Topical Sodium Nitrite for Chronic Leg Ulcers in Adult Patients With Blood Disorders
Condition: Sickle Cell Anemia; Sickle Cell Disease; Chronic Hemolytic Disorders
MeSH terms: Anemia; Anemia, Sickle Cell; Leg Ulcer; Hemolysis
Study type: Interventional
Phase: Phase 1

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 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.
    

Intervention name(s): Sodium Nitrite Cream
Intervention type(s): Drug
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sickle Cell Disease; Hemolysis; Anemia; Nitric Oxide; Blood Flow; Leg Ulcer; Sickle Cell Anemia; Thalassemia; Hemolytic Blood Disorder