Diabetic Foot, Foot Ulcer, Diabetic
Conditions
Keywords
Diabetes, diabetic foot ulcer, foot sore, type 2 diabetes, type 1 diabetes, neuropathy, DFU
Brief summary
This study is designed to test the hypothesis that daily treatment of diabetic foot ulcers with an enzymatic debriding agent, SANTYL, for up to 6 weeks will result in more rapid decrease in ulcer area than diabetic foot ulcers treated with a topical treatment containing silver. After meeting study criteria, participants will be randomly assigned to apply SANTYL or a topical treatment containing silver to their to foot ulcer for up to 6 weeks. At the end of 6 weeks, participants will be followed for an additional 4 weeks to examine the outcome of the study treatment.
Detailed description
The objectives of this study were to compare outcomes of diabetic foot ulcers (DFUs) treated with SANTYL or silver-containing products, both in combination with sharp debridement as needed. One hundred two subjects with qualifying DFUs were randomized to daily treatment with either SANTYL or a silver-containing product for 6 weeks followed by a 4 -week follow-up period. The primary outcome was the mean percent reduction in DFU area. A secondary outcome was the incidence of ulcer infections between groups.
Interventions
BIOLOGICALSantyl
OTHERProduct containing silver
Silver product not specified by the protocol; Investigators choose the appropriate silver containing product for each diabetic foot ulcer
Sponsors
Smith & Nephew, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent, which will consist of reading, signing, and dating the informed consent document after the Investigator, sub-Investigator or other designated study staff member has explained the study procedures, risks, and contact information. 2. Eighteen (18) years of age or older, of either sex, and of any race or skin type. 3. Willing and able to make all required study visits. 4. Able to follow instructions and perform the dressing changes at home or have a caregiver who can perform the dressing changes according to the protocol. 5. Willing to use an appropriate off-loading device to keep weight off of foot ulcers. 6. An ulcer present on any part of the plantar surface of the neuropathic foot or hallux which is 0.5 cm2 - 10 cm2 inclusive (as measured at the Screening Visit using the ARANZ Silhouette imaging device). The target ulcer duration must be ≥ 6 weeks but not more than 52 weeks (12 months) as documented in the subject's history or by subject report of onset, and which requires debridement. 7. Adequate arterial blood flow as evidenced by an ankle brachial index (ABI) of \> 0.70 and ≤ 1.20. If ABI \> 1.2, perfusion at or near the site of the ulcer should be confirmed; the foot is warm to the touch and has palpable pulses. 8. Separation of at least 5 cm (closest ulcer edge to other closest ulcer edge) if ≥ 2 ulcers are present as measured using the ARANZ Silhouette imaging device. 9. Diabetes mellitus (Type 1 or 2) requiring insulin or oral/injectable medications to control blood glucose levels. 10. Target ulcer is not infected based on clinical assessment.
Exclusion criteria
1. Contraindications or hypersensitivity to the use of clostridial collagenase or products containing silver. 2. Participation in another clinical trial within thirty (30) days of Visit 1, or planned participation overlapping with this study. 3. Bleeding disorder that would preclude sharp debridement during the study. 4. Active cellulitis of the target ulcer, lymphangitic streaking, deep tissue abscess, gangrene, or infection of muscle, tendon, joint or bone. 5. Infection with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, azotemia). 6. A target ulcer which involves the underlying tissues of tendon, muscle, or bone. 7. Diagnosis of chronic granulomatous disease, leukocyte adhesion defects, or severe neutropenia. 8. Current treatment (at the time of the Screening Visit) with any of the following: * Systemic corticosteroids. If corticosteroid treatment was for ≥ 10 days, there must be a 1 week interval between discontinuation and screening. * Immunosuppressive agents * Chemotherapeutic agents * Antiviral agents * Systemic antibiotic therapy (for any reason) or topical antibiotic treatment of the target ulcer 9. Treatment of target ulcer with bioactive therapies within 1 month of screening: * Platelet-derived growth factor (e.g., Regranex®) * Living skin equivalent (e.g., Apligraf®) * Dermal substitute (e.g., Dermagraft®, Integra®, Oasis®, etc.) * Amniotic membrane products (e.g., EpiFix®, Grafix®, etc.) 10. Prior treatment of target ulcer for any length of time with clostridial collagenase ointment (SANTYL®). 11. Radiation therapy to the target lower extremity within 30 days prior to screening. 12. Medical or physical condition that, in the opinion of the Investigator, would preclude safe subject participation in the study. 13. Blood counts and blood chemistry values as follows: * Alanine aminotransferase (ALT) \> 3x upper limit of normal * Aspartate aminotransferase (AST) \> 3x upper limit of normal * Gamma Glutamyl Transferase (GGT) \> 2.5x upper limit of normal * Serum albumin \< 2.0 g/dL • Pre-albumin levels of \< 10 mg/dL * Alkaline phosphatase \> 500 U/L • Serum total bilirubin \> 3.0 mg/dL * Serum BUN \> 75 mg/dL • Serum creatinine \> 4.5 mg/dL * HbA1c \> 12% • Hemoglobin (Hgb) \< 8.0 g/dL * WBC \< 2.0 x 109/L • Absolute neutrophil count \< 1.0 x 109/L * Platelet count \< 50 x 109/L
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Ulcer Area From Baseline to the End of the Treatment. | 6 weeks | Ulcer area was measured using the ARANZ Silhouette digital imaging and measurement device. |
Secondary
| Measure | Time frame |
|---|---|
| Target Ulcer Infection Rates in Each Treatment Group During the Treatment Period as Determined by Investigator-reported Adverse Events | 6 weeks |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Closure for Ulcers Achieving Closure in Treatment Period | 6 weeks | Days to closure for ulcers that closed by end of treatment period. |
| Time to Closure for Ulcers Achieving Closure by End of Follow-up | 10 weeks | Days to closure for ulcers that closed by end of follow-up period. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Santyl Collagenase ointment applied topically once per day for up to 6 weeks. | 51 |
| Product Containing Silver Products containing silver was applied per Investigator instructions and instructions for use/package insert for up to 6 weeks. Silver product was not specified by the protocol; Investigators chose the appropriate silver containing product for each diabetic foot ulcer. | 51 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Non-Compliance | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Santyl | Product Containing Silver |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 14 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 37 Participants | 39 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 12 | 56.4 years STANDARD_DEVIATION 13.1 | 57.6 years STANDARD_DEVIATION 10.8 |
| Ankle Brachial Index | 1 ABI ratio (mmHg/mmHg) STANDARD_DEVIATION 1 | 1 ABI ratio (mmHg/mmHg) STANDARD_DEVIATION 0.1 | 1 ABI ratio (mmHg/mmHg) STANDARD_DEVIATION 0.2 |
| Body Mass Index (BMI) | 34 kg/m^2 STANDARD_DEVIATION 7 | 34.3 kg/m^2 STANDARD_DEVIATION 7.7 | 33.6 kg/m^2 STANDARD_DEVIATION 6.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 14 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 37 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Foot Perfusion N/A, ABI not > 1.2 | 93 Participants | 48 Participants | 45 Participants |
| Foot Perfusion No | 9 Participants | 3 Participants | 6 Participants |
| Foot Perfusion Yes | 0 Participants | 0 Participants | 0 Participants |
| Height | 69.2 inches STANDARD_DEVIATION 3.5 | 69.6 inches STANDARD_DEVIATION 3.2 | 68.8 inches STANDARD_DEVIATION 3.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 3 Participants | 3 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 94 Participants | 47 Participants | 47 Participants |
| Region of Enrollment Canada | 20 Participants | 10 Participants | 10 Participants |
| Region of Enrollment United States | 82 Participants | 41 Participants | 41 Participants |
| Sex: Female, Male Female | 24 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 78 Participants | 42 Participants | 36 Participants |
| Target Ulcer Area | 1.6 cm^2 STANDARD_DEVIATION 1.9 | 1.6 cm^2 STANDARD_DEVIATION 1.8 | 1.7 cm^2 STANDARD_DEVIATION 2 |
| Target Ulcer Location Forefoot | 75 Participants | 33 Participants | 42 Participants |
| Target Ulcer Location Hallux | 16 Participants | 12 Participants | 4 Participants |
| Target Ulcer Location Heel | 7 Participants | 3 Participants | 4 Participants |
| Target Ulcer Location Lateral Heel | 1 Participants | 1 Participants | 0 Participants |
| Target Ulcer Location Medial Forefoot | 3 Participants | 2 Participants | 1 Participants |
| Ulcer Duration | 112.4 days STANDARD_DEVIATION 76.3 | 106.8 days STANDARD_DEVIATION 75.2 | 118.1 days STANDARD_DEVIATION 77.7 |
| Weight | 232.1 lbs STANDARD_DEVIATION 53 | 237.6 lbs STANDARD_DEVIATION 56.7 | 226.6 lbs STANDARD_DEVIATION 49.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 51 | 1 / 51 |
| other Total, other adverse events | 25 / 51 | 25 / 51 |
| serious Total, serious adverse events | 5 / 51 | 8 / 51 |
Outcome results
Primary
Mean Percent Change in Ulcer Area From Baseline to the End of the Treatment.
Ulcer area was measured using the ARANZ Silhouette digital imaging and measurement device.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Santyl | Mean Percent Change in Ulcer Area From Baseline to the End of the Treatment. | 57.6 percentage of change from baseline (cm2) | Standard Deviation 53.1 |
| Product Containing Silver | Mean Percent Change in Ulcer Area From Baseline to the End of the Treatment. | 41.3 percentage of change from baseline (cm2) | Standard Deviation 58.3 |
Secondary
Target Ulcer Infection Rates in Each Treatment Group During the Treatment Period as Determined by Investigator-reported Adverse Events
Time frame: 6 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Santyl | Target Ulcer Infection Rates in Each Treatment Group During the Treatment Period as Determined by Investigator-reported Adverse Events | 5 Participants |
| Product Containing Silver | Target Ulcer Infection Rates in Each Treatment Group During the Treatment Period as Determined by Investigator-reported Adverse Events | 11 Participants |
Post Hoc
Incidence of Debridements During Treatment Period
Number of debridements performed during the treatment period by treatment group.
Time frame: 6 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Santyl | Incidence of Debridements During Treatment Period | 305 occurences |
| Product Containing Silver | Incidence of Debridements During Treatment Period | 272 occurences |
Other Pre-specified
Time to Closure for Ulcers Achieving Closure by End of Follow-up
Days to closure for ulcers that closed by end of follow-up period.
Time frame: 10 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Santyl | Time to Closure for Ulcers Achieving Closure by End of Follow-up | 43.0 days | Standard Deviation 18.6 |
| Product Containing Silver | Time to Closure for Ulcers Achieving Closure by End of Follow-up | 50.8 days | Standard Deviation 14.6 |
Other Pre-specified
Time to Closure for Ulcers Achieving Closure in Treatment Period
Days to closure for ulcers that closed by end of treatment period.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Santyl | Time to Closure for Ulcers Achieving Closure in Treatment Period | 31.1 days | Standard Deviation 9 |
| Product Containing Silver | Time to Closure for Ulcers Achieving Closure in Treatment Period | 37.1 days | Standard Deviation 7.7 |