Chronic Foot Ulcers
Conditions
Keywords
type 2 diabetes, healing, foot ulcers, vildagliptin
Brief summary
A randomized versus placebo trial designed to evaluate the clinical and humoral effects of 4 months of vildagliptin on healing of chronic ulcers in type 2 diabetes.
Detailed description
The chronic foot ulcer is a leading cause of hospital admissions for people with diabetes in the developed world and is a major morbidity associated with diabetes, often leading to pain, suffering, and a poor quality of life for patients. Chronic diabetic foot ulcers are estimated to occur in 15% of all patients with diabetes and precede 84% of all diabetes-related lower-leg amputations.The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, the most important predisposing factors being diabetic neuropathy and vasculopathy. Both micro and macroangiopathy strongly contribute to development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. HIF-1α and VEGF, as well as the NO production from iNOS, may contribute to limitation of hypoxic injury by promoting angiogenesis and wound healing. Experimental and pathological studies suggest that suggest that he incretin hormone glucagon-like peptide-1 (GLP-1) may improves VEGF generation, and promote pancreatic islet viability through the up-regulation of HIF1α. Therefore, aim of this study is to evaluate the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase IV (DPP-4), such as vildagliptin, on HIF-1α, VEGF and iNOS in diabetic chronic ulcers.
Interventions
DRUGPlacebo
Placebo is added to the standard good medical practice. Plus Metformin and/or Sulfonylurea
DRUGvildagliptin
50 mg per os b.i.d. for 4 months of treatment, added to the standard good medical practice.Plus Metformin and/or Sulfonylurea
Sponsors
University of Campania Luigi Vanvitelli
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes * Oral hypoglycemic agents treatment * Chronic foot ulcers * Adequate blood circulation (perfusion) was assessed by a dorsum transcutaneous oxygen test \>30 -mmHg, anklebrachial index values \> 0.7 and \< 1.2 with toe pressure \> 30 mmHg, or Doppler arterial aveforms that were triphasic or biphasic at the ankle of the affected leg * Written consensus
Exclusion criteria
* Active Charcot disease * Ulcers resulting from electrical, chemical, or radiation burns * Collagen vascular disease * Ulcer malignancy * Untreated osteomyelitis, or cellulitis * Ulcer treatment with normothermic or hyperbaric oxygen therapy * Concomitant medications such as corticosteroids, immunosuppressive medications, or -chemotherapy * Recombinant or autologous growth factor products * Skin and dermal substitutes within 30 days of study start * Use of any enzymatic debridement treatments * Pregnant or nursing mothers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Full Epithelialization of the Wound | 3 months of treatment with vildagliptin | Biopsy is performed from the periphery of the ulcer, before and after treatment with vildagliptin, in order to evaluate the above referred outcome. Optic microscopy is used to evaluate the epithelialization of the wound. |
| Capillary Density | 3 months of treatment with vildagliptin | Biopsy is performed from the periphery of the ulcer, before and after treatment with vildagliptin, in order to evaluate the above referred outcome. Capillary density is measured using immunohistochemistry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HIF-1α | 3 months | The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate HIF-1α concentration. Higher values represent more factor. |
| VEGF | 3 months | The factor is assessed by immunoblot analysis (commercial kits).Arbitrary unit of measure are used to evaluate VEGF concentration. Higher values represent more factor. |
| VEGF-R1 (Total and Phosphorylated Form), VEGF-R2 (Total and Phosphorylated Form) | 3 months | The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate VEGF-R1 concentration. Higher values represent more factor. |
| iNOS | 3 months | The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate iNOS concentration. Higher values represent more factor. |
Countries
Italy
Participant flow
Recruitment details
Completed
Participants by arm
| Arm | Count |
|---|---|
| Placebo In the placebo group, the dose of other concomitant hypoglycemic medication was changed to obtain a similar profile of metabolic parameters. Additional antidiabetic therapy, including sulfonylurea, metformin, and insulin, was titrated for optimal glycemic control for 3 months. All patients had diabetes and at least one full-thickness wound below the ankle for \>3 months. All patients were examined weekly for the first 4 weeks (day 28) then every other week until day 120 or ulcer closure by any means. At each visit, tracings of the wound margins were made for computer planimetry to document changes in wound size, and photographs were taken for a visual record. All patients followed the regular treatment at the multidisciplinary diabetes foot clinic, included treatment of infection, debridement, off-loading, and metabolic control according to high international standards and standard good medical practice.
placebo: Placebo is added to the standard good medical practice. | 53 |
| Vildagliptin The experimental arm followed the same treatment of placebo group, but received also vildagliptin 50 mg per os b.i.d. for 4 months
vildagliptin: 50 mg per os b.i.d. for 4 months of treatment, added to the standard good medical practice. | 53 |
| Total | 106 |
Baseline characteristics
| Characteristic | Vildagliptin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 41 Participants | 40 Participants | 81 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 13 Participants | 25 Participants |
| Age, Continuous | 64 years STANDARD_DEVIATION 15 | 63 years STANDARD_DEVIATION 14 | 64 years STANDARD_DEVIATION 21 |
| Region of Enrollment Italy | 53 participants | 53 participants | 106 participants |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Male | 35 Participants | 34 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 53 | 0 / 53 |
| serious Total, serious adverse events | 0 / 53 | 0 / 53 |
Outcome results
Primary
Capillary Density
Biopsy is performed from the periphery of the ulcer, before and after treatment with vildagliptin, in order to evaluate the above referred outcome. Capillary density is measured using immunohistochemistry
Time frame: 3 months of treatment with vildagliptin
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Capillary Density | 3 months data | 50 capillaries/mm2 |
| Placebo | Capillary Density | baseline data | 48 capillaries/mm2 |
| Vildagliptin | Capillary Density | 3 months data | 140 capillaries/mm2 |
| Vildagliptin | Capillary Density | baseline data | 46 capillaries/mm2 |
Comparison: * Vildagliptin vs Placebo at 3 months.~* Placebo baseline versus placebo 3 months.~* Vildagliptin baseline versus Vildagliptin 3 months.p-value: <0.05t-test, 2 sided
Primary
Full Epithelialization of the Wound
Biopsy is performed from the periphery of the ulcer, before and after treatment with vildagliptin, in order to evaluate the above referred outcome. Optic microscopy is used to evaluate the epithelialization of the wound.
Time frame: 3 months of treatment with vildagliptin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Full Epithelialization of the Wound | 16 participants |
| Vildagliptin | Full Epithelialization of the Wound | 8 participants |
Comparison: * Vildagliptin vs Placebo at 3 months.~* Placebo baseline versus placebo 3 months.~* Vildagliptin baseline versus Vildagliptin 3 months.p-value: <0.05t-test, 2 sided
Secondary
HIF-1α
The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate HIF-1α concentration. Higher values represent more factor.
Time frame: 3 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | HIF-1α | 3 months data | 200 arbitrary units |
| Placebo | HIF-1α | Baseline data | 205 arbitrary units |
| Vildagliptin | HIF-1α | 3 months data | 600 arbitrary units |
| Vildagliptin | HIF-1α | Baseline data | 215 arbitrary units |
Comparison: p-values from multiple comparisons: placebo at baseline vs. placebo at 3 months; placebo at 3 months vs. Vildagliptin at 3 months; Vildagliptin at baseline vs. Vildagliptin at 3 months.p-value: <0.05t-test, 2 sided
Secondary
iNOS
The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate iNOS concentration. Higher values represent more factor.
Time frame: 3 months
Population: The analysis was not performed because an inadequate amount of biopsy tissue
Secondary
VEGF
The factor is assessed by immunoblot analysis (commercial kits).Arbitrary unit of measure are used to evaluate VEGF concentration. Higher values represent more factor.
Time frame: 3 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | VEGF | 3 months data | 200 arbitrary units |
| Placebo | VEGF | Baseline data | 210 arbitrary units |
| Vildagliptin | VEGF | 3 months data | 580 arbitrary units |
| Vildagliptin | VEGF | Baseline data | 215 arbitrary units |
p-value: <0.05t-test, 2 sided
Secondary
VEGF-R1 (Total and Phosphorylated Form), VEGF-R2 (Total and Phosphorylated Form)
The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate VEGF-R1 concentration. Higher values represent more factor.
Time frame: 3 months
Population: The analysis was not performed because an inadequate amount of biopsy tissue