The TRAfermin in Neuropathic Diabetic Foot Ulcer Study - Southern Europe The TRANS-South Study
Condition: Diabetic Foot Ulcer of Neuropathic Origin
MeSH terms: Diabetic Foot; Foot Ulcer; Ulcer
Intervention: Trafermin 0.01% spray
Intervention description: For ulcers with a maximum diameter (longest axis) of less or equal to 6 cm, the daily dose of trafermin 0.01% spray is 5 puffs (30 microgram) sprayed onto the wound surface. If the maximum diameter (longest axis) of the ulcer is >6 cm, the ulcer should be sprayed in two parts, i.e. 5 puffs (30 microgram) sprayed onto each half of the wound surface
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 201.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diabetic foot; Neuropathic; Wound; Growth factor

Summary:

      Trafermin is a recombinant human basic fibroblast growth factor (bFGF; original development
      code, KCB-1), which is manufactured by genetic engineering using Escherichia coli by Kaken
      Pharmaceutical Co., Ltd. (Tokyo, Japan). Trafermin 0.01% cutaneous spray product kit
      consisting of a glass bottle containing lyophilized trafermin, a glass bottle with solvent
      for solution and a spray part to fit the glass bottle after reconstitution of the final
      product.

      The investigators conduct a multinational, randomized, double-blind, placebo controlled,
      parallel-group, multicentre study consisting of a placebo run-in phase (2w), a treatment
      phase (max. 12w) and a follow-up phase (3mo+6mo). The primary objective of the study is to
      demonstrate a superior wound closure rate of diabetic foot ulcers (DFUs) of neuropathic
      origin after 12 weeks topical daily application of trafermin 0.01% spray compared with
      placebo, in addition to best local care (off-loading, dressings). Approximately 210 patients
      will be randomized and it is planned that this study will be conducted at approximately 30
      investigational sites in an estimated 4 countries in Europe (Czech
      Republic,France,Hungary,Italy,).
    

Eligibility criteria:

        Selection Criteria

        Patients who fulfill all of the following criteria (and none of the exclusion criteria
        described below) are eligible to enter the placebo run-in phase of the study:

          1. Provide written informed consent to participate.

          2. Male or female patients age 18 years or older.

          3. Type 1 or 2 diabetes.

          4. A single full-thickness DFU that has been present for at least 2 weeks.

          5. DFU wound surface area below or equal 34 cm2 on the target foot.

          6. No exposure of bone in the target DFU.

          7. Neuropathy confirmed by loss of protective sensation to monofilament test
             (Semmes-Weinstein 5.07 monofilament).

          8. No predominant ischemia requiring further exploration or treatment, and confirmed by
             either:

               -  ABPI on the target leg ( >0.9;below or equal 1.3) or if ABPI is >1.3 or is not
                  assessable,TBPI on target foot above or equal 0.7, OR

               -  ABPI on target leg (above or equal 0.7;below or equal 0.9) or if ABPI is >1.3 or
                  is not assessable, TBPI on target foot <0.7, AND a toe blood pressure >40 mmHg

        Inclusion Criteria

        Patients who fulfill all of the following criteria are eligible for randomization:

          1. All of the selection criteria and none of the exclusion criteria are met.

          2. Completed the 2-week placebo run-in period during which they were compliant to
             off-loading and to daily application of placebo spray, without major protocol
             violation. Compliance with the placebo run-in treatment regimen must be "excellent" or
             "acceptable"

          3. Glycosylated hemoglobin (HbA1c) below or equal 10% (from a blood sample taken during
             the placebo run-in period).

          4. Non-infected target foot DFU of confirmed neuropathic origin with:

               -  ABPI on the target leg (>0.9;below or equal 1.3) or if ABPI is >1.3 or is not
                  assessable,TBPI on target foot above or equal 0.7, OR

               -  ABPI on target leg (above or equal 0.7;below or equal 0.9) or if ABPI is >1.3 or
                  is not assessable, TBPI on target foot <0.7, AND a toe blood pressure >40 mmHg

          5. Target DFU appropriately debrided (<10% black and at least 50% of red/pink on a
             colorimetric scale)

          6. Target DFU of grade A1 or A2 on the University of Texas Wound Classification System or
             of Grade 1 or 2 of the Wagner classification

          7. DFU surface area above or equal 0.9 cm2 and below or equal 20 cm2 confirmed by the
             investigator's measurement, and its surface area not decreased by more than 40%
             compared to the selection value.

        Exclusion Criteria

        Patients who fulfill any of the following criteria are not eligible to be enrolled in the
        study:

          1. Active Charcot foot, or inactive Charcot foot, if the target DFU cannot be properly
             offloaded.

          2. Ulcers of non-neuropathic origin (e.g., rheumatoid, radiation-related,
             vasculitis-related ulcers).

          3. Presence of any foot ulcer (whether or not on the target foot) for which local or
             systemic antibiotic treatment is required.

          4. Evidence of skin cancer within or adjacent to the target ulcer.

          5. Any infected ulcers, defined as any problem such as (but not limited to) cellulitis,
             osteomyelitis, gangrene, or deep tissue infection requiring local or systemic
             antibiotic therapy.

          6. Another wound on the same foot as the target DFU. (i.e. Patients with another wound on
             the same limb as the target DFU are eligible for the study provided the concomitant
             wound is not infected and is above the ankle of the target foot).

          7. Any known active malignancy that requires general, local, surgical or radiation
             therapy either ongoing or within the previous 6 months; or patients whose treatment
             has been suspended for compassionate reasons, or who are not considered as cured from
             any malignancy.

          8. Morbid obesity, defined as body mass index (BMI) above or equal 45kg/m2.

          9. Clinically significant medical conditions, in the investigator's opinion, that could
             impair wound healing (e.g. hepatic impairment, immunocompromised patients).

         10. Severe renal failure, defined as requirement for hemodialysis or peritoneal dialysis.

         11. Females who are pregnant or breastfeeding, or who are of childbearing potential and
             not practicing a medically approved method of contraception.

         12. Concomitant treatment with high dose oral or parenteral corticosteroids, defined as a
             daily dose of at least 7.5 mg prednisone or equivalent.

         13. Participation in another clinical study within the previous 3 months.

         14. Current participation in another clinical study with any drug or device.

         15. History of drug or alcohol abuse within the previous year.

         16. Concurrent severe psychiatric disease (including severe depressive disorder).

         17. Known intolerance to the IMP or to any of its excipients.

         18. Known to be uncooperative or noncompliant.

         19. Outpatients who are unable to comply with the requirement for daily spray application
             at home (either application by a family member or by a visiting nurse).

         20. Any other condition which, in the opinion of the investigator, would render the
             patient unsuitable for the study.