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

Abstract

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).

Conflict of interest statement

Declaration of interests

We declare no competing interests.

Figures

Figure 1. Changes in leg ulcer surface area before and after application of sodium nitrite cream

(A) Wound size measured by digital planimetry. (B) Wound sizes measured manually (longest length and widest width). (C) Changes in wound size according to sodium nitrite concentration. Arrows in (A) and (B) represent first application of cream. Plotted points or bars are mean values and error bars are standard error of the mean. *p=0.0058 compared with first application. †p

Figure 2. Changes in leg ulcer pain during the topical sodium nitrite treatment period

Patients were asked to score pain from the ulcer treated with topical sodium nitrite and any additional ulcers not treated with topical sodium nitrite. (A) Changes in VAS pain scores for the ulcer treated with topical sodium nitrite at all doses, from screening to the end of the study. (B) Changes in VAS score for additional ulcers not treated with topical sodium nitrite (n=9). (C) Changes in VAS scores for the study ulcer treated with sodium nitrite cream at at different concentrations. (D) Mean weekly use of opioid analgesics (total morphine equivalents) by all patients at the beginning of treatment compared with the end of treatment. Error bars are standard deviations. VAS=visual analogue scale.

Figure 3. Changes in the brief pain inventory scores during treatment of leg ulcers with topical sodium nitrite

Significant reductions were recorded in (A) the pain severity subscore and (B) the pain interference subscore averaged from all treated patients after eight treatments over 4 weeks (n=18, paired t test). (C, D) Changes in scores according to sodium nitrite concentration. Bars indicate mean values and error bars are standard error of the mean.

Figure 4. Cutaneous imaging before and after first application of topical sodium nitrite cream

Changes after the first application of sodium nitrite cream for all 18 trial participants in (A) cutaneous peri-wound temperature by infrared thermography and (B) cutaneous peri-wound blood flow by laser speckle contrast imaging. The infrared thermography and laser speckle contrast measurement of cutaneous blood flow data are calculated by spatial averaging of the region of interest followed by time averaging over the 5 min before application of sodium nitrite cream and the final 5 min of the imaging 30 min after the application. (C, D) Subgroup analysis results categorised according to the concentration of sodium nitrite cream.