Sickle Cell AnemiaPhase 2NCT00009581
Nitric Oxide to Improve Blood Flow in Sickle Cell Disease
A Phase 2 study testing L-NMMA and Acetylcholine in people with Sickle Cell Anemia, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
Trial summary
Nitric oxide is important in regulating blood vessel dilation, and consequently, blood flow. This gas is continuously produced by cells that line the blood vessels. It is also transported from the lungs by hemoglobin in red blood cells. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Sickle Cell Anemia
- What is being tested?
- L-NMMA and Acetylcholine
- How many people
- 65 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2001to Jan 2003
- Phase
- Phase 2
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Males or females 18 to 65 years of age are eligible.
- Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S beta(0) thallassemia genotype is required).
- Hematocrit greater than 18 percent (with an absolute reticulocyte count greater than 100,000/ml).
- Volunteer subjects taking hydroxyurea must have been on therapy with the drug for at least four months. Volunteer subjects not taking hydroxyurea must have been off of therapy with the drug for at least 4 months.
Who cannot join
- Clinically unstable sickle cell anemia defined as having an acute pain crisis within the last week.
- Age less than 18 years or greater than 65 years.
- Current pregnancy or lactation.
- Conditions that may independently affect endothelial function:
- Diabetes mellitus or Fasting blood sugar greater than 120 mg/dL
- Cigarette smoking within two years
Show all 13Show fewer
- Hypertension (diastolic blood pressure greater than 90 mmHg)
- Lipid abnormalities (LDL cholesterol greater than 160 mg/dL, HDL cholesterol less than 30 mg/dL, triglycerides greater than 500 mg/dL)
- Creatinine greater than 1.0 mg/dL
- Hematocrit less than or equal to 18 percent: however, patients may return for evaluation at a later date.
- No aspirin or non-steroidal antiinflammatory drugs (NSAIDs for one week and caffeine the day of the study). Patients on opiates and acetaminophen will not be excluded.
- Patients taking sildenafil (Viagra) will be excluded from the study.
- Recent transfusion (last 4 weeks) or hemoglobin A greater than 5 percent.
Trial locations and contacts
1 site in 1 country.
United States1 site
Warren G. Magnuson Clinical Center (CC)
Bethesda, Maryland, 20892
About this study
Official title: Targeted Delivery of Nitric Oxide by Hemoglobin to Improve Regional Blood Flow in Sickle Cell Disease
Nitric oxide is important in regulating blood vessel dilation, and consequently, blood flow. This gas is continuously produced by cells that line the blood vessels. It is also transported from the lungs by hemoglobin in red blood cells. This study will examine how this gas regulates blood vessels and blood flow in people with sickle cell anemia. It will also look at a possible benefit of using certain genetic information to compare the white blood cells of people with sickle cell anemia to those without the disease.
Patients with sickle cell anemia and healthy normal volunteers 18 to 65 years of age may be eligible for this study. Candidates will be screened with a medical history, cardiovascular physical examination, electrocardiogram and routine blood tests. Participation of volunteers without sickle cell anemia will be limited to a single blood draw for genetic study. Sickle cell disease patients will undergo the following procedures:
Read more
Patients will lie in a reclining chair during the study. After administration of a local anesthetic, small tubes will be inserted through a needle into the artery and vein of the patient's forearm. These are used to measure blood pressure and draw blood samples during the study. Forearm blood flow will be measured using pressure cuffs placed on the wrist and upper arm, and a strain gauge (a rubber band device) placed around the forearm. When the cuffs are inflated, blood flows into the arm, stretching the strain gauge, and the flow measurement is recorded. A small lamp will be positioned over the hand. Light reflected back from the hand provides information about nitric oxide and hemoglobin in the blood of the skin. A squeezing device called a dynamometer will be used to measure handgrip strength.
Baseline blood flow, nitric oxide, hemoglobin, and handgrip will be measured after an infusion of glucose (sugar) and water. These measurements will be repeated at various times before, during and after administration of small doses of the following drugs:
- Sodium nitroprusside - causes blood vessels to dilate and increases blood flow to the heart
- Acetylcholine - causes blood vessels to dilate and slows heart rate
- LNMMA - decreases blood flow by blocking the production of nitric oxide
There will be a 20- to 30-minute rest period between injections of the different drugs.
When the above tests are completed, the patient will breathe a mixture of room air and nitric oxide for 1 hour through a facemask placed over the face, after which forearm blood flow and light reflected from the hand will be measured. Then the patient will do the handgrip exercise for 5 minutes, after which blood flow and hand lamp measurements will be taken. After a 20-minute rest period (with continued breathing of room air/nitric oxide), L-NMMA will be infused again. The handgrip exercise, blood flow and hand lamp measurements will be repeated. The face mask will then be removed, and the tubes will be removed 20 minutes later.
Blood samples will be collected at various times during the 5- to 6-hour study through the tubes in the arm. Some of the blood will be used to look at genes that make proteins involved in cell-to-cell communication, inflammation, and in making red and white blood cells stick to the lining of blood vessels.
Read the detailed description
Sickle cell anemia 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. Acute pain crisis and acute chest syndrome are common complications of sickle cell anemia. Inhaled nitric oxide (NO) has been proposed as a possible therapy for the acute chest syndrome. Anecdotally, NO has been described to rapidly improve the hypoxemia and the clinical course of the acute chest syndrome. Furthermore, a number of recent studies have suggested that NO may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia. This clinical trial is designed to test the hypotheses that 1) individuals with sickle cell anemia have endothelial dysfunction with reduced local synthesis and release of NO, that may reduce regional perfusion at rest and impair the vasodilator response to stress, and 2) during NO inhalation, delivery of NO bound to hemoglobin will be enhanced and will improve these abnormalities in regional vascular perfusion. Studies will be performed on untreated sickle cell anemia patients and on patients managed with chronic hydroxyurea therapy. Demonstration of improved regional perfusion with NO therapy could have significant implications for patient management during acute pain crisis and the acute chest syndrome.
- Conditions
- Sickle Cell Anemia
- Being tested
- L-NMMA, Acetylcholine
- Keywords
- Endothelial Function, Hydroxyurea, Leukocyte Gene Expression, Nitrosylated Hemoglobin, Sickle Cell Anemia, Nitric Oxide
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-NMMADrug
AcetylcholineDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2001 (estimated)
- Study startJan 2001
- Study completionJan 2003
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.
- 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 2
- Primary purpose
- Treatment
- Enrolment
- 65 participants
Sponsor and investigators
- Lead sponsor
- National Institutes of Health Clinical Center (CC)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00009581
- Sponsor's protocol ID
- 010078
- Other IDs
- 01-CC-0078
- Status last verified
- Jan 2003
- First submitted
- 1 Feb 2001
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology. 1997 Oct;87(4):988-90. doi: 10.1097/00000542-199710000-00037. No abstract available.
PubMed 9357905Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood. 2000 Oct 1;96(7):2451-9.
PubMed 11001897Cardillo C, Kilcoyne CM, Cannon RO 3rd, Panza JA. Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation. Hypertension. 1998 Jun;31(6):1235-9. doi: 10.1161/01.hyp.31.6.1235.
PubMed 9622135
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeted Delivery of Nitric Oxide by Hemoglobin to Improve Regional Blood Flow in Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT00009581
- Acronym / sponsor ID
- 010078
- Conditions
- Sickle Cell Anemia
- Keywords
- Endothelial Function, Hydroxyurea, Leukocyte Gene Expression, Nitrosylated Hemoglobin, Sickle Cell Anemia, Nitric Oxide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants
- Lead sponsor
- National Institutes of Health Clinical Center (CC)US National Institutes of Health
- Study start
- Jan 2001
- Study completion
- Jan 2003
- First posted
- 2 Feb 2001 (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.
Nitric oxide is important in regulating blood vessel dilation, and consequently, blood flow. This gas is continuously produced by cells that line the blood vessels. It is also transported from the lungs by hemoglobin in red blood cells. This study will examine how this gas regulates blood vessels and blood flow in people with sickle cell anemia. It will also look at a possible benefit of using certain genetic information to compare the white blood cells of people with sickle cell anemia to those without the disease.
Patients with sickle cell anemia and healthy normal volunteers 18 to 65 years of age may be eligible for this study. Candidates will be screened with a medical history, cardiovascular physical examination, electrocardiogram and routine blood tests. Participation of volunteers without sickle cell anemia will be limited to a single blood draw for genetic study. Sickle cell disease patients will undergo the following procedures:
Patients will lie in a reclining chair during the study. After administration of a local anesthetic, small tubes will be inserted through a needle into the artery and vein of the patient's forearm. These are used to measure blood pressure and draw blood samples during the study. Forearm blood flow will be measured using pressure cuffs placed on the wrist and upper arm, and a strain gauge (a rubber band device) placed around the forearm. When the cuffs are inflated, blood flows into the arm, stretching the strain gauge, and the flow measurement is recorded. A small lamp will be positioned over the hand. Light reflected back from the hand provides information about nitric oxide and hemoglobin in the blood of the skin. A squeezing device called a dynamometer will be used to measure handgrip strength.
Baseline blood flow, nitric oxide, hemoglobin, and handgrip will be measured after an infusion of glucose (sugar) and water. These measurements will be repeated at various times before, during and after administration of small doses of the following drugs:
- Sodium nitroprusside - causes blood vessels to dilate and increases blood flow to the heart
- Acetylcholine - causes blood vessels to dilate and slows heart rate
- LNMMA - decreases blood flow by blocking the production of nitric oxide
There will be a 20- to 30-minute rest period between injections of the different drugs.
When the above tests are completed, the patient will breathe a mixture of room air and nitric oxide for 1 hour through a facemask placed over the face, after which forearm blood flow and light reflected from the hand will be measured. Then the patient will do the handgrip exercise for 5 minutes, after which blood flow and hand lamp measurements will be taken. After a 20-minute rest period (with continued breathing of room air/nitric oxide), L-NMMA will be infused again. The handgrip exercise, blood flow and hand lamp measurements will be repeated. The face mask will then be removed, and the tubes will be removed 20 minutes later.
Blood samples will be collected at various times during the 5- to 6-hour study through the tubes in the arm. Some of the blood will be used to look at genes that make proteins involved in cell-to-cell communication, inflammation, and in making red and white blood cells stick to the lining of blood vessels.
Detailed description
Sickle cell anemia 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. Acute pain crisis and acute chest syndrome are common complications of sickle cell anemia. Inhaled nitric oxide (NO) has been proposed as a possible therapy for the acute chest syndrome. Anecdotally, NO has been described to rapidly improve the hypoxemia and the clinical course of the acute chest syndrome. Furthermore, a number of recent studies have suggested that NO may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia. This clinical trial is designed to test the hypotheses that 1) individuals with sickle cell anemia have endothelial dysfunction with reduced local synthesis and release of NO, that may reduce regional perfusion at rest and impair the vasodilator response to stress, and 2) during NO inhalation, delivery of NO bound to hemoglobin will be enhanced and will improve these abnormalities in regional vascular perfusion. Studies will be performed on untreated sickle cell anemia patients and on patients managed with chronic hydroxyurea therapy. Demonstration of improved regional perfusion with NO therapy could have significant implications for patient management during acute pain crisis and the acute chest syndrome.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- Males or females 18 to 65 years of age are eligible.
- Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S beta(0) thallassemia genotype is required).
- Hematocrit greater than 18 percent (with an absolute reticulocyte count greater than 100,000/ml).
- Volunteer subjects taking hydroxyurea must have been on therapy with the drug for at least four months. Volunteer subjects not taking hydroxyurea must have been off of therapy with the drug for at least 4 months.
Key exclusion criteria (13 listed)
- Clinically unstable sickle cell anemia defined as having an acute pain crisis within the last week.
- Age less than 18 years or greater than 65 years.
- Current pregnancy or lactation.
- Diabetes mellitus or Fasting blood sugar greater than 120 mg/dL
- Cigarette smoking within two years
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 | – |
| Acetylcholine | Drug | – |
Primary outcome
Not reported in the source record.
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 4 Mar 2008.
- Background: PubMed 9357905Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology. 1997 Oct;87(4):988-90. doi: 10.1097/00000542-199710000-00037. No abstract available.
- Background: PubMed 11001897Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood. 2000 Oct 1;96(7):2451-9.
- Background: PubMed 9622135Cardillo C, Kilcoyne CM, Cannon RO 3rd, Panza JA. Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation. Hypertension. 1998 Jun;31(6):1235-9. doi: 10.1161/01.hyp.31.6.1235.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing L-NMMA and Acetylcholine in people with Sickle Cell Anemia, run by National Institutes of Health Clinical Center (CC) 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 4 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 4 Mar 2008. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00009581, 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 4 Mar 2008.