Diabetic Foot Ulcer of Neuropathic Origin
Conditions
Keywords
Diabetic foot, Neuropathic, Wound, Growth factor
Brief 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,).
Interventions
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
Sponsors
Olympus Biotech Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wound Closure Rate of Diabetic Foot Ulcers (DFUs) of Neuropathic Topical Daily Application of Trafermin 0.01% Spray Compared With Placebo, in Addition | 12 weeks | Wound closure is defined as 100% reepithelialization of the target DFU, without exudate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Wound Area Regression of 40% or More at 6 Week | 6 weeks | The incidence of wound area regression of at least 40% at week 6 was considered as an important exploratory secondary efficacy variable. The wound area regression was calculated as percentage change from inclusion at week 6 using centralized wound area data. |
Countries
Czechia, France, Hungary, Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trafermin Trafermin 0.01% spray | 99 |
| Placebo Matching placebo spray | 102 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Patient Non-compliant | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Surgery on the Target Limb | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Total | Trafermin | Placebo |
|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 9.6 | 62.0 years STANDARD_DEVIATION 10 | 61.7 years STANDARD_DEVIATION 9.4 |
| BMI | 30.78 Kg/m2 STANDARD_DEVIATION 4.71 | 30.91 Kg/m2 STANDARD_DEVIATION 4.42 | 30.65 Kg/m2 STANDARD_DEVIATION 5 |
| Peripheral blood perfusion Impaired | 74 participants | 36 participants | 38 participants |
| Peripheral blood perfusion Normal | 127 participants | 63 participants | 64 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 199 Participants | 99 Participants | 100 Participants |
| Sex: Female, Male Female | 31 Participants | 15 Participants | 16 Participants |
| Sex: Female, Male Male | 170 Participants | 84 Participants | 86 Participants |
| Wound size ≤5cm^2 | 157 participants | 77 participants | 80 participants |
| Wound size >5cm^2 | 44 participants | 22 participants | 22 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 99 | 21 / 102 |
| serious Total, serious adverse events | 23 / 99 | 17 / 102 |
Outcome results
Primary
Wound Closure Rate of Diabetic Foot Ulcers (DFUs) of Neuropathic Topical Daily Application of Trafermin 0.01% Spray Compared With Placebo, in Addition
Wound closure is defined as 100% reepithelialization of the target DFU, without exudate.
Time frame: 12 weeks
Population: The primary analysis of the efficacy criteria was conducted on the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trafermin | Wound Closure Rate of Diabetic Foot Ulcers (DFUs) of Neuropathic Topical Daily Application of Trafermin 0.01% Spray Compared With Placebo, in Addition | 14.1 percentage of participants |
| Placebo | Wound Closure Rate of Diabetic Foot Ulcers (DFUs) of Neuropathic Topical Daily Application of Trafermin 0.01% Spray Compared With Placebo, in Addition | 10.8 percentage of participants |
p-value: 0.410995% CI: [0.6, 3.43]Regression, Logistic
Secondary
Relative Wound Area Regression of 40% or More at 6 Week
The incidence of wound area regression of at least 40% at week 6 was considered as an important exploratory secondary efficacy variable. The wound area regression was calculated as percentage change from inclusion at week 6 using centralized wound area data.
Time frame: 6 weeks
Population: The analysis of the efficacy criteria was conducted on the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trafermin | Relative Wound Area Regression of 40% or More at 6 Week | 60.9 percentage of participants |
| Placebo | Relative Wound Area Regression of 40% or More at 6 Week | 52.9 percentage of participants |
95% CI: [0.78, 2.4]Regression, Logistic