Sickle Cell AnemiaPhase 1NCT01316796
Topical Sodium Nitrite for Chronic Leg Ulcers in Adult Patients With Blood Disorders
A Phase 1 study testing Sodium Nitrite Cream in people with Sickle Cell Anemia and Sickle Cell Disease, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
Background: Chronic leg ulcers are a complication of many blood disorders such as sickle cell disease, thalassemia, and other red blood cell disorders. In these disorders, red blood cells break down earlier than normal, which researchers suspect may cause or contribute to the development of leg ulcers; however, the… Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Sickle Cell Anemia, Sickle Cell Disease, Chronic Hemolytic Disorders
- What is being tested?
- Sodium Nitrite Cream
- How many people
- 28 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Mar 2011to 12 Oct 2018
- 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 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Each subject must meet all of the following inclusion criteria during the screening process in order to participate in the study:
- Subjects must have a diagnosis of sickle cell disease (SS, SC, S-beta-thalassemia), other hemoglobinopathies, or hemolytic disorders, such as hereditary spherocytosis.
- Be at least 18 years old.
- Have a leg ulcer of at least 4 weeks (28 days) duration.
- Leg ulcer must be no smaller than 2.5 cm(2) and no larger than 100 cm(2).
- Provide written informed consent.
Who cannot join
- Subjects meeting any of the following criteria during baseline evaluation will be excluded from entry into the study:
- Exposure to therapeutic nitric oxide, L-arginine, nitroprusside or nitroglycerine within the past 1 week.
- Subjects presenting with clinically diagnosed bacterial infection (e.g., osteomyelitis, pneumonia, sepsis or meningitis).
- Subjects who have a pre-existing methemoglobinemia (more than 2.5 percent), unless the cytochrome b5 reductase (methemoglobin reductase) is within normal limits and the methemoglobin is no greater than 3 percent)
- Patients who are currently enrolled in any other investigational drug study (this does not include observational or natural history protocols).
- Use of PDE5 inhibitors, such as sildenafil, 4 days prior to screening.
Show all 26Show fewer
- Pregnant women (urine or serum HCG plus) or nursing mothers.
- The following list of drugs and agents may cause methemoglobinemia and should be avoided while on this study:
- Anesthetics (local): Benzocaine, procaine, prilocaine, Anbesol, Orajel
- Antimalarials: chloroquine, primaquine, quinacrine
- Aniline dyes
- Chlorates
- Dapsone
- Diarylsulfonylureas
- Doxorubicin
- Metoclopramide
- Nitric and nitrous oxide
- Nitrobenzenes (shoe and floor polish and in paint solvents)
- Nitroethane (artificial nail remover, propellent, fuel additive)
- Nitrofurantoin (furadantin)
- Pyridium (phenazopyridine)
- Phenacetin (acetaminophen)
- Phenylhydrazine
- Rasburicase
- Sulfonamides (sulfacetamide, sulfamethoxazole, sulfanilamide, sulfapyridine)
- If a subject participant meets exclusion criteria while participating in the trial, then the subject will be removed from the study.
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
Official title: A Phase I Study of the Use of Topical Sodium Nitrite for Chronic Leg Ulcers in Adult Patients With Hemolytic Disorders
Background:
- Chronic leg ulcers are a complication of many blood disorders such as sickle cell disease, thalassemia, and other red blood cell disorders. In these disorders, red blood cells break down earlier than normal, which researchers suspect may cause or contribute to the development of leg ulcers; however, the exact cause is unknown, and current therapies are not very effective. Researchers are interested in determining if a research cream made with sodium nitrite, a substance that is known to increase blood flow by dilating blood vessels, may speed up the healing of skin ulcers.
Read more
Objectives:
- To evaluate the safety and effectiveness of topical sodium nitrite cream as a treatment for chronic leg ulcers in individuals with sickle cell disease or other red blood cell disorders.
Eligibility:
- Individuals at least 18 years of age who have sickle cell disease or another red cell disorder and have had a leg ulcer for more than 4 weeks.
Design:
- Participants will be screened with a physical examination, medical history, blood tests, and an examination of the ulcer, including x-ray of the leg(s) with the ulcer and swabs from the wound.
- Participants will be scheduled for a 5-day inpatient stay at the Clinical Center, with the following procedures:
- Days 1 and 2: Participants will have blood draws, a wound assessment, ultrasound of the affected leg, imaging studies (magnetic resonance imaging and infrared photography), thermo-patch application to monitor temperature changes, measurements of blood flow in the skin, and questionnaires about pain and quality of life. An optional skin biopsy may also be conducted with samples taken near the skin ulcer
- Day 3: Participants will have one ulcer treated with the topical cream. Frequent blood draws will be conducted before application and then regularly for up to 6 hours after application of the cream. Thirty minutes after the research cream is applied, participants will have imaging studies of the treated leg and measurements of pain levels and blood flow.
- Day 4: Participants will have a blood draw and temperature recordings taken.
- Day 5: Participants will have the research cream applied and the same imaging studies as before, and will be discharged for care at home.
- For the following 3 weeks, participants will come to the clinical center twice a week to have the research cream applied to the leg ulcer and tests performed by the study researchers.
- For the fourth and final week, participants will return for additional cream treatment sessions, imaging studies, blood draws, and other tests as directed by the study researchers.
- Study participation will end in the following week (week 5). Subjects will come for a final visit one month after the end of the study.
Read the detailed description
Leg ulcerations have long been identified as a serious and debilitating complication of SCD and even the first SCD patient described in North America in 1910 had leg ulcerations. The prevalence varies, being low before 10 years of age, and in genotypes other than SS, and it is influenced by geographical location, with an occurrence as high as 75 percent of SS patients in Jamaica, and 8-10 percent in North America. The etiology of chronic ulcers in SCD and other hemolytic disorders is unknown, mechanical obstruction by dense sickled red cell, increased venous pressure, bacterial infections, abnormal autonomic control with excessive vasoconstriction when in the dependent position, degree of anemia with decrease in oxygen carrying capacity, and in situ thrombosis, have all been proposed as potential contributing factors. Recent studies have reported increased incidence of leg ulcers in patients with pulmonary hypertension. Our group has pioneered the notion of an association between the hemolytic phenotype and leg ulcers. Current treatment options for leg ulcerations, including antibiotics, compression bandages, dressing changes, Unna boots, silver and zinc oxide gauze, skin grafts and maggot therapy rely mostly on bacterial containment, stimulation of granulation formation and decrease of venostasis. Pathological changes in the microcirculation associated with ulceration are not addressed. Nitric oxide metabolism has been the focus of our branch research over the past several years. We know that it mediates essential biological processes, including vasodilatation, wound healing, and angiogenesis and has antimicrobial activity. Moreover, NO has an antiplatelet effect and influences several growth factors involved in endothelial homeostasis.
We propose a Phase I study of a topical cream containing escalating doses of sodium nitrite, a local donor of NO when in the presence of heme, as a novel approach to the therapy for chronic leg ulcers in hemolytic disorders. The primary objectives are to evaluate topical sodium nitrite cream s safety and tolerability in patients with sickle cell disease or other hemolytic disorders and chronic leg ulcers and to determine the optimal concentration of the study drug that is tolerated. Subjects will be treated at the Clinical Center for 4 weeks.
Potential benefit will be a durable resolution or improvement of the leg ulcer. Possible side effects include hypotension and methemoglobinemia, secondary to sodium nitrite absorption for the ulcerated skin. Safety measures will be used and pharmacokinetics analysis of sodium nitrite absorption in this setting will be obtained. As a secondary endpoint, we will study the biology of leg ulcer formation in patients with hemolytic disorders, its pathological appearance on a skin biopsy, and the role of microvascular changes in its formation and (possibly) resolution. Sophisticated and novel studies of blood flow and temperature changes during sodium nitrite application, as well as macrovascular appearance on MRI will allow for a better understanding of ulcer formation. This may lead to novel approaches to the therapy of ulcer in hemolytic and non-hemolytic disorders, such as diabetes and decubitus ulceration.
- Being tested
- Sodium Nitrite Cream
- Keywords
- Sickle Cell Disease, Hemolysis, Anemia, Nitric Oxide, Blood Flow, Leg Ulcer, Sickle Cell Anemia, Thalassemia, Hemolytic Blood Disorder
- Medical subject headings
- Anemia, Sickle Cell, Hemolysis, Anemia, Leg Ulcer, Thalassemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium Nitrite CreamDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluate topical sodium nitrite cream's safety and tolerability in patients with sickle cell disease or other hemolytic disorders and chronic leg ulcers.
Determine the optimal concentration of topical nitrite cream that is tolerated.
Secondary outcomes (4)
Determine whether changes of local temperature correlates with ulcer appearance, modification, or healing.
Determine whether topical nitrite therapy changes regional blood flow to the affected skin area and surrounding.
Determine whether it shows preliminary evidence for accelerating wound healing.
Determine the pharmacokinetics of topical sodium nitrite cream and methemolglobin profile 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 posted16 Mar 2011 (estimated)
- Study start15 Mar 2011
- Primary completion18 Sep 2015
- Study completion12 Oct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)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
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Investigators
- Matthew M Hsieh, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01316796
- Sponsor's protocol ID
- 110121
- Other IDs
- 11-H-0121
- Status last verified
- 12 Oct 2018
- First submitted
- 15 Mar 2011
- Last updated
- 22 Oct 2018
- Results posted
- No
- FDA-regulated drug
- Yes
Publications
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Yale J Biol Med. 2001 May-Jun;74(3):179-84. No abstract available.
PubMed 11501714Akinyanju O, Akinsete I. Leg ulceration in sickle cell disease in Nigeria. Trop Geogr Med. 1979 Mar;31(1):87-91.
PubMed 483376Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, Flournoy-Gill Z, Levy P. Leg ulcers in patients with sickle cell disease. Blood. 1989 Sep;74(4):1403-8.
PubMed 2475188Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney KM, Seidel M, Malik N, Peters-Lawrence M, Cantilena C, Nichols JS, Mendelsohn L, Conrey A, Grimes G, Kato GJ. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. Lancet Haematol. 2014 Dec 1;1(3):e95-e103. doi: 10.1016/s2352-3026(14)00019-2.
PubMed 25938131
Study at a glance
From the registry record, last updated by the sponsor on 22 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of the Use of Topical Sodium Nitrite for Chronic Leg Ulcers in Adult Patients With Hemolytic Disorders
- ClinicalTrials.gov ID
- NCT01316796
- Acronym / sponsor ID
- 110121
- Keywords
- Sickle Cell Disease, Hemolysis, Anemia, Nitric Oxide, Blood Flow, Leg Ulcer, Sickle Cell Anemia, Thalassemia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 15 Mar 2011
- Primary completion
- 18 Sep 2015 (actual)
- Study completion
- 12 Oct 2018 (actual)
- First posted
- 16 Mar 2011 (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.
Background:
- Chronic leg ulcers are a complication of many blood disorders such as sickle cell disease, thalassemia, and other red blood cell disorders. In these disorders, red blood cells break down earlier than normal, which researchers suspect may cause or contribute to the development of leg ulcers; however, the exact cause is unknown, and current therapies are not very effective. Researchers are interested in determining if a research cream made with sodium nitrite, a substance that is known to increase blood flow by dilating blood vessels, may speed up the healing of skin ulcers.
Objectives:
- To evaluate the safety and effectiveness of topical sodium nitrite cream as a treatment for chronic leg ulcers in individuals with sickle cell disease or other red blood cell disorders.
Eligibility:
- Individuals at least 18 years of age who have sickle cell disease or another red cell disorder and have had a leg ulcer for more than 4 weeks.
Design:
- Participants will be screened with a physical examination, medical history, blood tests, and an examination of the ulcer, including x-ray of the leg(s) with the ulcer and swabs from the wound.
- Participants will be scheduled for a 5-day inpatient stay at the Clinical Center, with the following procedures:
- Days 1 and 2: Participants will have blood draws, a wound assessment, ultrasound of the affected leg, imaging studies (magnetic resonance imaging and infrared photography), thermo-patch application to monitor temperature changes, measurements of blood flow in the skin, and questionnaires about pain and quality of life. An optional skin biopsy may also be conducted with samples taken near the skin ulcer
- Day 3: Participants will have one ulcer treated with the topical cream. Frequent blood draws will be conducted before application and then regularly for up to 6 hours after application of the cream. Thirty minutes after the research cream is applied, participants will have imaging studies of the treated leg and measurements of pain levels and blood flow.
- Day 4: Participants will have a blood draw and temperature recordings taken.
- Day 5: Participants will have the research cream applied and the same imaging studies as before, and will be discharged for care at home.
- For the following 3 weeks, participants will come to the clinical center twice a week to have the research cream applied to the leg ulcer and tests performed by the study researchers.
- For the fourth and final week, participants will return for additional cream treatment sessions, imaging studies, blood draws, and other tests as directed by the study researchers.
- Study participation will end in the following week (week 5). Subjects will come for a final visit one month after the end of the study.
Detailed description
Leg ulcerations have long been identified as a serious and debilitating complication of SCD and even the first SCD patient described in North America in 1910 had leg ulcerations. The prevalence varies, being low before 10 years of age, and in genotypes other than SS, and it is influenced by geographical location, with an occurrence as high as 75 percent of SS patients in Jamaica, and 8-10 percent in North America. The etiology of chronic ulcers in SCD and other hemolytic disorders is unknown, mechanical obstruction by dense sickled red cell, increased venous pressure, bacterial infections, abnormal autonomic control with excessive vasoconstriction when in the dependent position, degree of anemia with decrease in oxygen carrying capacity, and in situ thrombosis, have all been proposed as potential contributing factors. Recent studies have reported increased incidence of leg ulcers in patients with pulmonary hypertension. Our group has pioneered the notion of an association between the hemolytic phenotype and leg ulcers. Current treatment options for leg ulcerations, including antibiotics, compression bandages, dressing changes, Unna boots, silver and zinc oxide gauze, skin grafts and maggot therapy rely mostly on bacterial containment, stimulation of granulation formation and decrease of venostasis. Pathological changes in the microcirculation associated with ulceration are not addressed. Nitric oxide metabolism has been the focus of our branch research over the past several years. We know that it mediates essential biological processes, including vasodilatation, wound healing, and angiogenesis and has antimicrobial activity. Moreover, NO has an antiplatelet effect and influences several growth factors involved in endothelial homeostasis.
We propose a Phase I study of a topical cream containing escalating doses of sodium nitrite, a local donor of NO when in the presence of heme, as a novel approach to the therapy for chronic leg ulcers in hemolytic disorders. The primary objectives are to evaluate topical sodium nitrite cream s safety and tolerability in patients with sickle cell disease or other hemolytic disorders and chronic leg ulcers and to determine the optimal concentration of the study drug that is tolerated. Subjects will be treated at the Clinical Center for 4 weeks.
Potential benefit will be a durable resolution or improvement of the leg ulcer. Possible side effects include hypotension and methemoglobinemia, secondary to sodium nitrite absorption for the ulcerated skin. Safety measures will be used and pharmacokinetics analysis of sodium nitrite absorption in this setting will be obtained. As a secondary endpoint, we will study the biology of leg ulcer formation in patients with hemolytic disorders, its pathological appearance on a skin biopsy, and the role of microvascular changes in its formation and (possibly) resolution. Sophisticated and novel studies of blood flow and temperature changes during sodium nitrite application, as well as macrovascular appearance on MRI will allow for a better understanding of ulcer formation. This may lead to novel approaches to the therapy of ulcer in hemolytic and non-hemolytic disorders, such as diabetes and decubitus ulceration.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Each subject must meet all of the following inclusion criteria during the screening process in order to participate in the study:
- Subjects must have a diagnosis of sickle cell disease (SS, SC, S-beta-thalassemia), other hemoglobinopathies, or hemolytic disorders, such as hereditary spherocytosis.
- Be at least 18 years old.
- Have a leg ulcer of at least 4 weeks (28 days) duration.
- Leg ulcer must be no smaller than 2.5 cm(2) and no larger than 100 cm(2).
Key exclusion criteria (26 listed)
- Subjects meeting any of the following criteria during baseline evaluation will be excluded from entry into the study:
- Exposure to therapeutic nitric oxide, L-arginine, nitroprusside or nitroglycerine within the past 1 week.
- Subjects presenting with clinically diagnosed bacterial infection (e.g., osteomyelitis, pneumonia, sepsis or meningitis).
- Subjects who have a pre-existing methemoglobinemia (more than 2.5 percent), unless the cytochrome b5 reductase (methemoglobin reductase) is within normal limits and the methemoglobin is no greater than 3 percent)
- Patients who are currently enrolled in any other investigational drug study (this does not include observational or natural history protocols).
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 |
|---|---|---|
| Sodium Nitrite Cream | Drug | – |
Primary outcome
Evaluate topical sodium nitrite cream's safety and tolerability in patients with sickle cell disease or other hemolytic disorders and chronic leg ulcers.
Determine the optimal concentration of topical nitrite cream that is tolerated.
4 secondary outcomes
Determine whether changes of local temperature correlates with ulcer appearance, modification, or healing.
Determine whether topical nitrite therapy changes regional blood flow to the affected skin area and surrounding.
Determine whether it shows preliminary evidence for accelerating wound healing.
Determine the pharmacokinetics of topical sodium nitrite cream and methemolglobin profile 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 22 Oct 2018.
- Background: PubMed 11501714Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Yale J Biol Med. 2001 May-Jun;74(3):179-84. No abstract available.
- Background: PubMed 483376Akinyanju O, Akinsete I. Leg ulceration in sickle cell disease in Nigeria. Trop Geogr Med. 1979 Mar;31(1):87-91.
- Background: PubMed 2475188Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, Flournoy-Gill Z, Levy P. Leg ulcers in patients with sickle cell disease. Blood. 1989 Sep;74(4):1403-8.
- Derived from this study: PubMed 25938131Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney KM, Seidel M, Malik N, Peters-Lawrence M, Cantilena C, Nichols JS, Mendelsohn L, Conrey A, Grimes G, Kato GJ. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. Lancet Haematol. 2014 Dec 1;1(3):e95-e103. doi: 10.1016/s2352-3026(14)00019-2.
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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.
Matthew M Hsieh, 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 Sodium Nitrite Cream in people with Sickle Cell Anemia and Sickle Cell Disease, 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 6 inclusion and 26 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 22 Oct 2018. 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?
Evaluate topical sodium nitrite cream's safety and tolerability in patients with sickle cell disease or other hemolytic disorders and chronic leg ulcers.. The study lists 2 primary outcomes in all. 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 NCT01316796, which also lists 4 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 22 Oct 2018.