Foot Ulcer, Diabetic, Infection
Conditions
Brief summary
This is a phase 3, randomized, controlled, blinded, multicenter study conducted in 3 parallel cohorts of diabetic patients with at least 1 infected foot ulcer. Patients will be randomized to receive 1 of 3 study treatments; systemic antibiotic therapy and standard ulcer care with either (A) daily application of a gentamicin-sponge, (B) daily application of a placebo-sponge or (C) no-sponge, in the ratio 2:1:1. Patients will be treated for approximately 28 days and return to the clinic weekly for safety and efficacy assessments. After completing treatment, patients will return to the clinic for scheduled follow-up visits approximately 10, 30, 60 and 90 days after treatment is stopped.
Detailed description
This is a phase 3, randomized, controlled, blinded, multicenter study conducted in 3 parallel cohorts of diabetic patients with at least 1 infected foot ulcer. Patients will be randomized using an electronic randomization system to receive 1 of 3 study treatments; systemic antibiotic therapy and standard ulcer care with either (A) daily application of a gentamicin-sponge, (B) daily application of a placebo-sponge or (C) no-sponge, in the ratio 2:1:1. The investigator will be blinded to the patient's treatment group assignment and patients randomized to one of the 2 sponge groups will be blinded as to whether the sponge is active or placebo. If a patient has multiple infected ulcers, the assigned treatment will be administered to all infected ulcers. The investigator will determine the highest severity ulcer to be used for all efficacy evaluations and will also determine the size and number of sponges (up to 4) that a patient will use in order to completely cover all infected ulcers. The investigator will prescribe an empiric systemic antibiotic therapy based on protocol instructions. Patients will be treated for approximately 28 days and return to the clinic weekly for safety and efficacy assessments. The investigator will stop study treatment if a patient achieves clinical cure by or after the 3rd treatment visit (approximately study day 15). After completing treatment, patients will return to the clinic for scheduled follow-up visits or until ulcer closure. The final efficacy assessments used in the primary efficacy analyses will be obtained at the first follow-up visit approximately 10 days after treatment is stopped. The remaining follow-up visits will occur at approximately 30, 60 and 90 days after treatment is stopped when patients will be assessed for ulcer closure and any re-infection.
Interventions
Up to 4 topical Gentamicin Collagen Sponges each containing 50 mg of gentamicin sulfate (equivalent to 32.5 mg of gentamicin base)
OTHERPlacebo
Matching collagen sponge
Sponsors
Innocoll
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 85 Years
Healthy volunteers
No
Inclusion criteria
* Has diabetes mellitus, according to the American Diabetes Association (ADA) criteria. * 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). * 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) * Has received appropriate surgical intervention to remove all necrotic and infected bone if diagnosed with osteomyelitis. * Has received appropriate surgical debridement to remove all gangrenous tissue.
Exclusion criteria
* Has a known history of hypersensitivity to gentamicin (or other aminoglycosides). * Has a known or suspected hypersensitivity to bovine collagen. * 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. * Has an ulcer associated with prosthetic material or an implanted device. * 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. * Requires or is likely to require treatment with any concomitant topical product or wound therapy before the first follow-up study visit. * Is severely immunocompromised, or likely to become severely immunocompromised during the study, in the opinion of the investigator. * Has a history of myasthenia gravis or other neurological condition where gentamicin use is contraindicated as determined by the investigator. * Has a history of epilepsy. * Has a history of alcohol or substance abuse in the past 12 months. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure (Resolution of All Clinical Signs and Symptoms of Infection) | approximately 10 days after end of treatment | The primary efficacy variable is the percent of patients with a clinical outcome of clinical cure (Resolution of all clinical signs and symptoms of infection) at F/U visit 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure and Baseline Pathogen Eradication (Resolution of All Clinical Signs and Symptoms of Infection) and Baseline Pathogen Eradication) | Approximately 10 days after end of treatment | Percent of patients with both a clinical outcome of clinical cure (Resolution of all clinical signs and symptoms of infection) and baseline pathogen eradication at F/U visit 1 |
| Reinfection (Percent of Patients With Re-infection) | Approximately 90 days after end of treatment | Percent of patients with re-infection |
| Time to Clinical Cure | Approximately 10 days after end of treatment | Actual time to clinical cure (Resolution of all clinical signs and symptoms of infection) |
| Amputation (Percent of Patients That Have an Amputation Associated With the Target Ulcer) | Within approximately 90 days of end of treatment | Percent of patients that have an amputation associated with the target ulcer |
| Ulcer Closure (Percent of Patients With Target Ulcer Closure) | within approximately 30 days of end of treatment | Percent of patients with ulcer closure within approximately 30 days of end of treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gentamicin Sponge Group Topical Gentamicin Collagen Sponge: Up to four collagen sponges each containing 50 mg of gentamicin sulfate (equivalent to 32.5 mg of gentamicin base) administered daily, with systemic antibiotic therapy and standard ulcer care (gentamicin-sponge group) for up to 28 days.
Gentamicin collagen sponge: Up to 4 topical Gentamicin Collagen Sponges each containing 50 mg of gentamicin sulfate (equivalent to 32.5 mg of gentamicin base) | 305 |
| Placebo Sponge Group Matching placebo collagen sponge administered daily, with systemic antibiotic therapy and standard ulcer care (gentamicin-sponge group) for up to 28 days.
Placebo: Matching collagen sponge | 154 |
| No Sponge Group Systemic antibiotic therapy and standard ulcer care (gentamicin-sponge group) for up to 28 days. | 153 |
| Total | 612 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 3 | 7 |
| Overall Study | Death | 0 | 4 | 1 |
| Overall Study | Lost to Follow-up | 13 | 8 | 8 |
| Overall Study | Physician Decision | 4 | 2 | 4 |
| Overall Study | protocol specific treatment unrelated | 18 | 11 | 11 |
| Overall Study | Protocol Violation | 3 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 5 | 11 |
Baseline characteristics
| Characteristic | Gentamicin Sponge Group | Placebo Sponge Group | No Sponge Group | Total |
|---|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 10.84 | 57.1 years STANDARD_DEVIATION 11.12 | 56.7 years STANDARD_DEVIATION 11.16 | 57.3 years STANDARD_DEVIATION 10.98 |
| Region of Enrollment United States | 305 participants | 154 participants | 153 participants | 612 participants |
| Sex: Female, Male Female | 65 Participants | 47 Participants | 34 Participants | 146 Participants |
| Sex: Female, Male Male | 240 Participants | 107 Participants | 119 Participants | 466 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 305 | 4 / 154 | 1 / 153 |
| other Total, other adverse events | 135 / 305 | 72 / 154 | 65 / 153 |
| serious Total, serious adverse events | 44 / 305 | 22 / 154 | 26 / 153 |
Outcome results
Primary
Clinical Cure (Resolution of All Clinical Signs and Symptoms of Infection)
The primary efficacy variable is the percent of patients with a clinical outcome of clinical cure (Resolution of all clinical signs and symptoms of infection) at F/U visit 1
Time frame: approximately 10 days after end of treatment
Population: modified intent to treat population consisted of randomized patients who received any dose of gentamicin-sponge or placebo-sponge or who were randomized to the no sponge arm, and who were not early-terminated for any of the treatment-unrelated reasons before F/U visit 1,
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gentamicin Sponge Group | Clinical Cure (Resolution of All Clinical Signs and Symptoms of Infection) | 115 Participants |
| Placebo Sponge Group | Clinical Cure (Resolution of All Clinical Signs and Symptoms of Infection) | 64 Participants |
| No Sponge Group | Clinical Cure (Resolution of All Clinical Signs and Symptoms of Infection) | 48 Participants |
Secondary
Amputation (Percent of Patients That Have an Amputation Associated With the Target Ulcer)
Percent of patients that have an amputation associated with the target ulcer
Time frame: Within approximately 90 days of end of treatment
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gentamicin Sponge Group | Amputation (Percent of Patients That Have an Amputation Associated With the Target Ulcer) | 2 Participants |
| Placebo Sponge Group | Amputation (Percent of Patients That Have an Amputation Associated With the Target Ulcer) | 3 Participants |
| No Sponge Group | Amputation (Percent of Patients That Have an Amputation Associated With the Target Ulcer) | 5 Participants |
Secondary
Clinical Cure and Baseline Pathogen Eradication (Resolution of All Clinical Signs and Symptoms of Infection) and Baseline Pathogen Eradication)
Percent of patients with both a clinical outcome of clinical cure (Resolution of all clinical signs and symptoms of infection) and baseline pathogen eradication at F/U visit 1
Time frame: Approximately 10 days after end of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gentamicin Sponge Group | Clinical Cure and Baseline Pathogen Eradication (Resolution of All Clinical Signs and Symptoms of Infection) and Baseline Pathogen Eradication) | 87 Participants |
| Placebo Sponge Group | Clinical Cure and Baseline Pathogen Eradication (Resolution of All Clinical Signs and Symptoms of Infection) and Baseline Pathogen Eradication) | 47 Participants |
| No Sponge Group | Clinical Cure and Baseline Pathogen Eradication (Resolution of All Clinical Signs and Symptoms of Infection) and Baseline Pathogen Eradication) | 34 Participants |
Secondary
Reinfection (Percent of Patients With Re-infection)
Percent of patients with re-infection
Time frame: Approximately 90 days after end of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gentamicin Sponge Group | Reinfection (Percent of Patients With Re-infection) | 12 Participants |
| Placebo Sponge Group | Reinfection (Percent of Patients With Re-infection) | 5 Participants |
| No Sponge Group | Reinfection (Percent of Patients With Re-infection) | 2 Participants |
Secondary
Time to Clinical Cure
Actual time to clinical cure (Resolution of all clinical signs and symptoms of infection)
Time frame: Approximately 10 days after end of treatment
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gentamicin Sponge Group | Time to Clinical Cure | 41 Days |
| Placebo Sponge Group | Time to Clinical Cure | 33 Days |
| No Sponge Group | Time to Clinical Cure | 46 Days |
Secondary
Ulcer Closure (Percent of Patients With Target Ulcer Closure)
Percent of patients with ulcer closure within approximately 30 days of end of treatment
Time frame: within approximately 30 days of end of treatment
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gentamicin Sponge Group | Ulcer Closure (Percent of Patients With Target Ulcer Closure) | 67 Participants |
| Placebo Sponge Group | Ulcer Closure (Percent of Patients With Target Ulcer Closure) | 32 Participants |
| No Sponge Group | Ulcer Closure (Percent of Patients With Target Ulcer Closure) | 29 Participants |