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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | In the placebo group, the dose of other concomitant hypoglycemic medication was changed to obtain a similar profile of metabolic parameters. 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. |
|
| Vildagliptin | Experimental | The experimental arm followed the same treatment of placebo group, but received also vildagliptin 50 mg per os b.i.d. for 4 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Placebo is added to the standard good medical practice. Plus Metformin and/or Sulfonylurea |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 3 months of treatment with vildagliptin |
| 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 | 3 months of treatment with vildagliptin |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 3 months |
| VEGF |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Raffaele Marfella, MD, PhD | Second University Naples | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Second university of Naples | Naples | I-80100 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23197976 | Result | Marfella R, Sasso FC, Rizzo MR, Paolisso P, Barbieri M, Padovano V, Carbonara O, Gualdiero P, Petronella P, Ferraraccio F, Petrella A, Canonico R, Campitiello F, Della Corte A, Paolisso G, Canonico S. Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp Diabetes Res. 2012;2012:892706. doi: 10.1155/2012/892706. Epub 2012 Nov 1. |
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Completed
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Number | participants | 3 months of treatment with vildagliptin |
|
1 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Raffaele Marfella | Second University Naples | ++390815665110 | raffaele.marfella@unina2.it |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D016523 | Foot Ulcer |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000077597 | Vildagliptin |
| ID | Term |
|---|---|
| D009570 | Nitriles |
| D009930 | Organic Chemicals |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| vildagliptin | Drug | 50 mg per os b.i.d. for 4 months of treatment, added to the standard good medical practice.Plus Metformin and/or Sulfonylurea |
|
The factor is assessed by immunoblot analysis (commercial kits).Arbitrary unit of measure are used to evaluate VEGF concentration. Higher values represent more factor.
| 3 months |
| 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. | 3 months |
| 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. | 3 months |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | The study group comprised 106 type 2 diabetic with chronic non-healing diabetic foot ulcers for more than 3 months duration. Patients were enrolled in the study between December 2008 and March 2011. Fifty-three diabetic patients were randomized (simple randomization, open labeled) to receive vildagliptin (50 mg b.i.d., n= 53) in addition to other concomitant hypoglycemic medication for 3 months. | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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. |
|
|
|
| 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 | Posted | Median | Inter-Quartile Range | capillaries/mm2 | 3 months of treatment with vildagliptin |
|
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | arbitrary units | 3 months |
|
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | arbitrary units | 3 months |
|
|
|
|
| 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. | The analysis was not performed because an inadequate amount of biopsy tissue | Posted | 3 months |
|
|
| 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. | The analysis was not performed because an inadequate amount of biopsy tissue | Posted | 3 months |
|
|
| 0 |
| 53 |
| 0 |
| 53 |
| EG001 | 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. | 0 | 53 | 0 | 53 |
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| D004700 | Endocrine System Diseases |
| D005534 | Foot Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D007871 | Leg Ulcer |
| D012883 | Skin Ulcer |
| D006571 |
| Heterocyclic Compounds |