Cream provides relief for leg ulcers in SCD

MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).

The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.

A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.

But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.

“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . .  remains a clinical and economic burden,” Dr Minniti noted.

“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”

With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.

Patient characteristics and treatment

The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).

Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm² (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm² (range, 2.51-14.66).

The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).

For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.

Adverse events

There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.

Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.

For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.

Effects on ulcer size

Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).

Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.

One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.

The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.

Effects on pain and blood flow

One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.

There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).

Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).

“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”

Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).

Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.

MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).

The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.

A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.

But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.

“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . .  remains a clinical and economic burden,” Dr Minniti noted.

“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”

With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.

Patient characteristics and treatment

The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).

Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm² (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm² (range, 2.51-14.66).

The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).

For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.

Adverse events

There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.

Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.

For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.

Effects on ulcer size

Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).

Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.

One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.

The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.

Effects on pain and blood flow

One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.

There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).

Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).

“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”

Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).

Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.

MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).

The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.

A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.

But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.

“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . .  remains a clinical and economic burden,” Dr Minniti noted.

“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”

With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.

Patient characteristics and treatment

The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).

Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm² (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm² (range, 2.51-14.66).

The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).

For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.

Adverse events

There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.

Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.

For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.

Effects on ulcer size

Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).

Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.

One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.

The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.

Effects on pain and blood flow

One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.

There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).

Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).

“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”

Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).

Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.