Topical Sodium Nitrite for Chronic Leg Ulcers in Adult Patients With Blood Disorders
| Status: | Completed |
|---|---|
| Conditions: | Other Indications, Anemia, Gastrointestinal, Hematology, Hematology |
| Therapuetic Areas: | Gastroenterology, Hematology, Other |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 10/24/2018 |
| Start Date: | March 15, 2011 |
| End Date: | October 12, 2018 |
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.
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.
- 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.
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.
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.
- INCLUSION CRITERIA:
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.
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, 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.
- 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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