Skin and Subcutaneous Tissue Bacterial Infections, Skin Structures and Soft Tissue Infections
Conditions
Keywords
Bacterial skin infection, infection, skin, delafloxacin, vancomycin, aztreonam, methicillin-resistant Staphylococcus aureus (MRSA) bacteria, bacterial infection, Anti-Infective Agents
Brief summary
The purpose of this study is to evaluate the effects of Delafloxacin versus Vancomycin plus Aztreonam in the treatment of patients with acute bacterial skin and soft tissue infections.
Detailed description
The purpose of this study is to determine if delafloxacin, an investigational drug, is safe and effective in the treatment of skin and nearby tissue infections compared with a combination of other antibiotics, vancomycin and aztreonam.
Interventions
Sponsors
Melinta Therapeutics, Inc.
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
* Adult (≥ 18 years of age) men or women with a diagnosis of 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 compromised immune system, 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: * Received ≥ 48 hours of antibiotic therapy for ABSSSI AND clinical progression is documented (i.e., not by patient history alone). * 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. * 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 of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge. | 48 to 72 hrs 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-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Study Day 14 ± 1 | 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-assessed Response of Signs and Symptoms of Infection 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
Argentina, Brazil, Bulgaria, Chile, Estonia, Georgia, Hungary, Latvia, Mexico, Moldova, Peru, Romania, Slovakia, South Korea, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Delafloxacin 300mg iv Q12H for 6 doses, 450mg oral tablet Q12H for a minimum of 10 up to a maximum of 28 doses total | 423 |
| Vancomycin Plus Aztreonam Vancomycin 15mg/kg iv plus two grams Aztreonam every 12 hours for a minimum of 10 up to a maximum of 28 doses total | 427 |
| Total | 850 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 12 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 3 | 6 |
| Overall Study | Lost to Follow-up | 25 | 24 |
| Overall Study | Noncompliance with study drug | 2 | 1 |
| Overall Study | Physician Decision | 4 | 2 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Study drug not available at site | 1 | 1 |
| Overall Study | Subject had inadequate IV access | 0 | 1 |
| Overall Study | Subject incarcerated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 9 |
Baseline characteristics
| Characteristic | Delafloxacin | Vancomycin Plus Aztreonam | Total |
|---|---|---|---|
| Age, Continuous | 51.2 years STANDARD_DEVIATION 15.98 | 50.2 years STANDARD_DEVIATION 16.03 | 50.7 years STANDARD_DEVIATION 16 |
| Age, Customized <= 65 years | 344 Participants | 352 Participants | 696 Participants |
| Age, Customized > 65 years | 79 Participants | 75 Participants | 154 Participants |
| Age, Customized > 75 years | 35 Participants | 31 Participants | 66 Participants |
| BMI (Body Mass Index) | 30.4 kg/m2 STANDARD_DEVIATION 7.44 | 30.7 kg/m2 STANDARD_DEVIATION 7.54 | 30.5 kg/m2 STANDARD_DEVIATION 7.49 |
| BMI category < 30 kg/m2 | 212 Participants | 213 Participants | 425 Participants |
| BMI category >= 30 kg/m2 | 211 Participants | 214 Participants | 425 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 132 Participants | 99 Participants | 231 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 291 Participants | 328 Participants | 619 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Presence of diabetes | 53 Participants | 54 Participants | 107 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 12 Participants | 7 Participants | 19 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 15 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 18 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 37 Participants | 30 Participants | 67 Participants |
| Race (NIH/OMB) White | 348 Participants | 355 Participants | 703 Participants |
| Region of Enrollment Argentina | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment Brazil | 0 Participants | 5 Participants | 5 Participants |
| Region of Enrollment Chile | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Europe | 165 Participants | 173 Participants | 338 Participants |
| Region of Enrollment Mexico | 8 Participants | 4 Participants | 12 Participants |
| Region of Enrollment North America | 202 Participants | 196 Participants | 398 Participants |
| Region of Enrollment Peru | 34 Participants | 29 Participants | 63 Participants |
| Region of Enrollment South Korea | 8 Participants | 13 Participants | 21 Participants |
| Region of Enrollment Taiwan | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 161 Participants | 151 Participants | 312 Participants |
| Sex: Female, Male Male | 262 Participants | 276 Participants | 538 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 417 | 2 / 425 |
| other Total, other adverse events | 55 / 417 | 32 / 425 |
| serious Total, serious adverse events | 16 / 417 | 17 / 425 |
Outcome results
Primary
Objective Response of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge.
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 hrs after starting treatment
Population: ITT Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin | Objective Response of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge. | Responder | 354 Participants |
| Delafloxacin | Objective Response of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge. | Nonresponder | 69 Participants |
| Vancomycin Plus Aztreonam | Objective Response of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge. | Responder | 344 Participants |
| Vancomycin Plus Aztreonam | Objective Response of ≥20% Reduction in Lesion Erythema Area Compared to Baseline at 48 to 72 Hours After Initiation of Treatment as Determined by Digital Measurements of the Leading Edge. | Nonresponder | 83 Participants |
95% CI: [-2, 8.3]
Secondary
Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [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
Population: ITT Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Improved | 125 Participants |
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Indeterminate/Missing | 37 Participants |
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Failure | 17 Participants |
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Cure | 244 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Cure | 255 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Improved | 107 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Failure | 21 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Follow up Visit (European Medicines Agency [EMA] Primary Endpoint) | Indeterminate/Missing | 44 Participants |
95% CI: [-8.6, 4.6]
Secondary
Investigator-assessed Response of Signs and Symptoms of Infection 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
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Cure | 287 Participants |
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Improved | 66 Participants |
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Failure | 21 Participants |
| Delafloxacin | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Indeterminate/Missing | 49 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Indeterminate/Missing | 52 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Cure | 303 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Failure | 24 Participants |
| Vancomycin Plus Aztreonam | Investigator-assessed Response of Signs and Symptoms of Infection at the Late Follow-up Visit | Improved | 48 Participants |
95% CI: [-9.3, 3.1]