Efficacy and Safety Evaluation of the Intralesional Recombinant Human Epidermal Growth Factor (rhEGF) in Subjects With Diabetic Foot Ulcer.
Efficacy and Safety Evaluation of the Intralesional Recombinant Human Epidermal Growth Factor (rhEGF) in Subjects With Diabetic Foot Ulcer.
Phase III clinical trial, multicenter, controlled, randomized, double-blind, with two
 parallel groups (experimental and control). Both study groups will receive standard therapy
 currently available in treatment centers for diabetic foot ulcer (DFU). Associate with the
 standard therapy, it will be given the recombinant human Epidermal Growth Factor (rhEGF) to
 experimental group and in the control group, it will be given a formulation without
 pharmacological effect (placebo) in order to masking and control of intralesional
 application. Participants with type 1 and type 2 diabetes mellitus (DM) diagnosed with DFU
 for at least 4 weeks, treated in referral centers participating in the study, agreeing to
 participate after reading, understanding and signing of Informed Consent (IC); meet all the
 inclusion criteria; and presenting no exclusion criteria. The Informed Consent (IC) should be
 applied to potential participants, as recommended by the regulations and ethical consensus
 before beginning any procedure related to the clinical trial. In the early weeks,
 participants will be evaluated at the research centers by the study team (doctors and / or
 staff). The number of visits will be determined by the investigator, thus ensuring
 appropriate assistance to participants, and avoiding any complications with DFU. By meeting
 the eligibility requirements (inclusion and exclusion criteria), the participant will undergo
 a thorough evaluation of the DFU before the start of treatment. This assessment is precisely
 to classify the condition of the ulcer before treatment and provide relevant information for
 statistical analysis of the protocol. If eligible, the participant will be randomly set to
 treatment arm (placebo or rhEGF) and the administration of investigational product associated
 with predefined standardized outpatient therapy will be initiated. This administration occurs
 three times per week until the DFU is scarred, not exceeding 8 weeks of treatment (T.01 to
 T.08) .The study will be randomized and balanced according to the type and size of the DFU.
 This balancing is necessary to ensure that both treatment groups are homogeneous for
 participants under different conditions. All participants will be applied established
 standard therapy for the treatment of DFU. The objective is to provide regular care for
 healing and reduce possible bias in the efficacy analysis and product safety. After the
 treatment period (last dose of the experimental drug) the participant will start the
 follow-up period, with 16 weeks duration. The participant shall be subjected to weekly visits
 for ongoing assessment of DFU, however, according to the investigator, may result in
 unscheduled visits to assess local or general clinical events. After the monitoring period,
 the participant will be observed for 24 additional weeks, visits every 4 weeks (E.01 E.24 a)
 having beginning one week after the last visit of follow-up. This period is intended to
 assess possible events related to the efficacy and safety that can happen in the period,
 mainly for analysis of secondary endpoints.
Inclusion Criteria:

 1. DM type 1 or 2 diagnosis

 2. DFU persisting for a minimum of 4 weeks If the participant have more than one DFU,
 then it will be treated the one with the largest extension and that follows the
 inclusion and exclusion criteria.

 3. DFU 's rating according to the PEDIS system:Perfusion: grades 1 or 2; Extension: Area
 ≥ 2 cm2; Depth: grades 2 or 3; Infection: grades 1 or 2; Sensitivity: grade 2

 If the consented participant is classified as having infection grade 3 without the presence
 of osteomyelitis, it will be possible to treat it with antibiotics empirically. However,
 randomization will be made only after this treatment and only if the infection has
 regressed to grade 1 or 2;

 Exclusion Criteria:

 1. Age less than 18 years;

 2. Pregnancy or breastfeeding (women in childbearing age will need to use a contraception
 method);

 3. Evidence of bone involvement : direct visualization of bone structures; positive
 survey (probe to bone) ; image investigation (simple x-ray or MRI);

 4. Urgent or imminent need of amputation;

 5. Eminent indication for revascularization;

 6. Glycated hemoglobin (HbA1c) counted greater than 11 %

 7. Use of drugs that can affect or contribute to the healing of ulcers as
 corticosteroids; immunosuppressive; chemotherapy; other growth factors;

 8. Clinical signs of malnutrition or serum albumin <30 g / L;

 9. Angina pectoris classified as 3 or 4 (according to the Canadian Cardiovascular Society
 Angina Classification);

 10. Congestive heart failure class IV (according to the New York Heart Association);

 11. Severe hepatic impairment, defined as ALT and / or AST greater than 5 (five) times the
 normal maximum reference value;

 12. Acute renal failure, defined as serum creatinine levels equal or higher than 1.5 times
 the baseline value in the last 7 days (according to KDIGO and RIFLE classification);

 13. End-stage renal disease (creatinine clearance equal or lower than 30 ml / min or on
 dialysis);

 14. History or suspected neoplasia (according to previous laboratory tests, imaging or
 biopsy);

 15. Psychiatric disorders that may alter the participants evaluation, or prevent proper
 consent and / or cognitive aspects that demonstrate the possibility of noncompliance
 with treatment or the adoption of aseptic criteria;

 16. Occurrence of the following events 30 days prior to inclusion in the protocol:
 participation in other clinical studies; hypoglycemic coma (blood glucose less than or
 equal to 30 mg / dL with loss of consciousness or need for help); diabetic
 ketoacidosis or hyperosmolar state within 30 days prior to inclusion;

 17. Occurrence of the following events 60 days prior to inclusion in the protocol:
 hospitalization for acute coronary syndrome, percutaneous intervention (eg cardiac,
 cerebrovascular, aortic) or greater cardiac surgery; myocardial infarction;
 cerebrovascular accident; cardiac arrest; sustained ventricular tachycardia; acute
 coronary syndrome, in investigator opinion; uncontrolled severe hypertension, defined
 as systolic blood pressure equal or higher than 180 mmHg and / or diastolic blood
 pressure equal or higher than 110 mmHg;