Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial

Abstract

Summary Background Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. Methods We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5–100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. Findings Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3–4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium nitrite was very low. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging (p=0.0002), corroborated by increased peri-wound skin temperature by infrared thermography (p=0.0119). We recorded a dose-dependent decrease in leg ulcer size (p=0.0012) and 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). In our post-hoc analysis of pain, brief pain inventory scores improved in pain severity (p=0.0048) and pain interference (p=0.0013). Interpretation Our results indicate that topical sodium nitrite 2% cream is suitable for additional clinical trials in adults with sickle cell anaemia to promote healing of leg ulcers. Funding National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health).

Critical Reviews: How we treat sickle cell patients with leg ulcers

“…NO regulates vascular homoeostasis, including vasodilation, and affects growth factors involved in endothelial homoeostasis [82,83]. We have recently conducted a phase I study in patients with sickle cell and chronic leg ulcers of topically applied sodium nitrite, a known NO donor [84] which showed promising preliminary efficacy data. Others have used NO nanoparticles platforms successfully in animal models [85].…”

2015 Clinical trials update in sickle cell anemia

“…According to a press release on April 14, 2015 by Prolong Pharmaceuticals (South Plain-field, NJ; http://www.prolongpharma.com/press-14APR2015) phase 2 trials are planned for VOCs and leg ulcers. A topical sodium nitrate 2% cream was shown to be safe and well tolerated in a phase 1 study in 18 patients with SCD [14]. Increases in per-wound cutaneous blood flow and decreased ulcer size were also observed in this trial.…”

Sickle cell disease: Classification of clinical complications and approaches to preventive and therapeutic management

“…Certain modalities for the management of leg ulcers that are not commonly used in SCD include topical application of platelet-derived growth factor prepared either autologously (Procuren) [50] or by recombinant technology (Regranex) [51], topical sodium nitrite for chronic leg ulcers [52], and the use of cultured skin grafts [53]. In addition, mānuka honey from New Zealand has been reported to heal diabetic foot ulcers [54,55].…”