| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diabetic Patients with an Infected Foot Ulcer |
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| E.1.1.1 | Medical condition in easily understood language |
| Diabetic Patients with an Infected Foot Ulcer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021784 |
| E.1.2 | Term | Infected skin ulcer |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the effect of the Topical Gentamicin-Collagen Sponge (gentamicin sponge) in combination with systemic antibiotic therapy compared to placebo-sponge and no-sponge, both in combination with systemic antibiotic therapy on diabetic patients’ clinical outcome in the treatment of infected foot ulcers. |
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| E.2.2 | Secondary objectives of the trial |
To determine the effect of the gentamicin-sponge in combination with systemic antibiotic therapy compared to placebo-sponge and no-sponge, both in combination with systemic antibiotic therapy on microbiological outcome and eradication of baseline ulcer pathogens.
To assess the safety and tolerability of the gentamicin-sponge in combination with systemic antibiotic therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient will be eligible for study participation if he/she meets the following criteria before enrollment:
1. Is aged ≥ 18 and ≤ 85 years.
2. Has diabetes mellitus, according to the American Diabetes Association (ADA) criteria.
3. Has at least 1 skin ulcer located on or below the malleolus that presents with the following clinical manifestations of a moderate or severe infection based on the Infectious Disease Society of America guidelines for the “Diagnosis and Treatment of Diabetic Foot Infections” (CID 2012; 54:132-173) (IDSA guidelines):
• has ≥ 2 manifestations of inflammation (local swelling or induration, erythema, local tenderness or pain, local warmth, purulent discharge (thick, opaque to white or sanguineous secretion)
• has ≥ 1 of the following characteristics: erythema > 2cm, or involving structures deeper than skin and subcutaneous tissues (e.g. abscess, osteomyelitis, septic arthritis, fasciitis)
For patients with multiple infected ulcers, the ulcer with the highest Diabetic Foot Infection Wound score (DFI score) must be on or below the malleolus and all infected ulcers must be completely coverable using no more than 4 sponges (sponges cannot be cut).
4. Has documented adequate arterial perfusion in the affected limb(s) (either palpable dorsalis pedis and posterior tibial pulses, or normal Doppler wave forms, a toe blood pressure ≥ 45 mm Hg or participation is approved by a vascular surgeon)
5. Has received appropriate surgical intervention to remove all necrotic and infected bone if diagnosed with osteomyelitis. [Note: The investigator is referred to Diabetes Metab Res Rev 2008; 24(Suppl 1): S145–S161 for recommendations for the diagnosis of diabetic foot osteomyelitis.]
6. Has received appropriate surgical debridement to remove all gangrenous tissue.
7. If female, is nonpregnant (negative pregnancy test results at the baseline/randomization visit) and nonlactating.
8. If female, is either not of childbearing potential (defined as postmenopausal for ≥ 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy or hysterectomy]) or practicing 1 of the following medically acceptable methods of birth control and agrees to continue with the regimen throughout the duration of the study:
• Oral, implantable or injectable contraceptives for 3 consecutive months before the baseline/randomization visit.
• Total abstinence from sexual intercourse (≥ 1 complete menstrual cycle before the baseline/randomization visit).
• Intrauterine device (IUD).
• Double barrier method (condoms, sponge, diaphragm or vaginal ring with spermicidal jellies or cream).
9. Is willing and able to return to the study facility for all follow-up visits.
10. Is able to fluently speak and understand the local language and is able to provide meaningful written informed consent for the study.
Once baseline clinical laboratory results become available, a patient will continue to be eligible for study participation after enrollment if he or she meets the following criteria:
11. Has the following laboratory values
• white blood cells (WBC) ≥ 4000 cells/mm3 and/or absolute neutrophil count (ANC) ≥ 1500 cells/mm3
• hematocrit > 25%,
• hemoglobin > 8 g/L,
• platelet count > 75 000/mm3
• coagulation test results less than 1.5 times the upper limit of normal (unless on anticoagulant therapy).
Any subject whose baseline laboratory results fall outside of these parameters will be withdrawn from the study.
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| E.4 | Principal exclusion criteria |
A patient will be excluded from the study if he/she meets any of the following criteria:
1. Has a known history of hypersensitivity to gentamicin (or other aminoglycosides).
2. Has a known or suspected hypersensitivity to bovine collagen.
3. Has an ulcer infection which, based upon the patient’s known history of hypersensitivity and/or as otherwise in the opinion of the investigator, cannot be adequately treated with at least one of the empiric systemic antibiotic regimens allowed by this protocol.
4. Has an ulcer associated with prosthetic material or an implanted device.
5. Has received any systemic or topical antibiotic therapy for any reason within 7 days of randomization unless it was administered to specifically treat the infected ulcer(s) and only within 36 hours of randomization.
6. Requires or is likely to require treatment with any concomitant topical product or wound therapy before the first follow-up study visit.
7. Is severely immunocompromised, or likely to become severely immunocompromised during the study, in the opinion of the investigator.
8. Has a history of myasthenia gravis or other neurological condition where gentamicin use is contraindicated as determined by the investigator.
9. Has a history of epilepsy.
10. Has a history of alcohol or substance abuse in the past 12 months.
11. Has an uncontrolled illness that, in the opinion of the investigator, is likely to cause the patient to be withdrawn from the trial or would otherwise interfere with interpreting the results of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the percent of patients with a clinical outcome of “clinical cure” at Follow-up visit 1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy variables in order of hierarchy are as follows:
• Percent of patients with both a clinical outcome of “clinical cure” and “baseline pathogen eradication” at F/U visit 1
• Percent of patients with re-infection
• Time (days) to a clinical outcome of “clinical cure”
• Percent of patients that have an amputation associated with the target ulcer
• Percent of patients with target ulcer closure at or before F/U visit 2
• Time (days) to closure of the target ulcer
Other secondary efficacy variables are as follows:
• Percent of patients with a clinical outcome of “clinical cure” at the End-of-treatment visit
• Percent of patients with a clinical outcome of “clinical cure” at or before treatment visits 2, 3, 4, and 5
• Percent of patients with “clinical response” at End-of-treatment visit and at F/U visit 1, respectively
• Percent of patients with “clinical response” at or before treatment visits 2, 3, 4, and 5
• Time (days) to “clinical response”
• Percent of patients with “baseline pathogen eradication” at the End-of-treatment visit and at F/U visit 1, respectively
• Percent of patients with “baseline pathogen improvement” at the End-of-treatment visit and at F/U visit 1, respectively
• Percent of total baseline pathogens (all species from all subjects) eradicated at the End-of-treatment visit and at F/U visit 1, respectively
• Percent of patients with a microbiological outcome of “microbiological success”
• Percent of patients with a microbiological outcome of “microbiological response”
• Percent of patients with both a clinical outcome of “clinical cure” at F/U visit 1 and a microbiological outcome of “microbiological success”
• Percent of patients with both “clinical response” at F/U visit 1 and “microbiological response”
• Percent of patients with both “clinical response” and “baseline pathogen response” at F/U visit 1
• Percent of patients with target ulcer closure at or before each study visit (except F/U visit 2, which is evaluated as a key secondary efficacy variable)
• Percent of patients that have any surgical intervention (other than sharp debridement) associated with the target ulcer |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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