Topical Sodium Nitrite in Sickle Cell Disease and Leg Ulcers

Study Overview
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Brief Summary
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The investigators are conducting a Phase II prospective and placebo controlled 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. Funding source FDA OOPD.

Detailed Description
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Chronic leg ulcers are a complication of many blood disorders such as sickle cell disease, thalassemia, and other red blood cell disorders. In these disorders, red blood cells break down earlier than normal, which researchers suspect may cause or contribute to the development of leg ulcers; however, the exact cause is unknown, and current therapies are not very effective. Researchers are interested in determining if a research cream made with sodium nitrite, a substance that is known to increase blood flow by dilating blood vessels, may speed up the healing of skin ulcers. Investigators are planning to enroll fifty patients with sickle cell disease to be randomized and treated twice a week with sodium nitrite cream or a placebo for ten weeks. The following events will be compared in treatment and placebo arms: a) changes in blood pressure; b) changes in pulse oximetry; c) changes in methemoglobin levels; d) any adverse events; e) rate of SCD related complications; f) changes in biomarkers of inflammation and other laboratory data such as complete blood count and chemistries. In order to determine if topical sodium nitrite accelerates wound healing and decreases pain at the wound site compared to placebo in patients receiving similar levels of wound care, investigators will a) accurately measure and photograph ulcers at baseline, after a two week run-in period and at predefined time points during the study and compare treatment arm to placebo; b) pain scores at wound sites will be recorded and compared for the two groups, c) Investigators will calculate opioid intake in the two arms and d) quality of life measures before and at the end of the trial

Official Title
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A Phase II Study of Topical Sodium Nitrite in Patients With Sickle Cell and Leg Ulcers

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Topical Sodium Nitrite
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a diagnosis of sickle cell disease (SS, SC, Sß-thalassemia, SD, SOArab). Have one or more ulcers of the one or both leg or foot. Total surface area of leg ulcer(s) that will receive treatment must be no larger than 100 cm2. No history of congenital methemoglobinemia. Have documented normal G6PD activity. Exclusion Criteria: Exposure to therapeutic nitric oxide, L-arginine, nitroprusside or nitroglycerine within the past 1 week. Subjects presenting with clinically diagnosed bacterial infection (e.g., osteomyelitis, pneumonia, sepsis or meningitis). Subjects who have a pre-existing methemoglobinemia (more than 3.5% on two different occasions). Patients who are currently enrolled in any other investigational drug study (this does not include observational or natural history protocols). Use of PDE5 inhibitors, such as sildenafil, 4 days prior to screening. Pregnant women (urine or serum HCG +) or nursing mothers. The following list of drugs and agents may cause methemoglobinemia and should be avoided while on this study: Anesthetics (local): Benzocaine, procaine, prilocaine, Anbesol, Orajel Antimalarials: chloroquine, primaquine, quinacrine Aniline dyes Chlorates Dapsone Diarylsulfonylureas Doxorubicin Metoclopramide Nitric and nitrous oxide Nitrobenzenes (shoe and floor polish and in paint solvents) Nitroethane (artificial nail remover, propellant, fuel additive) Nitrofurantoin (furadantin) Pyridium (phenazopyridine) Phenacetin Phenylhydrazine Rasburicase Sulfonamides (sulfacetamide, sulfamethoxazole, sulfanilamide, sulfapyridine)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: control<br>patients will receive placebo and standard of care | Other: Placebo<br>* Subjects will have Placebo applied to total ulcerated area. If a subject has more than one ulcer, all of them will be treated with placebo in this intervention.<br>|
| Experimental: topical sodium nitrite<br>patients will receive 2% topical sodium nitrite cream and standard of care | Drug: Topical Sodium Nitrite<br>* Subjects will have 0.1 cm of 2% sodium nitrite cream applied per 1 cm2 of the total ulcerated area. Areas will be rounded to the nearest 1 cm2. If a subject has more than one ulcer, all of them will be treated with either study cream in this intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of tolerability | The investigators will assess if the application of study cream is well tolerated by subjects. The frequency of each adverse event as per CTCAE v4.0 will be tabulated. To compare the safety of prolonged (10 weeks) treatments between the experimental treatment and placebo group, the investigators will apply non-parametric a Mann-Whitney test on the number of adverse events. | 10 Weeks | 
| Ulcer size reduction | Effect sizes of the treatment on the ulcer size reduction will be determined by differences in response rates or odds-ratios, and the 95% CI's will accordingly be estimated. To test if topical sodium nitrite accelerates wound healing, as defined by >25% improvement over placebo arm, the investigators will apply Chi-square test. Logistic regression models will be applied if inclusion of confounding variables deems necessary. The investigator will also test if declines of weekly-measured absolute ulcer size on a continuous scale over the study period will be different between the two groups by applying mixed effects linear models for analysis of repeated-measure outcomes. | 10 Weeks | 
| Ulcer pain reduction | Effect sizes of the treatment on the pain reduction will be determined by differences in response rates or odds-ratios, and the 95% CI's will accordingly be estimated. To test if topical sodium nitrite decreases pain at the wound site >20% over placebo, the investigators will apply Chi-square test. Logistic regression models will be applied if inclusion of confounding variables deems necessary. The investigators will also test if declines of weekly-measured absolute pain VAS scores on a continuous scale over the study period will be different between the two groups by applying mixed effects linear models for analysis of repeated-measure outcomes. | 10 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hydroxyurea Effect | Study outcomes between subjects with use and non-use of hydroxyurea will be compared using Chi-square, Mann-Whitney, and mixed-effect linear models depending on the outcome scales and the format of the data (cross-sectional vs. longitudinal). Also assess whether Hydroxyurea Effect on the outcomes will be different between treatment arms by modeling interaction effects in pertinent statistical models. | 10 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle cell disease, sodium nitrite, wound healing, Ulcer