Sickle Cell Anemia, Skin Ulcers
Conditions
Keywords
dermatologic disorders, genetic diseases and dysmorphic syndromes, hematologic disorders, rare disease, sickle cell anemia, skin ulcers, thalassemia major
Brief summary
OBJECTIVES: I. Compare the efficacy of local care alone vs local care plus arginine butyrate in terms of healing rate in patients with refractory sickle cell ulcers. II. Determine the effect of arginine butyrate therapy on tissue factors related to promotion or inhibition of wound healing in these patients. III. Determine whether the regimen used in this study is appropriate for testing in pivotal trials.
Detailed description
PROTOCOL OUTLINE: This is a randomized, multicenter study. Patients are randomized to one of two treatment arms. Arm I: Patients receive arginine butyrate IV over 6-9 hours at night 5 days a week for 12 weeks, plus concurrent standard local therapy consisting of cleaning, saline irrigation, and dressing changes as prescribed by each patient's physician. Patients who experience progressive healing receive arginine butyrate 3-4 times a week. Arginine butyrate treatment may be discontinued and reinstated following a single 2 week medical complication. Arm II: Patients receive standard local therapy alone for 12 weeks. Patients randomized to arm II may cross over to receive arginine butyrate if no or less than 25% healing is observed after 12 weeks. Patients whose ulcers have closed by at least 15% per cycle may receive 2 additional 8-week cycles of arginine butyrate therapy and are followed for 2 months after healing is completed.
Interventions
To determine if Arginine Butyrate accelerates healing of refractory leg ulcers over Standard Local Care alone.
OTHERStandard local care dressing
To heal leg ulcers.
Sponsors
Boston Medical Center
University of Illinois at Chicago
Icahn School of Medicine at Mount Sinai
University of Tennessee
Schneider Children's Medical Center, Israel
Susan P. Perrine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
PROTOCOL CRITERIA INCLUSION: --Disease Characteristics-- Significant sickle cell syndrome including Hemoglobin SS (HbSS), Hemoglobin S-beta thalassemia, and hemoglobin variants. Lower extremity or ankle ulcer (or ulcers) present for at least 6 months without healing --Patient Characteristics-- Age: 16-60 yrs Performance status: Not specified Hematopoietic: Not specified Hepatic: No hepatic compromise Transaminases no greater than 250 IU Renal: No renal compromise Creatinine no greater than 1.2 mg/mL (adults) Creatinine no greater than 0.9 mg/mL (teenagers) Other: Not pregnant Fertile patients must use effective contraception No poorly controlled seizure disorders No other secondary conditions that might inhibit immune function * Prior/Concurrent Therapy Other: Must be treated with antibiotics prior to entry for complicating cellulitis or secondary infections EXCLUSION : --Prior/Concurrent Therapy-- Biologic therapy: chronic transfusion therapy Chemotherapy: prior or concurrent cancer chemotherapy concurrent butyrate derivatives Endocrine therapy: concurrent corticosteroid therapy Radiotherapy: Not specified Surgery: Not specified --Patient Characteristics-- Hepatic: hepatic compromise Transaminases greater than 250 IU Renal: renal compromise Creatinine greater than 1.2 mg/mL (adults) Creatinine greater than 0.9 mg/mL (teenagers) Other: pregnant; Fertile patients with no effective contraception Poorly controlled seizure disorders other secondary conditions that might inhibit immune function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area | participants were followed for an average of 3 months | Treatment Arm: The AB is given as an IV infusion at 500 mg/kg over 6-9 hrs. 5 days per week for 12 weeks. After 12 weeks of therapy, if he ulcer has decreased by 25% , the AB may be continued for additional 8 weeks (twice) or, until ulcer closes plus 2 weeks, additionally. Ulcers photographed, traced, and ulcer areas calculated by computerized planimetry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % Ulcers Which Completely Healed in Each Group, After 3 Months | two additional courses of 8 week cycles | Control Arm: given option to crossover to Treatment Arm if, ulcers have not closed after 12 weeks standard local care alone. |
Countries
United States
Participant flow
Recruitment details
Study began 1998, contacted physicians at several medical centers with patients under their care for SCD with refractory leg ulcers. Electronic materials describing the study and its sponsor were transmitted to medical centers.
Participants by arm
| Arm | Count |
|---|---|
| Standard Local Care Dressing Standard local care dressing including cleaning, saline irrigation, dressing changes only for 8 weeks twice a week. | 8 |
| Arginine Butyrate Arginine Butyrate IV plus Standard local care dressing for a total of 12 weeks. Low dose 250 mg/kg or, increased dose 750 mg/kg. First week AB given 5 days in a row, over 8 to 12hours. | 12 |
| Crossover Patients are randomly assigned (following a table of random numbers prepared by a blinded statistician) between two arms of the study. Arm I is Standard local care dressing only, and Arm II is standard local care plus Arginine Butyrate (AB), the Investigational New Drug. Ulcers observed & traced weekly. Ulcer area calculated by computerized planimetry. After 12 weeks of therapy, if the ulcer size decreased by at least 25%, the AB may be continued for another 8 weeks (twice), or until the ulcer closes, plus an additional 2 weeks. The patients randomized to the Control Arm ( standard local care) were given the option of crossing over to Arm II If, ulcers did not close after 8 weeks of standard local care. | 3 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomized Period | Moved to Crossover Period | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Standard Local Care Dressing | Arginine Butyrate | Crossover | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 12 Participants | 3 Participants | 23 Participants |
| Age, Continuous | 31 years STANDARD_DEVIATION 12.57478 | 33 years STANDARD_DEVIATION 9.14985 | 31 years STANDARD_DEVIATION 2.3094 | 32 years STANDARD_DEVIATION 1.1547 |
| Region of Enrollment Israel | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 8 participants | 12 participants | 2 participants | 22 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 11 | 0 / 15 |
| serious Total, serious adverse events | 5 / 11 | 9 / 15 |
Outcome results
Primary
Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area
Treatment Arm: The AB is given as an IV infusion at 500 mg/kg over 6-9 hrs. 5 days per week for 12 weeks. After 12 weeks of therapy, if he ulcer has decreased by 25% , the AB may be continued for additional 8 weeks (twice) or, until ulcer closes plus 2 weeks, additionally. Ulcers photographed, traced, and ulcer areas calculated by computerized planimetry.
Time frame: participants were followed for an average of 3 months
Population: Per protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Local Care Dressing | Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area | 24 percentage of healed ulcers |
| Arginine Butyrate | Healing Defined as a Decrease in Ulcer Area by at Least 25% of the Initial Area | 78 percentage of healed ulcers |
Comparison: Percentage of ulcers undergoing partial and complete healing compared at 12 weeks. Mean Ulcer areas were calculated utilizing computerized planimetry, ulcer area tracings, and photography for baseline and 12 weeks and compared between the two study Arms.p-value: 0.05Fisher Exact
Secondary
% Ulcers Which Completely Healed in Each Group, After 3 Months
Control Arm: given option to crossover to Treatment Arm if, ulcers have not closed after 12 weeks standard local care alone.
Time frame: two additional courses of 8 week cycles
Population: Per Protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Local Care Dressing | % Ulcers Which Completely Healed in Each Group, After 3 Months | 8 percentage of completely healed ulcers |
| Arginine Butyrate | % Ulcers Which Completely Healed in Each Group, After 3 Months | 31 percentage of completely healed ulcers |