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


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health).
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Caterina P
CP
Minniti
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Alexander M
AM
Gorbach
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Dihua
D
Xu
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Yuen Yi
YY
Hon
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Kara-Marie
KM
Delaney
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Miles
M
Seidel
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Nitin
N
Malik
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Marlene
M
Peters-Lawrence
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Carly
C
Cantilena
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
James S
JS
Nichols
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Laurel
L
Mendelsohn
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Anna
A
Conrey
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
George
G
Grimes
National Heart, Lung and Blood Institute (Prof C P Minniti MD, D Xu PhD, K-M Delaney MD, M Peters-Lawrence RN, C Cantilena BS, J S Nichols RN, L Mendelsohn BS, A Conrey NP, Prof G J Kato MD), Pharmaceutical Development Services, Clinical Center Pharmacy Department (Y Y Hon PharmD, G Grimes PharmD), and Infrared and Thermometry Unit, National Institute of Biomedical Imaging and Bioengineering (A M Gorbach PhD, M Seidel BS, N Malik BS), National Institutes of Health, Bethesda, MD, USA; and Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Prof G J Kato).
Gregory J
GJ
Kato