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Topical Sodium Nitrite in Sickle Cell Disease and Leg Ulcers

Primary Purpose

Sickle Cell Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Topical Sodium Nitrite
Placebo
Sponsored by
Montefiore Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring Sickle cell disease, sodium nitrite, wound healing, Ulcer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Montefiore Medical Center - Albert Einstein College of Medicine
  • Duke University Medical CenterRecruiting
  • University of Pittsburgh

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

control

topical sodium nitrite

Arm Description

patients will receive placebo and standard of care

patients will receive 2% topical sodium nitrite cream and standard of care

Outcomes

Primary Outcome Measures

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.
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.
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.

Secondary Outcome Measures

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.

Full Information

First Posted
May 16, 2016
Last Updated
March 6, 2023
Sponsor
Montefiore Medical Center
Collaborators
Duke University
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1. Study Identification

Unique Protocol Identification Number
NCT02863068
Brief Title
Topical Sodium Nitrite in Sickle Cell Disease and Leg Ulcers
Official Title
A Phase II Study of Topical Sodium Nitrite in Patients With Sickle Cell and Leg Ulcers
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 6, 2018 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Montefiore Medical Center
Collaborators
Duke University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
Sickle cell disease, sodium nitrite, wound healing, Ulcer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
control
Arm Type
Placebo Comparator
Arm Description
patients will receive placebo and standard of care
Arm Title
topical sodium nitrite
Arm Type
Experimental
Arm Description
patients will receive 2% topical sodium nitrite cream and standard of care
Intervention Type
Drug
Intervention Name(s)
Topical Sodium Nitrite
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Assessment of tolerability
Description
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.
Time Frame
10 Weeks
Title
Ulcer size reduction
Description
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.
Time Frame
10 Weeks
Title
Ulcer pain reduction
Description
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.
Time Frame
10 Weeks
Secondary Outcome Measure Information:
Title
Hydroxyurea Effect
Description
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.
Time Frame
10 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marilyn Telen, M.D.
Phone
919-684-5378
Email
marilyn.telen@duke.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Nirmish Shah, MD
Phone
252-258-5628
Email
nirmish.shah@duke.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Caterina Minniti, M.D.
Organizational Affiliation
Montefiore Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montefiore Medical Center - Albert Einstein College of Medicine
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marilyn Telen, MD
Phone
919-684-5378
Email
marilyn.telen@duke.edu
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15260
Country
United States
Individual Site Status
Completed

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
25938131
Citation
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. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. Lancet Haematol. 2014 Dec 1;1(3):e95-e103. doi: 10.1016/s2352-3026(14)00019-2.
Results Reference
result

Learn more about this trial

Topical Sodium Nitrite in Sickle Cell Disease and Leg Ulcers

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