Diabetic foot routine treatment without intervention

On the basis of routine treatment of diabetic foot, adipose stem cells will be added to treat diabetic foot

Diabetes Mellitus Foot Ulcer

intramuscular injection of adipose stem cells treat diabetic foot

MSCs treatment

Clinical Study of Adipose-derived Stem Cells in the Treatment of Diabetic Foot

Ulcer healing rate = number of cases of complete wound healing / total number of ulcers in this group

Amputation rate = number of amputations / total number of amputations in this group

Evaluate patients' limbs blood flow by ultrasound，We will record blood flow velocities, for example， 4ml/second.

The ratio of ankle artery pressure to brachial artery pressure was obtained by measuring the contractile pressure of the posterior tibial artery, anterior tibial artery and brachial artery of the ankle.ABI≥0.9 means normal,0.8≥ABI≥0.7means mild arterial obstruction,0.6≥ABI≥0.4means moderate arterial obstruction,ABI＜0.4means severe arterial obstruction.

Evaluate patients'oxygen level by TcPO2,TcPO2＜20mmHg means very severe lesion.

Evaluate patients' limbs blood flow by CTA,We will record blood flow velocities, for example， 4ml/second.

Evaluate patients' limbs blood flow by Rutherford classification，Grade 0: Normal Grade 1: Walking over 500 meters with lameness Grade 2: Walking 200-500 meters with lameness Grade 3: Walking within 200 meters with lameness Grade 4: Resting pain Grade 5: Small ulcer Grade 6: Large ulcer.

Evaluate patients' degree of pain by Wong-Baker Faces Pain Rating Scale.There are 6 faces in the Wong-Baker Pain Scale. The first face represents a pain score of 0, and indicates "no hurt". The second face represents a pain score of 2, and indicates "hurts a little bit." The third face represents a pain score of 4, and indicates "hurts a little more". The fourth face represents a pain score of 6, and indicates "hurts even more". The fifth face represents a pain score of 8, and indicates "hurts a whole lot"; the sixth face represents a pain score of 10, and indicates "hurts worst.

Maoquan Li

Prof. Dr. Li

Gel of treprostinil 1 mg/mL (target concentration)
Part 1: 1 administration/day, on separate days, with 72h between two doses. Ascending doses are 0.025 mg/mL, 0.05mg/mL, 0.1 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 0.7 mg/mL, and 1 mg/mL. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm².
Part 2: 1 administration/day at the maximum tolerated dose (MTD) for 10 days; dressing will be changed by a trained nurse every 2 days. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm².

Placebo will be made from the placebo of Remodulin® incorporated into hydrogel (Suprasorb® G). The route and frequency of administration will be the same as for the investigational drug (topical administration by iontophoresis).

subjects randomized to the standard of care group (no iontophoresis) will only undergo standard blood test at visit 0 or 1, unless tests <1 month before inclusion are available This group is not double blind Standard care consists on debridement and dressings

Diabetic Foot Ulcer

We will administer treprostinil at increasing doses by a iontophoresis.

Treprostinil iontophoresis

Placebo iontophoresis will be performed using Remodulin® placebo (United Therapeutics) delivered with Axion GmbH electrodes connected to a PeriIont generator (Perimed).
Part 1: 1 administration/day, on separate days, with 72h between two doses. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm².
Part 2: 1 administration/day for 10 days. The intensity will be set at 120 µA during 60 minutes, i.e. a total current of 17.3 mC/cm².

Remodulin® placebo iontophoresis

CHU Grenoble Alpes

Iontophoresis of Treprostinil to Enhance Wound Healing in Diabetic Foot Skin Ulcers

Wound closure is expressed as the percentage change non-reepithelialized skin area over time (12-week follow-up), assessed with a digital camera and image analysis software.

Wound area will be assessed with a digital camera and image analysis software.

Time to complete reepithelialization will be sought in the medical record on a monthly basis.

Cutaneous perfusion will be assessed as cutaneous vascular conductance, and compared between groups

Comparison using transcutaneous pressure of oxygen

8-hour PK profile. AUC0-8 will be calculated from seven time points: immediately after the end of iontophoresis ( T0), 15 min, 30 min, 1h, 2h, 4h, and 8h

All adverse events will be rated according to the NIH Common Terminology Criteria for Adverse Events.

Blood pressure will be continuously recorded with digital photoplethysmography.

Photographs of the wound will be taken and sent to investigators, blinded to the group

University Hospital, Grenoble

2 sub-studies:
Preliminary safety study, Phase I: single ascending dose study that aims at establishing the safety, tolerability, and PK of the procedure in patients with active ulcers; we propose an accelerated titration design with 7 doses of gel. The accelerated phase (first four doses) uses single-patient cohorts per dose. After these doses, a standard 3+3 design will be performed. Any occurrence of dose-limiting toxicity (DLT) during the accelerated phase halts the accelerated titration and the cohort is expended to the standard 3+3 design. Two instances of DLT at a dose level halt escalation, and D-1 is the maximum tolerated dose.
Proof-of-concept study, Phase II: Thirty-six patients with DFU associated with microvascular dysfunction will be randomized into three groups: Treprostinil iontophoresis; Placebo iontophoresis; Standard care. Drug administration, but not standard care, will be double-blind. After a 10-day treatment, follow-up includes 6 visits over 10 weeks.

Double blind (for the two groups treated with iontophoresis of treprostinil or placebo); open for the standard of care group.
The preparation of syringes of gel containing treprostinil or placebo will be centralized. Both gels will be physically identical, and investigators will not have access to the randomization list or to preparation records. This ensures proper blinding at treatment initiation. Treatment kits will subsequently be given to research nurses to continue the treatment at home. Nurses will not have access to the randomization list or preparation records either, which guarantees proper blinding throughout the 10-day treatment.
Unblinding will be done in case of any suspicion of an unexpected serious adverse reaction, prior to the declaration of the event to the competent authorities. Unblinding may be done 24/24h by the Pharmacy department.

diabetic foot/главобоља

Clinical Study of Adipose-derived Stem Cells in the Treatment of Diabetic Foot

Iontophoresis of Treprostinil to Enhance Wound Healing in Diabetic Foot Skin Ulcers

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