This clinical study is a twelve-week single-center, randomized, double-blind evaluation of the safety and efficacy of a folic acid wound treatment (FAWT) versus Placebo in the promotion of healing of chronic (greater than 4-weeks), early stage diabetic foot ulcer (ES-DFU) wounds (PEDIS-Grade 1 or 2 Depth - wound above fascia without exposed muscle, tendon or bone). Study wound areas will be between 1.0 and 12.0 cm-square.~The chronic, non-healing DFU is a serious and common complication of diabetes. Chronic DFU complications are among the most frequent diabetes-related diagnoses for hospitalization and the leading cause of diabetes-associated lower limb amputations. Increased levels of the tumor suppressor protein p53 in wound keratinocytes from non-healing DFUs suggests increased cell death due to significant (p<0.05) transcription factor activation. Treatment with high dose folic acid (5mg/day) correlates to improved healing in ES-DFU wounds, perhaps by improving folate/methionine metabolism which provides support for DNA repair, the generation of reductive equivalents and regulates DNA methylation, an important epigenetic regulator of p53 transcription activity. Folinic acid calcium salt (calcium folinate) is the bioactive metabolite of folic acid that does not require reduction by dihydrofolate reductase (DHFR). In this study, FAWT (2.5-percent by weight) is provided by compounding 1.25-gms of folinic acid calcium salt with 50-gms of the Placebo (Plurogel Burn and Wound Dressing™, Medline Industries, Inc.). Experimental studies of topical folinic acid demonstrate significant improvements in wound healing parameters with decreased cellular markers of inflammation and increased active signaling of tissue repair. Topical administration of FAWT removes the potential for the adverse impact of high blood folate levels observed with oral high dose folic acid, that could include an increase in the occurrence of sub-classes of colon or prostate cancer.~The study hypothesis is that during a twelve-week evaluation period FAWT may provide significant (p<0.05) improvements, as compared to Placebo, in the rate of healing and complete closure (re-epithelialization) of chronic ES-DFU wounds.~The study will have two phases: Screening and Treatment.~The Screening Phase (first 4 weeks) is designed to determine if male and female Veterans selected as study participants are eligible to proceed to the Treatment Phase of the study. This phase consists of screening assessments that will include evaluation of the rate of study wound closure while the participants receive standard of care (SOC) therapy, including off-loading. SOC treatment will include wound cleansing and sharp debridement, fluorescent surveillance of wounds for microbial colonization and the management of infections. Participants observed with greater than 50-percent wound area reduction at the end of 4-weeks will be excluded from entering the Treatment Phase. Those observed with less than 50-percent wound area reduction and who continue to meet the inclusion/exclusion criteria will be allowed to enter the Treatment Phase of the study.~The Treatment Phase (12 weeks) will continue with assessments of the eligibility of the remaining study participants. Thirty study participants (n=30) selected after the four-week Screening Phase will be randomly assigned to either the FAWT or Placebo group of fifteen subjects each (n=15). Study participants and the treating staff members will be blinded to the treatment (FAWT or Placebo) being provided to each participant. During the Treatment Phase subjects will be evaluated every two weeks. These evaluations will include the collection of selected blood chemistries, assessment of ulcer wound healing, wound measurements and microbial surveillance using digital imaging. Paired marginal wound tissue biopsies (3-mm) will be obtained during two points of the Treatment Phase: 1) at the beginning of the Treatment Phase and 2) following the complete closure of the wound or after twelve weeks of Treatment. Study evaluations of the wound will continue until the wound is closed or at twelve weeks, whichever occurs first.
This is a twelve-week single-center, randomized, double-blind, clinical study to evaluate the safety and efficacy of a folic acid wound treatment (FAWT) versus Placebo in the promotion of healing of chronic, early stage diabetic foot ulcer (ES-DFU) wounds. Male and female Veterans with type-2 diabetes mellitus and chronic ES-DFUs acceptable to the study inclusion/exclusion criteria will be considered for enrollment.