 10.1161/01.res.61.6.866.
PubMed 2890446Rees DD, Palmer RM, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418-24. doi: 10.1111/j.1476-5381.1989.tb11833.x.
PubMed 2924084
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT00095472
- Acronym / sponsor ID
- 050016
- Conditions
- Sickle Cell Anemia
- Keywords
- Blood Flow, Nitric Oxide, Vascular Function, Vasodilation, Vaso-Occlusive Pain Crisis, Sickle Cell Disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 1 Nov 2004
- Primary completion
- 24 Aug 2007 (actual)
- Study completion
- 24 Aug 2007 (actual)
- First posted
- 5 Nov 2004 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study examines ways in which nitric oxide (NO), an important molecule that controls how blood flows through the body's vessels, might be restored with a compound called sodium nitrite. It is hoped that the result will reverse the effect of decreased flow of blood due to sickled cells-that is, cells that have changed into the shape of a crescent or sickle. Sickle cell disease is the most common genetic disease affecting African Americans. About 8% of that population has the sickle cell trait. The changed cells can become attached to blood vessels, decreasing blood flow to vital organs. There can be the loss of needed proteins, including hemoglobin, that deliver oxygen throughout the body.
Adults at least 18 years of age who have the SS form of sickle cell disease or S-beta-thalassemia, are in either a steady state or crisis, give informed and written consent for participation, and have had a negative pregnancy test may be eligible for this study. Adults with any other disease that puts them at risk for reduced circulation are not eligible. Women who are breastfeeding are not eligible.
Participants will undergo a medical history, including family medical history, and a detailed physical evaluation, to take about 1 hour. There will be a collection of blood; echocardiogram, which involves taking a picture of the heart and its four chambers; and measurement of exhaled carbon monoxide, carbon dioxide, and NO. A procedure called orthogonal polarization spectral imaging will be performed. A small object the size of a Popsicle stick will be placed under the tongue or on a fingertip. This procedure presents a picture of blood flow and how the red blood cells appear as they circulate through blood vessels. The study will be conducted in the Vascular Laboratory/Cardiovascular Floor or Intensive Care and will last about 4 hours.
During the study, patients will lie in an adjustable reclining bed and chair. Small tubes will be placed in the artery and vein of the forearm at the inside of the elbow. A small pressure cuff will be applied to the wrist and a larger one to the upper arm. Both cuffs will be inflated with air. A strain gauge, resembling a rubber band, will go around the widest part of the forearm. When the pressure cuffs fill with air, blood will flow into the arm, and information from the strain gauge will be recorded. Between administrations of each medicine, there will be 30-minute rests. Normal saline will be put into the small tube in the artery. Measurements of the blood flow in the forearm will be taken, and a small blood sample will be taken to measure blood counts, proteins, and other natural body chemicals. Then a medicine called sodium nitroprusside, which causes blood vessels to expand and increase blood flow, will be placed into the forearm. It will be given at three different doses for 3 minutes each, with measurements recorded after each dose. Then a medicine called L-NMMA will be placed into the forearm. L-NMMA generally decreases local blood flow by preventing nitric oxide from being produced in the cells lining the blood vessels. It will be given at two different doses for 5 minutes each, with blood flow measured after each dose. Next, nitrite will be placed in the forearm at three different doses for 5 minutes each. Before and after nitrite is given, the researchers will measure the amount of the NO, carbon monoxide, and carbon dioxide that the patients breathe out. Then the procedure for administering normal saline, sodium nitroprusside, and L-NMMA will be repeated, as will a blood test.
This study will not have a direct benefit for participants. However, it is hoped that the information gained from the study will help to develop treatment options for patients with sickle cell disease.
Detailed description
Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, microvascular obstruction, inflammation, and end-organ ischemia-reperfusion injury and infarction. Our published data indicate that up to 50% of sickle cell patients have endothelial dysfunction due to impaired bioavailability of endogenous nitric oxide due in large part to scavenging of nitric oxide by cell-free plasma hemoglobin. These data suggest that therapies directed at restoring NO bioavailability might prove beneficial. We have recently discovered that the nitrite anion, available currently for human use as a component of the cyanide antidote kit, is a vasodilator in vivo by generating nitric oxide (NO) in tissues with lower oxygen tension and pH. The mechanism involves a novel physiological function of human hemoglobin as an oxygen- and pH dependent nitrite reductase. To date we have observed that nitrite infusions in animal models significantly reduce liver and cardiac ischemia-reperfusion injury and infarction in mouse models, prevent cerebral vasospasm after subarachnoid hemorrhage in primates, and decrease pulmonary hypertension in newborn hypoxic sheep. The current protocol is designed as a phase I/II trial to address the hypothesis that nitrite infusions will vasodilate the circulation in patients with sickle cell disease at rest and during vaso-occlusive pain crisis, inactivate circulating cell-free plasma hemoglobin, reduce pulmonary artery pressures and reduce ischemia-reperfusion injury (measured by circulating markers of oxidant stress).
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Must be at least 18 years of age
- Homozygous sickle cell disease or S beta-0-thalassemia/alpha-thalassemia
- Provides informed, written consent for participation
Key exclusion criteria (13 listed)
- Patients with currently uncontrolled hypertension (diastolic blood pressures greater than 95 mmHg)
- Hypercholesterolemia (LDL cholesterol greater than 130 mg/dL)
- Diabetes mellitus (fasting blood glucose greater than 120 mg/dL)
- Smoking within one month
- Dietary ingestions of herbal medications, alcohol or caffeine within 12 hours of the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-NMMA | Drug | – |
| Sodium Nitrite | Drug | – |
Primary outcome
Determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent regional blood flow in patients with sickle cell disease.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2019.
- Background: PubMed 6253831Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
- Background: PubMed 2890446Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987 Dec;61(6):866-79. doi: 10.1161/01.res.61.6.866.
- Background: PubMed 2924084Rees DD, Palmer RM, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418-24. doi: 10.1111/j.1476-5381.1989.tb11833.x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John F Tisdale, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing L-NMMA and Sodium Nitrite in people with Sickle Cell Anemia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent regional blood flow in patients with sickle cell disease.. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00095472, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2019.