Sickle Cell Disease
Conditions
Keywords
Sickle cell disease, sodium nitrite, wound healing, Ulcer
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 sickle cell disease (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
Interventions
DRUGTopical Sodium Nitrite
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.
OTHERPlacebo
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.
Sponsors
Duke University
caterina P minniti
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 Glucose-6-Phosphate Dehydrogenase (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 Phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, 4 days prior to screening * Pregnant women - urine or serum Human chorionic gonadotropin (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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Tolerability (Methemoglobin Level) | Baseline through last available measurement, up to 10 weeks | Assessment of tolerability was determined by evaluating the change in methemoglobin level from baseline through the end of study at week 10. Samples were collected and Methemoglobin levels were measured by co-oximetry Results are summarized by study arm using basic descriptive statistics and expressed as a percentage of the total hemoglobin in the sample. |
| Change in Total Ulcerated Surface Area | From Baseline through last study visit at 10 weeks | Change in total ulcerated surface area from baseline was assessed through the last study visit at 10 weeks. Surface area measurements of the ulcer were obtained and photographed with defined lighting, distance, exposure, and camera type. Total ulcerated surface area measurements were obtained using digital planimetry and measuring the longest length and widest width of the ulcer(s). Results are summarized by study arm using basic descriptive statistics and reported in cm\^2. Negative results are indicative of a reduction in group median total ulcerated surface area from baseline and positive results are indicative of an increase in group median total ulcerated surface area from baseline. |
| Change in Ulcer Pain | From Baseline through last study visit at 10 weeks | Change in Ulcer Pain from baseline through the last study visit at 10 weeks were assessed using the Visual Analog Scale (VAS). The VAS is a widely used tool to quantify subjective pain perception over time and in this study was used to determine the efficacy of the topical sodium nitrite. Participants were asked to mark a point on a line indicating the severity of their pain on a 0-10 scale, with 0 representing No pain and 10 representing the Worst possible pain. A decrease in VAS score is indicative of a reduction in ulcer pain. Scores were summarized by study arm using basic descriptive statistics. |
| Number of Participants With Total Ulcerated Surface Area Reduction | From Baseline through last study visit at 10 weeks | The number of participants who achieved an objective reduction in total surface area of the ulcer of \>= 25% from baseline is summarized and reported as a dichotomous (No or Yes) variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hydroxyurea Effect on Change in Total Ulcerated Surface Area | From Baseline through last study visit at 10 weeks | Hydroxyurea effect on Change in Total Ulcerated Surface Area was conducted to evaluate the effect of hydroxyurea in combination with the topical sodium nitrite or placebo. Surface area measurements of the ulcer were obtained and photographed with defined lighting, distance, exposure, and camera type. Total ulcerated surface area measurements were obtained using digital planimetry and measuring the longest length and widest width of the ulcer(s). Study outcomes between participants with use of (HU) and non-use of (No HU) hydroxyurea are summarized by study arm as an increase or decrease in total ulcerated surface area in cm\^2 and analyzed using Wilcoxon-Mann-Whitney and Fisher Exact statistical testing. Negative results are indicative of a reduction in group median total ulcerated surface area from baseline and positive results are indicative of an increase in group median total ulcerated surface area from baseline (with or without Hydroxyurea). |
| Hydroxyurea Effect on Change in Ulcer Pain | From Baseline through last study visit at 10 weeks | Hydroxyurea effect on change in Ulcer Pain was conducted to evaluate the effect of hydroxyurea in combination with the topical sodium nitrite or placebo. Ulcer pain assessments were conducted using the Visual Analog Scale (VAS). The VAS is used to quantify subjective pain perception over time and in this study was used to determine the efficacy of the topical sodium nitrite. Participants were asked to mark a point on a line indicating the severity of their pain on a 0-10 scale, with 0 representing No pain and 10 representing the Worst possible pain. Study outcomes between participants with use of (HU) and non-use of (No HU) hydroxyurea are summarized by study arm as an increase or decrease in ulcer pain and analyzed using Wilcoxon-Mann-Whitney statistical testing. Negative results are indicative of a decrease in group median ulcer pain from baseline and positive results are indicative of an increase in group median ulcer pain from baseline (with or without Hydroxyurea). |
| Hydroxyurea Effect on Assessment of Tolerability | From Baseline through last study visit at 10 weeks | Hydroxyurea effect on Assessment of Tolerability, as determined by the change in Methemoglobin level, was conducted to evaluate the effect of hydroxyurea in combination with the topical sodium nitrite or placebo. Samples were collected and Methemoglobin levels were measured by co-oximetry. Study outcomes between participants with use of (HU) and non-use of (No HU) hydroxyurea are summarized as an increased or decreased percentage by study arm and analyzed using Wilcoxon-Mann-Whitney statistical testing. |
Countries
United States
Participant flow
Pre-assignment details
26 patients (pts) were screened and 24 consented (one was consented twice as the IRB required a reconsent due to the time interval which had lapsed between the consent process and study initiation during COVID). Of the 24 unique pts, 2 were lost to follow up during the run-in period and 4 pts had a reduction in ulcer size by \>25%, via normal wound care, during the run-in period and were not eligible for study-defined treatment and not enrolled into the study. As such, 18 pts were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants will receive placebo and standard of care
Placebo: Participants will have Placebo applied to total ulcerated area. If a participant has more than one ulcer, all of them will be treated with placebo in this intervention. | 10 |
| Topical Sodium Nitrite Participants will receive 2% topical sodium nitrite cream and standard of care
Topical Sodium Nitrite: Participants will have 0.1 cm of 2% sodium nitrite cream applied per 1 cm\^2 of the total ulcerated area. Areas will be rounded to the nearest 1 cm\^2. If a participant has more than one ulcer, all of them will be treated with either study cream in this intervention. | 8 |
| Total | 18 |
Baseline characteristics
| Characteristic | Placebo | Total | Topical Sodium Nitrite |
|---|---|---|---|
| Age, Continuous | 40.2 years STANDARD_DEVIATION 11 | 43.5 years STANDARD_DEVIATION 12.5 | 47.6 years STANDARD_DEVIATION 13.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 15 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hydroxyurea Usage No | 4 Participants | 9 Participants | 5 Participants |
| Hydroxyurea Usage Yes | 6 Participants | 9 Participants | 3 Participants |
| Methemoglobin Levels | 1.76 percentage of total hemoglobin STANDARD_DEVIATION 0.635 | 1.64 percentage of total hemoglobin STANDARD_DEVIATION 0.658 | 1.49 percentage of total hemoglobin STANDARD_DEVIATION 0.698 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 17 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 participants | 18 participants | 8 participants |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
| Sickle Cell Genotype HbSB+ | 0 Participants | 1 Participants | 1 Participants |
| Sickle Cell Genotype HbSC | 0 Participants | 0 Participants | 0 Participants |
| Sickle Cell Genotype HbSD | 0 Participants | 0 Participants | 0 Participants |
| Sickle Cell Genotype HbS/O (Arab) | 0 Participants | 0 Participants | 0 Participants |
| Sickle Cell Genotype HbSS | 10 Participants | 17 Participants | 7 Participants |
| Total Ulcerated Surface Area | 11.4 cm^2 STANDARD_DEVIATION 12.3 | 13.7 cm^2 STANDARD_DEVIATION 13.6 | 16.6 cm^2 STANDARD_DEVIATION 15.4 |
| Visual Analog Scale (VAS) for Pain Intensity | 5.3 score on a scale STANDARD_DEVIATION 2.49 | 4.84 score on a scale STANDARD_DEVIATION 2.15 | 4.28 score on a scale STANDARD_DEVIATION 1.62 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 9 / 10 | 4 / 8 |
| serious Total, serious adverse events | 4 / 10 | 3 / 8 |
Outcome results
Primary
Assessment of Tolerability (Methemoglobin Level)
Assessment of tolerability was determined by evaluating the change in methemoglobin level from baseline through the end of study at week 10. Samples were collected and Methemoglobin levels were measured by co-oximetry Results are summarized by study arm using basic descriptive statistics and expressed as a percentage of the total hemoglobin in the sample.
Time frame: Baseline through last available measurement, up to 10 weeks
Population: For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Assessment of Tolerability (Methemoglobin Level) | -0.05 percentage of total hemoglobin |
| Topical Sodium Nitrite | Assessment of Tolerability (Methemoglobin Level) | 0.25 percentage of total hemoglobin |
Comparison: Change in methemoglobin from baseline to end of study (EOS) for all participants.p-value: 0.2967Wilcoxon (Mann-Whitney)
Primary
Change in Total Ulcerated Surface Area
Change in total ulcerated surface area from baseline was assessed through the last study visit at 10 weeks. Surface area measurements of the ulcer were obtained and photographed with defined lighting, distance, exposure, and camera type. Total ulcerated surface area measurements were obtained using digital planimetry and measuring the longest length and widest width of the ulcer(s). Results are summarized by study arm using basic descriptive statistics and reported in cm\^2. Negative results are indicative of a reduction in group median total ulcerated surface area from baseline and positive results are indicative of an increase in group median total ulcerated surface area from baseline.
Time frame: From Baseline through last study visit at 10 weeks
Population: For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Total Ulcerated Surface Area | -1.50 cm^2 |
| Topical Sodium Nitrite | Change in Total Ulcerated Surface Area | -3.26 cm^2 |
Comparison: Change in total ulcerated surface area from baseline to end of study (EOS)p-value: 0.2818Wilcoxon (Mann-Whitney)
Comparison: Difference in frequency of 25% total ulcerated surface area reduction between treatment armsp-value: 1Fisher Exact
Primary
Change in Ulcer Pain
Change in Ulcer Pain from baseline through the last study visit at 10 weeks were assessed using the Visual Analog Scale (VAS). The VAS is a widely used tool to quantify subjective pain perception over time and in this study was used to determine the efficacy of the topical sodium nitrite. Participants were asked to mark a point on a line indicating the severity of their pain on a 0-10 scale, with 0 representing No pain and 10 representing the Worst possible pain. A decrease in VAS score is indicative of a reduction in ulcer pain. Scores were summarized by study arm using basic descriptive statistics.
Time frame: From Baseline through last study visit at 10 weeks
Population: For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Ulcer Pain | -0.5 score on a scale |
| Topical Sodium Nitrite | Change in Ulcer Pain | 0.9 score on a scale |
Comparison: Change in average pain from baseline to end of study (EOS)p-value: 0.3754Wilcoxon (Mann-Whitney)
Primary
Number of Participants With Total Ulcerated Surface Area Reduction
The number of participants who achieved an objective reduction in total surface area of the ulcer of \>= 25% from baseline is summarized and reported as a dichotomous (No or Yes) variable.
Time frame: From Baseline through last study visit at 10 weeks
Population: For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Total Ulcerated Surface Area Reduction | No | 5 Participants |
| Placebo | Number of Participants With Total Ulcerated Surface Area Reduction | Yes | 5 Participants |
| Topical Sodium Nitrite | Number of Participants With Total Ulcerated Surface Area Reduction | No | 4 Participants |
| Topical Sodium Nitrite | Number of Participants With Total Ulcerated Surface Area Reduction | Yes | 4 Participants |
Secondary
Hydroxyurea Effect on Assessment of Tolerability
Hydroxyurea effect on Assessment of Tolerability, as determined by the change in Methemoglobin level, was conducted to evaluate the effect of hydroxyurea in combination with the topical sodium nitrite or placebo. Samples were collected and Methemoglobin levels were measured by co-oximetry. Study outcomes between participants with use of (HU) and non-use of (No HU) hydroxyurea are summarized as an increased or decreased percentage by study arm and analyzed using Wilcoxon-Mann-Whitney statistical testing.
Time frame: From Baseline through last study visit at 10 weeks
Population: Number of participants analyzed identified in table below. For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Hydroxyurea Effect on Assessment of Tolerability | HU | -0.6 percentage of total hemoglobin |
| Placebo | Hydroxyurea Effect on Assessment of Tolerability | No HU | 0.3 percentage of total hemoglobin |
| Topical Sodium Nitrite | Hydroxyurea Effect on Assessment of Tolerability | HU | 0.2 percentage of total hemoglobin |
| Topical Sodium Nitrite | Hydroxyurea Effect on Assessment of Tolerability | No HU | 0.3 percentage of total hemoglobin |
Comparison: Change in methemoglobin from baseline to end of study (EOS) for participants on Hydroxyurea (HU).p-value: 0.1165Wilcoxon (Mann-Whitney)
Comparison: Change in methemoglobin from baseline to end of study (EOS) for participants off Hydroxyurea (HU).p-value: 0.4583Wilcoxon (Mann-Whitney)
Secondary
Hydroxyurea Effect on Change in Total Ulcerated Surface Area
Hydroxyurea effect on Change in Total Ulcerated Surface Area was conducted to evaluate the effect of hydroxyurea in combination with the topical sodium nitrite or placebo. Surface area measurements of the ulcer were obtained and photographed with defined lighting, distance, exposure, and camera type. Total ulcerated surface area measurements were obtained using digital planimetry and measuring the longest length and widest width of the ulcer(s). Study outcomes between participants with use of (HU) and non-use of (No HU) hydroxyurea are summarized by study arm as an increase or decrease in total ulcerated surface area in cm\^2 and analyzed using Wilcoxon-Mann-Whitney and Fisher Exact statistical testing. Negative results are indicative of a reduction in group median total ulcerated surface area from baseline and positive results are indicative of an increase in group median total ulcerated surface area from baseline (with or without Hydroxyurea).
Time frame: From Baseline through last study visit at 10 weeks
Population: Number of participants analyzed identified in table below. For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Hydroxyurea Effect on Change in Total Ulcerated Surface Area | HU | -1.34 cm^2 |
| Placebo | Hydroxyurea Effect on Change in Total Ulcerated Surface Area | No HU | -2.081 cm^2 |
| Topical Sodium Nitrite | Hydroxyurea Effect on Change in Total Ulcerated Surface Area | HU | -3.506 cm^2 |
| Topical Sodium Nitrite | Hydroxyurea Effect on Change in Total Ulcerated Surface Area | No HU | -0.57 cm^2 |
Comparison: Change in total ulcerated surface area from baseline to end of study (EOS) for participants on Hydroxyurea (HU).p-value: 0.068Wilcoxon (Mann-Whitney)
Comparison: Change in total ulcerated surface area from baseline to end of study (EOS) for participants off Hydroxyurea (HU).p-value: 0.5Wilcoxon (Mann-Whitney)
Comparison: Difference in frequency of 25% total ulcerated surface area reduction between treatment arms for participants on Hydroxyurea (HU).p-value: 1Fisher Exact
Comparison: Difference in frequency of 25% total ulcerated surface area reduction between treatment arms for participants off Hydroxyurea (HU).p-value: 1Fisher Exact
Secondary
Hydroxyurea Effect on Change in Ulcer Pain
Hydroxyurea effect on change in Ulcer Pain was conducted to evaluate the effect of hydroxyurea in combination with the topical sodium nitrite or placebo. Ulcer pain assessments were conducted using the Visual Analog Scale (VAS). The VAS is used to quantify subjective pain perception over time and in this study was used to determine the efficacy of the topical sodium nitrite. Participants were asked to mark a point on a line indicating the severity of their pain on a 0-10 scale, with 0 representing No pain and 10 representing the Worst possible pain. Study outcomes between participants with use of (HU) and non-use of (No HU) hydroxyurea are summarized by study arm as an increase or decrease in ulcer pain and analyzed using Wilcoxon-Mann-Whitney statistical testing. Negative results are indicative of a decrease in group median ulcer pain from baseline and positive results are indicative of an increase in group median ulcer pain from baseline (with or without Hydroxyurea).
Time frame: From Baseline through last study visit at 10 weeks
Population: Number of participants analyzed identified in table below. For this study, the fundamental analysis unit was the participant and not the ulcer(s). All data is presented accordingly.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Hydroxyurea Effect on Change in Ulcer Pain | HU | 0.35 score on a scale |
| Placebo | Hydroxyurea Effect on Change in Ulcer Pain | No HU | -2.70 score on a scale |
| Topical Sodium Nitrite | Hydroxyurea Effect on Change in Ulcer Pain | HU | 0.9 score on a scale |
| Topical Sodium Nitrite | Hydroxyurea Effect on Change in Ulcer Pain | No HU | 1.0 score on a scale |
Comparison: Change in average pain from baseline to end of study (EOS) for participants on Hydroxyurea (HU).p-value: 0.4298Wilcoxon (Mann-Whitney)
Comparison: Change in average pain from baseline to end of study (EOS) for participants off Hydroxyurea (HU).p-value: 0.2701Wilcoxon (Mann-Whitney)