Clinical trial NCT02632877: Efficacy of Pirfenidone Plus MODD in Diabetic Foot Ulcers
Official title: Efficacy of Pirfenidone Gel Combined With Modified Oxide Diallyl Disulfide (MODD) Versus Ketanserin for the Treatment of Diabetic Foot Ulcers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Diabetic Foot Ulcer
Keywords: pirfenidone
Modified oxide diallyl disulfide (MODD)
ketanserin
diabetic foot ulcer
Lead sponsor: University of Guadalajara
Sponsor class: OTHER
Collaborators: name: Cell Pharma
First posted: 2015-12-17
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Diabetic foot ulcers (DFU) develop because of the interaction of predisposing factors like neuropathy, angiopathy and infection. Likewise, environmental factors like lesion hygiene, diet and life style.

DFU results as a complication in diabetic patients and it is the most common cause of non-traumatic foot amputation in people older than 50 years. Foot amputation decreases patients´ quality of life since only 33% of them will continue walking with the use of a prothesis.

However, 30% of patients subjected to amputation will die in the first year after surgery and by the 5th year, post-surgery 50% of them will need the amputation of the remaining body extremity.

According to the World Foundation for Diabetes, in Latin America there are 18 million people with Diabetes Mellitus Type 2 (DM2). This number will increase in the next 20 years to 30 million.

Medical expenses for diabetic patients are calculated to be around 8,000 million dollars, annually. In Mexico, according to the Mexican Federation for Diabetes there are 6.5-10 millions of diabetic patients.

Amputation due to DFU complications has many social and economic implications. In Mexico in 2011 diabetes mellitus complications were the principal cause of death in the institute of mexican social security (IMSS) population.

On the other hand, 5-methyl-1-phenyl-2-(1h)-pyridone (PFD) is considered an anti-inflammatory drug that promotes re-epithelization due to fibroblast stimulation, angiogenesis and vasculogenesis during tissue remodeling.

According to this, the investigators believe that PFD could play an important role in DFU resolution and for this reason, the investigators consider necessary to analyze the efficacy of 5-methyl-1-phenyl-2-(1h)-pyridone for the treatment of DFU since it has showed improvement in chronic skin ulcers in pilot studies.

Nowadays, DFU treatment includes management of metabolism, angiopathy and neuropathy along with broad-spectrum antibiotic therapy. However, several reports indicate it is insufficient for and adequate control of diabetic patients.

Then, it is important to develop efficient therapies for the treatment of DFU. In this context, Ketanserin (Sufrexal™) is a drug to induce scar formation. It has been demonstrated to decrease peripheral vascular resistance, platelet aggregation and improves hemorheologic parameters.

Topical administration of ketanserin has showed beneficial effects in inflammation, granulation and epithelization.

Since these two drugs have showed beneficial effects in tissue regeneration, the investigators believe it is important to compare their safety and efficacy for the treatment of DFU

Detailed description: Subjects will be randomized using a random number table to distribute in the control (ketanserin) and the experimental group (PFD+MODD). Demographics data and medical history will be registered on a monthly basis, relative ulcer volume will be calculated by measuring the longest, widest and deepest ulcer side with sterile flexible graduated ruler. The ulcer will be classified according to Wagner scale and photographs will be taken. Ulcer area will be washed with aseptic solution (accua aseptic solution™) and a biopsy of around 10-15 mm3 will be taken from the middle of the ulcer using a scalpel blade. Patients in the experimental group will receive topical PFD+MODD (8% gel) three times a day and patients in control group will receive ketanserin (2% cream) twice a day. Both groups will apply the medicament for six months previous cleansing of the area. Biopsies will be taken at the beginning, at month one and month two. After this time, only photographs will be performed, and relative ulcer volume will be measured. 5 ml of blood will be taken at the beginning and the end of the study to measure general clinical parameters.

Eligibility criteria: Inclusion Criteria:

* Diagnostic for diabetic foot ulcer grade I to II according to Wagner scale
* Volunteer patients that accept to sign an informed consent letter
* Patients that agree to fill a clinical history, access to physical exploration and biochemical analysis samples, ulcer biopsy and photodocumentation of ulcer progress.
* Patients willing to sign a compliance letter to apply treatment as indicated by the principal investigator.

Exclusion Criteria:

* Patients with another chronic disease like venous insufficiency or cardiopathy.
* Patients with severe arteriopathy that do not have possibility to direct revascularization like the ones subject to graft tissue, plastics or stents positioning.
* Patients with severe arteriopathy that do not have possibility to indirect vascularization like the ones subject to sympathectomy .

Elimination criteria:

* Patients without adherence to treatment
* Patients that miss medical appointments
* Patients that show allergy to the 8% 5-methyl-1-phenyl-2-(1h pyridone gel and MODD or any of its components.
* Patients allergic to the 2% ketanserin gel or any of its components.

Primary outcomes:
measure: assessing change of ulcerated area
timeFrame: 1, 2, 3, 4, 5, and 6 months
Secondary outcomes:
measure: mRNA levels of collagen type I alpha (COL-1a)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Transforming growth factor 1-beta (TGFb-1)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Transforming growth factor 3-beta (TGFb-3)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Vascular endothelial growth factor (VEGF)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Tumor necrosis factor alpha (TNFa)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Hypoxia-inducible factor 1-alpha (HIF-1a)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Hypoxia-inducible factor 1-betha (HIF-1b)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Keratinocyte Growth Factor (KGF)
timeFrame: 0, 1 and 2 months
measure: mRNA levels of Matrix metalloproteinase-1 (MMP-1)
timeFrame: 0, 1 and 2 months
Other outcomes:
Locations:
city: Guadalajara
country: Mexico
facility: Molecular Biology and Gene Therapy Institute
state: Jalisco
city: Zapopan
country: Mexico
facility: Hospital Valentín Gómez Farías
state: Jalisco
Study officials:
affiliation: University of Guadalajara
name: Juan Armendariz-Borunda, PhD, FAASLD
role: STUDY_DIRECTOR
References: