Skin and Subcutaneous Tissue Bacterial Infections
Conditions
Keywords
Bacterial skin infection, skin infection, infection, skin, delafloxacin, vancomycin, aztreonam, MRSA bacteria, bacterial infection, Anti-Infective Agents, Anti-Bacterial Agents
Brief summary
This study was designed to evaluate the efficacy of delafloxacin patients with acute bacterial skin and soft tissue infections (ABSSSI).
Detailed description
The efficacy and safety of delafloxacin, compared to that of vancomycin plus aztreonam, will be evaluated in a population of patients with acute bacterial skin and soft tissue infections (ABSSSI), including major cutaneous abscesses, wound infections, cellulitis/erysipelas, and burn-related infections.
Interventions
Sponsors
Melinta Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult (≥ 18 years of age) men or women with a diagnosis of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) (cellulitis/erysipelas, wound infection, major cutaneous abscess, or burn infection) with surrounding redness of a minimum surface area of 75 cm\^2 and at least two signs of systemic infection * In the opinion of the investigator, the subject must require and be a suitable candidate for IV antibiotic therapy, and the subject must be able and willing to comply with protocol requirements
Exclusion criteria
* A medical history of significant hypersensitivity or allergic reaction to quinolones, beta-lactams, vancomycin, or vancomycin derivatives according to the judgment of the investigator * Women who are pregnant or lactating * Any chronic or underlying skin condition at the site of infection that may complicate the assessment of response, including infection involving a prosthetic joint, human or animal bite, osteomyelitis, decubitus ulcer, diabetic foot ulcer, septic arthritis, mediastinitis, necrotizing fasciitis, anaerobic cellulitis, or synergistic necrotizing cellulitis, myositis, tendinitis, endocarditis, sustained shock, gangrene or gas gangrene; burns covering ≥10% of body surface area; severely impaired arterial blood supply to an extremity with an ABSSSI, deep vein thrombosis or superficial thrombophlebitis, and requiring either an amputation or multiple debridement procedures * Receipt of systemic antibiotic therapy in the 14 days before enrollment unless 1 of the following was documented: 1. Received ≥ 48 hours of antibiotic therapy for ABSSSI AND clinical progression is documented (i.e., not by patient history alone). 2. Recently (within 14 days) completed a treatment course with an antibacterial drug for an infection other than ABSSSI and the drug does not have activity against bacterial pathogens that cause ABSSSI. 3. Received only 1 dose of either a single, potentially effective, short-acting antimicrobial drug or drug regimen for ABSSSI. * Any underlying disease that, in the opinion of the investigator, could interfere with the subject's ability to participate in the study including severe cardiac disease, known history of liver disease, end-stage renal disease, malignancy, psychiatric disorder, ongoing treatment for seizures or untreated history of seizures, or life expectancy of \<3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response at 48 to 72 Hours (FDA Primary Endpoint) | 48 to 72 hours after starting treatment | A patient was considered a responder if s/he had a ≥20% reduction in size of the area of erythema associated with the baseline ABSSSI, as determined by digital planimetry of the leading edge and had none of the reasons for clinical failure; a patient was considered a non-responder (failure) if s/he had \<20% reduction in size of the area of erythema associated with the baseline ABSSSI as determined by digital planimetry of the leading edge, or had major intervention such as another antibiotic or surgical intervention or died within 74 hours after initiation of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Study Day 14 +/- 1 day | A patient was considered a Cure if all baseline signs and symptoms of ABSSSI had resolved; if some symptoms remained, but the patient was improved to the extent that no additional antibiotic treatment was necessary, the response was Improved. A patient was considered a Failure for any of the following reasons: nonstudy antibacterial drug therapy was required because of lack of efficacy after at least 4 doses of study drug or for a treatment-related AE; study antibacterial drug therapy was required for longer than 28 doses; and/or unplanned surgical intervention was needed after study entry except for limited bedside debridement and standard wound care. Improved and Indeterminate responses were considered failures in the primary analysis. A sensitivity analysis was also performed, in which the assigned responses were Success (Cure + Improved) or Failure (Failure + Indeterminate/Missing). |
| Investigator Assessment at the Late Follow-up Visit | Study Day 21 to 28 | A patient was considered a Cure if all baseline signs and symptoms of ABSSSI had resolved; if some symptoms remained, but the patient was improved to the extent that no additional antibiotic treatment was necessary, the response was Improved. A patient was considered a Failure for any of the following reasons: nonstudy antibacterial drug therapy was required because of lack of efficacy after at least 4 doses of study drug or for a treatment-related AE; study antibacterial drug therapy was required for longer than 28 doses; and/or unplanned surgical intervention was needed after study entry except for limited bedside debridement and standard wound care. Improved and Indeterminate responses were considered failures in the primary analysis. A sensitivity analysis was also performed, in which the assigned responses were Success (Cure + Improved) or Failure (Failure + Indeterminate/Missing). |
Countries
Croatia, Israel, Latvia, Russia, Spain, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Delafloxacin + Placebo 300mg iv every 12 hours for a minimum of 10 and up to a maximum of 28 doses
Delafloxacin: Delafloxacin
Placebo: Placebo | 331 |
| Vancomycin Plus Aztreonam + Placebo Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 and up to a maximum of 28 doses
Vancomycin: Vancomycin
Aztreonam: Aztreonam
Placebo: Placebo | 329 |
| Total | 660 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Admitted to another facility | 1 | 0 |
| Overall Study | Adverse Event | 3 | 9 |
| Overall Study | Correct study drug not available on site | 1 | 0 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Insufficient venous access | 0 | 1 |
| Overall Study | Lack of Efficacy | 3 | 1 |
| Overall Study | Lost to Follow-up | 24 | 30 |
| Overall Study | Non-compliance with study drug/procedure | 3 | 3 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Subject incarcerated | 1 | 2 |
| Overall Study | Withdrawal by Subject | 16 | 10 |
Baseline characteristics
| Characteristic | Delafloxacin + Placebo | Vancomycin Plus Aztreonam + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 46.3 years STANDARD_DEVIATION 13.91 | 45.3 years STANDARD_DEVIATION 14.44 | 45.8 years STANDARD_DEVIATION 14.18 |
| Age, Customized <= 65 years | 309 Participants | 309 Participants | 618 Participants |
| Age, Customized > 65 years | 22 Participants | 20 Participants | 42 Participants |
| Age, Customized > 75 years | 7 Participants | 10 Participants | 17 Participants |
| BMI (Body Mass Index) | 28.36 kg/m2 STANDARD_DEVIATION 6.423 | 27.86 kg/m2 STANDARD_DEVIATION 6.363 | 28.11 kg/m2 STANDARD_DEVIATION 6.393 |
| BMI ranges < 25 | 113 Participants | 125 Participants | 238 Participants |
| BMI ranges >= 25 | 218 Participants | 204 Participants | 422 Participants |
| BMI ranges >= 30 | 120 Participants | 94 Participants | 214 Participants |
| BMI ranges >= 35 | 53 Participants | 42 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 101 Participants | 103 Participants | 204 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 230 Participants | 226 Participants | 456 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Presence of Diabetes | 30 Participants | 27 Participants | 57 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants | 19 Participants | 46 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 297 Participants | 304 Participants | 601 Participants |
| Region of Enrollment Europe | 63 participants | 55 participants | 118 participants |
| Region of Enrollment North America | 268 participants | 274 participants | 542 participants |
| Sex: Female, Male Female | 125 Participants | 120 Participants | 245 Participants |
| Sex: Female, Male Male | 206 Participants | 209 Participants | 415 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 324 | 1 / 326 |
| other Total, other adverse events | 91 / 324 | 111 / 326 |
| serious Total, serious adverse events | 12 / 324 | 12 / 326 |
Outcome results
Primary
Objective Response at 48 to 72 Hours (FDA Primary Endpoint)
A patient was considered a responder if s/he had a ≥20% reduction in size of the area of erythema associated with the baseline ABSSSI, as determined by digital planimetry of the leading edge and had none of the reasons for clinical failure; a patient was considered a non-responder (failure) if s/he had \<20% reduction in size of the area of erythema associated with the baseline ABSSSI as determined by digital planimetry of the leading edge, or had major intervention such as another antibiotic or surgical intervention or died within 74 hours after initiation of study drug.
Time frame: 48 to 72 hours after starting treatment
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin Plus Placebo | Objective Response at 48 to 72 Hours (FDA Primary Endpoint) | Non-Responder | 72 Participants |
| Delafloxacin Plus Placebo | Objective Response at 48 to 72 Hours (FDA Primary Endpoint) | Responder | 259 Participants |
| Vancomycin Plus Aztreonam + Placebo | Objective Response at 48 to 72 Hours (FDA Primary Endpoint) | Non-Responder | 63 Participants |
| Vancomycin Plus Aztreonam + Placebo | Objective Response at 48 to 72 Hours (FDA Primary Endpoint) | Responder | 266 Participants |
95% CI: [-8.8, 3.6]
Secondary
Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint)
A patient was considered a Cure if all baseline signs and symptoms of ABSSSI had resolved; if some symptoms remained, but the patient was improved to the extent that no additional antibiotic treatment was necessary, the response was Improved. A patient was considered a Failure for any of the following reasons: nonstudy antibacterial drug therapy was required because of lack of efficacy after at least 4 doses of study drug or for a treatment-related AE; study antibacterial drug therapy was required for longer than 28 doses; and/or unplanned surgical intervention was needed after study entry except for limited bedside debridement and standard wound care. Improved and Indeterminate responses were considered failures in the primary analysis. A sensitivity analysis was also performed, in which the assigned responses were Success (Cure + Improved) or Failure (Failure + Indeterminate/Missing).
Time frame: Study Day 14 +/- 1 day
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin Plus Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Cure | 172 Participants |
| Delafloxacin Plus Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Failure | 9 Participants |
| Delafloxacin Plus Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Improved | 98 Participants |
| Delafloxacin Plus Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Indeterminate | 52 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Improved | 108 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Cure | 166 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Indeterminate | 48 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Follow-up Visit (EMA Primary Endpoint) | Failure | 7 Participants |
Secondary
Investigator Assessment at the Late Follow-up Visit
A patient was considered a Cure if all baseline signs and symptoms of ABSSSI had resolved; if some symptoms remained, but the patient was improved to the extent that no additional antibiotic treatment was necessary, the response was Improved. A patient was considered a Failure for any of the following reasons: nonstudy antibacterial drug therapy was required because of lack of efficacy after at least 4 doses of study drug or for a treatment-related AE; study antibacterial drug therapy was required for longer than 28 doses; and/or unplanned surgical intervention was needed after study entry except for limited bedside debridement and standard wound care. Improved and Indeterminate responses were considered failures in the primary analysis. A sensitivity analysis was also performed, in which the assigned responses were Success (Cure + Improved) or Failure (Failure + Indeterminate/Missing).
Time frame: Study Day 21 to 28
Population: ITT Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin Plus Placebo | Investigator Assessment at the Late Follow-up Visit | Cure | 233 Participants |
| Delafloxacin Plus Placebo | Investigator Assessment at the Late Follow-up Visit | Indeterminate/Missing | 57 Participants |
| Delafloxacin Plus Placebo | Investigator Assessment at the Late Follow-up Visit | Improved | 32 Participants |
| Delafloxacin Plus Placebo | Investigator Assessment at the Late Follow-up Visit | Failure | 9 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Late Follow-up Visit | Failure | 6 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Late Follow-up Visit | Indeterminate/Missing | 56 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Late Follow-up Visit | Cure | 219 Participants |
| Vancomycin Plus Aztreonam + Placebo | Investigator Assessment at the Late Follow-up Visit | Improved | 48 Participants |