Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia

A phase 1 dose-fi nding safety and tolerability trial

Caterina P. Minniti, Alexander M. Gorbach, Dihua Xu, Yuen Yi Hon, Kara Marie Delaney, Miles Seidel, Nitin Malik, Marlene Peters-Lawrence, Carly Cantilena, James S. Nichols, Laurel Mendelsohn, Anna Conrey, George Grimes, Gregory J. Kato

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 fi ve 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 diff erent 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.

Original languageEnglish (US)
Pages (from-to)e95-e103
JournalThe Lancet Haematology
Volume1
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

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Sodium Nitrite
Leg Ulcer
Sickle Cell Anemia
Safety
Pain
Ulcer
Pharmacokinetics
Blood Pressure
Nitric Oxide Donors
Skin Temperature
Wounds and Injuries
National Institutes of Health (U.S.)
Wound Healing
Lasers
Clinical Trials
Equipment and Supplies
Skin

ASJC Scopus subject areas

  • Hematology

Cite this

Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia : A phase 1 dose-fi nding safety and tolerability trial. / Minniti, Caterina P.; Gorbach, Alexander M.; Xu, Dihua; Hon, Yuen Yi; Delaney, Kara Marie; Seidel, Miles; Malik, Nitin; Peters-Lawrence, Marlene; Cantilena, Carly; Nichols, James S.; Mendelsohn, Laurel; Conrey, Anna; Grimes, George; Kato, Gregory J.

In: The Lancet Haematology, Vol. 1, No. 3, 2014, p. e95-e103.

Research output: Contribution to journalArticle

Minniti, CP, Gorbach, AM, Xu, D, Hon, YY, Delaney, KM, Seidel, M, Malik, N, Peters-Lawrence, M, Cantilena, C, Nichols, JS, Mendelsohn, L, Conrey, A, Grimes, G & Kato, GJ 2014, 'Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: A phase 1 dose-fi nding safety and tolerability trial', The Lancet Haematology, vol. 1, no. 3, pp. e95-e103. https://doi.org/10.1016/S2352-3026(14)00019-2
Minniti, Caterina P. ; Gorbach, Alexander M. ; Xu, Dihua ; Hon, Yuen Yi ; Delaney, Kara Marie ; Seidel, Miles ; Malik, Nitin ; Peters-Lawrence, Marlene ; Cantilena, Carly ; Nichols, James S. ; Mendelsohn, Laurel ; Conrey, Anna ; Grimes, George ; Kato, Gregory J. / Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia : A phase 1 dose-fi nding safety and tolerability trial. In: The Lancet Haematology. 2014 ; Vol. 1, No. 3. pp. e95-e103.
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author = "Minniti, {Caterina P.} and Gorbach, {Alexander M.} and Dihua Xu and Hon, {Yuen Yi} and Delaney, {Kara Marie} and Miles Seidel and Nitin Malik and Marlene Peters-Lawrence and Carly Cantilena and Nichols, {James S.} and Laurel Mendelsohn and Anna Conrey and George Grimes and Kato, {Gregory J.}",
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TY - JOUR

T1 - Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia

T2 - A phase 1 dose-fi nding safety and tolerability trial

AU - Minniti, Caterina P.

AU - Gorbach, Alexander M.

AU - Xu, Dihua

AU - Hon, Yuen Yi

AU - Delaney, Kara Marie

AU - Seidel, Miles

AU - Malik, Nitin

AU - Peters-Lawrence, Marlene

AU - Cantilena, Carly

AU - Nichols, James S.

AU - Mendelsohn, Laurel

AU - Conrey, Anna

AU - Grimes, George

AU - Kato, Gregory J.

PY - 2014

Y1 - 2014

N2 - 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 fi ve 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 diff erent 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.

AB - 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 fi ve 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 diff erent 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.

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