Leg ulcerations have long been identified as a serious and debilitating complication of sickle cell disease (SCD).The first SCD patient described in North America in 1910 had leg ulcerations. Prevalence varies, being low before 10 years of age and in genotypes other than SS. It is influenced by geographical location, with occurrence as high as 75% in SS patients in Jamaica, and 8-10% in North America. The etiology of chronic ulcers in SCD and other hemolytic disorders is unknown - mechanical obstruction by dense sickled red cells, increased venous pressure, bacterial infections, abnormal autonomic control with excessive vasoconstriction when in dependent position, degree of anemia with decrease in oxygen carrying capacity, have all been proposed as potential contributing factors. Morbidity from chronic leg ulcers remains a substantial clinical burden in patients with SCD despite advances in care with disease-modifying agents such as hydroxyurea, blood transfusions, and improved supportive care. Patients with sickle cell disease and leg ulcers have biomarkers of more severe hemolytic anemia, a state associated with low bioavailability of nitric oxide. Existing therapeutic approaches for SCD ulcers are unsatisfactory, and are mostly based on treatments for venous and arterial ulcers in the general population. A recent Cochrane review identified only six prospective, randomized therapeutic trials for sickle cell disease leg ulcers over the past 30 years?four in Jamaica and two in the USA. Results were mixed; statistically significant increases in wound closure were reported only for topical Arg-Gly-Asp (RGD) peptide and intravenous arginine butyrate. As these agents remain in early-phase drug development, patients have few therapeutic options available. We selected sodium nitrite for clinical development on the basis of the extensive published literature about its safety profile when administered intravenously and orally, its vasodilating properties, and preliminary reports of the efficacy of acidified nitrite in the treatment of other patient populations with chronic skin ulcers. In animals, sodium nitrite therapy promotes revascularization of ischemic limbs, protects against ischemic infarction of the heart, liver, and brain, and has a protective effect against cardiac arrest-mediated heart and brain injury. The nitrite anion acts as a vasodilator in vivo by generating nitric oxide in tissues with low oxygen tension and pH, conditions which are likely to be present in chronic wounds. The mechanism involves oxygen- dependent and pH-dependent nitrite reductase activity of hemoproteins or xanthine oxidoreductase. Experimental models suggest beneficial effects of nitric oxide in the early and late phases of wound healing, including increased extracellular matrix production, immune response modulation, and stimulation of keratinocyte cell proliferation, angiogenesis, and bactericidal properties. Nitric oxide mediates essential vascular homoeostasis, including vasodilation, and antiplatelet activity, and affects several growth factors involved in endothelial homoeostasis. We have completed a dose escalation, safety and tolerability phase 1 study in 18 adult patients with sickle cell anemia and leg ulcers. There were no grade 3?4 adverse events serious adverse events or dose-limiting side- effects. Pharmacokinetic analysis showed low systemic absorption of sodium nitrite. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging and increased peri-wound skin temperature by infrared thermography. Interestingly, there was a dose-dependent decrease in leg ulcer size (p=0.0012) and ulcer associated pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). Post-hoc analysis of pain revealed decreased pain severity (p=0.0048) and pain interference (p=0.0013). On the basis of these encouraging results we propose a prospective, double blinded, randomized Phase II trial which aims at: 1. Further evaluate the safety and tolerability of prolonged (10 weeks), twice a week application of topical sodium nitrite in adult patients with sickle cell disease and leg ulcers in a randomized, double blind, placebo controlled Phase II trial. 2. Determine the effectiveness of topical sodium nitrite in accelerating wound healing and decrease pain at the wound site compared to placebo in patients receiving similar levels of wound care. 3. Improve our understanding of the pathobiology of leg ulcer formation and delayed healing in patients with SCD.
Chronic, recurrent leg ulcers are a serious and debilitating complication of sickle cell disease. We propose a Phase II study of a topical cream containing sodium nitrite compared to the current standard of care. Sodium nitrite is a local donor of nitric oxide, which is known to improve blood flow and decrease bacterial load in the ulcer bed. The primary objectives are to evaluate the safety of topical sodium nitrite cream treatment in patients with sickle cell disease and chronic leg ulcers and to determine its effectiveness in accelerating the healing process and decreasing the pain associated with ulceration. Potential benefit will be a durable resolution or improvement of the leg ulcer and its associated pain. Possible side effects include decreased blood pressure and methemoglobinemia, secondary to sodium nitrite absorption through the ulcerated skin. This trial may lead to novel approaches to the treatment of ulcers in hemolytic and non-hemolytic disorders, such as diabetes and decubitus ulcers (bed sores).This phase II study is the next step in the drug development plan, as we move from a phase 1 dose-finding study to a more prolonged safety and tolerability study at a fixed dose, and we compare to placebo. Successful completion of this trial would allow us to define the effect size to plan for the next appropriately powered Phase III study, a crucial step towards development of an effective therapy for this debilitating complication that affects patients with SCD worldwide.
