Surgical Site Infection
Conditions
Keywords
Infection, Surgical Infection
Brief summary
The purpose of this study is to assess the efficacy and safety of delafloxacin administered as IV and oral formulation in comparison with Best Available Therapy (BAT) in patients with superficial or deep incisional surgical site infection following a cardiothoracic/related leg or abdominal surgery.
Detailed description
This is a randomized, observer-blinded, active-controlled, parallel-group, multicenter, phase IIIb study for the treatment of incisional, superficial or deep, surgical site infection after cardiothoracic /related leg or abdominal surgery (i.e patients who are at risk of microbiologically resistant infections). IV to be switched to oral delafloxacin will be compared to treatments that represent the best available therapy (BAT) for either cardiothoracic/related leg or abdominal surgical site infection (SSI). Approximately 600 male and female eligible patients will be randomly assigned in a 1:1 ratio to receive delafloxacin or BAT. For patients who are randomised to BAT, the investigator will choose one out of two treatments available (two available for the cardiothoracic/related leg and two available for abdominal SSI) as most appropriate for patient characteristics and local epidemiological pattern. Duration of study depends on treatment duration (range: minimum 5 to maximum 14 days, as per Investigator's judgment) followed by visits up to 30 days after end of treatment. Patients will be hospitalized from Screening (within 30 days from surgery) and will remain hospitalized until considered improved or cure as per Investigator's judgment.
Interventions
DRUGDelafloxacin
Powder for solution for infusion 300 mg or tablet 450 mg, BID, for 5 to 14 days
DRUGVancomycin
Powder for solution for infusion 15mg/kg, BID, for 5 to 14 days
DRUGLinezolid
Solution for infusion or tablet, 600 mg BID, for 5 to 14 days
DRUGPiperacillin/Tazobactam
Powder for solution for infusion 4/0.5 g, TID, for 5 to 14 days
DRUGTigecycline
Powder for solution for infusion 50 mg, TID, for 5 to 14 days
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Only the blinded observer will be unaware of the treatment assigned to patient.
Intervention model description
The study will compare delafloxacin against best available therapy selected by the investigator for the cardiothoracic/leg related or abdominal site infection
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged more than 18 years. * Patients with a history of cardiothoracic / related leg or abdominal surgery, occurred within 30 days and no implant is left in place, and a diagnosis of superficial or deep SSI according to the CDC definition. * The severity of infection requires an IV treatment and patient hospitalization according to the Investigator's judgment.
Exclusion criteria
* Previous IV antimicrobial therapy exceeding 24-hour duration during 72 hours prior to first dose. * Any infection expected to require systemic antimicrobial agents other than study treatment(s). * Medical history of significant hypersensitivity or allergic reaction or contraindication to the study drugs * Medical history of central nervous system (CNS) disorders * Medical history of myasthenia gravis. * Medical history of C. difficile diarrhea. * Organ-space infection. * Complicated Intra-Abdominal Infection (cIAI) * Chronic or underlying conditions at site of infection that may complicate the assessment of clinical response or would interfere with SSI healing. * Underlying disease leading to deep immunosuppressive status. * End-stage renal disease, CrCl \<15 mL/min.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Success at Test Of Cure Visit | 7-14 days after last dose | Clinical Success defined as the clinical response of Cure or improved. Below the definitions: * Cure: The complete resolution of all baseline signs and symptoms of SSI * Improved: two or more signs and/or symptoms (but not all) were considered resolved thus the patient had improved to an extent that no additional antibiotic treatment was necessary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Infection Related Length of Stay (IRLOS) | up to 14 days | Length of Stay since beginning of therapy till patient stabilization and considered suitable for hospital discharge |
| Hospital Length of Stay (LOS) | up to 45 days (Late Follow Up visit) | Length of Stay since Screening till actual hospital discharge |
| Number of Participants Eligible to Switch to Oral Formulation According to Blinded Observer's Assessment | up to 14 days | Blinded assessment based on patient stabilization and ability to tolerate OS diet. In particular, the following details had to be met: Systolic blood pressure normal/not clinically significant abnormal No infection related tachycardia Afebrile status; body temperature \<38°C for at least 24 hours\* WBC count normalized/not clinically significant abnormal Patient able to tolerate PO diet/to take PO treatment and no GI absorption problem The measure counts only the participants eligible to switch, without taking into account the actually switched. Indeed, only linezolid in the BAT has an equivalent oral formulation suitable for the switch. |
| Microbiological Response | up to 14 days (End Of Treatment visit) and 7-14 days after last dose (Test Of Cure visit) | Documented or presumed eradication or persistence |
Countries
Italy
Participant flow
Recruitment details
Overall, the recruiment period lasted 13 months, since August 2019 to September 2020. The recruitment was mostly conducted at Abdominal and General surgery departments.
Pre-assignment details
In total, 274 patients were screened while 266 patients were randomized and treated (ITT population).
Participants by arm
| Arm | Count |
|---|---|
| Delafloxacin Delafloxacin IV with the option to switch to OS | 134 |
| Best Available Therapy Vancomycin and Linezolid for cardiothoracic SSI Piperacillin/Tazobactam and Tigecycline for abdominal SSI | 132 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Delafloxacin | Best Available Therapy | Total |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 13.65 | 63.7 years STANDARD_DEVIATION 13.71 | 64.9 years STANDARD_DEVIATION 13.7 |
| Depth of infection Deep SSI | 52 Participants | 53 Participants | 105 Participants |
| Depth of infection Superficial SSI | 82 Participants | 79 Participants | 161 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 131 Participants | 131 Participants | 262 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 133 Participants | 132 Participants | 265 Participants |
| Sex: Female, Male Female | 61 Participants | 53 Participants | 114 Participants |
| Sex: Female, Male Male | 73 Participants | 79 Participants | 152 Participants |
| Site of infection Abdominal SSI | 124 Participants | 122 Participants | 246 Participants |
| Site of infection Cardiothoracic SSI | 10 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 134 | 1 / 132 | 0 / 8 | 0 / 2 | 0 / 68 | 1 / 54 |
| other Total, other adverse events | 22 / 134 | 26 / 132 | 2 / 8 | 0 / 2 | 18 / 68 | 6 / 54 |
| serious Total, serious adverse events | 9 / 134 | 14 / 132 | 1 / 8 | 0 / 2 | 10 / 68 | 3 / 54 |
Outcome results
Primary
Number of Participants With Clinical Success at Test Of Cure Visit
Clinical Success defined as the clinical response of Cure or improved. Below the definitions: * Cure: The complete resolution of all baseline signs and symptoms of SSI * Improved: two or more signs and/or symptoms (but not all) were considered resolved thus the patient had improved to an extent that no additional antibiotic treatment was necessary.
Time frame: 7-14 days after last dose
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delafloxacin | Number of Participants With Clinical Success at Test Of Cure Visit | 123 Participants |
| Best Available Therapy | Number of Participants With Clinical Success at Test Of Cure Visit | 119 Participants |
Secondary
Hospital Infection Related Length of Stay (IRLOS)
Length of Stay since beginning of therapy till patient stabilization and considered suitable for hospital discharge
Time frame: up to 14 days
Population: CE population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Delafloxacin | Hospital Infection Related Length of Stay (IRLOS) | 130.9 hours | Standard Deviation 71.87 |
| Best Available Therapy | Hospital Infection Related Length of Stay (IRLOS) | 140.3 hours | Standard Deviation 68.98 |
Secondary
Hospital Length of Stay (LOS)
Length of Stay since Screening till actual hospital discharge
Time frame: up to 45 days (Late Follow Up visit)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Delafloxacin | Hospital Length of Stay (LOS) | 178.8 hours | Standard Deviation 95.44 |
| Best Available Therapy | Hospital Length of Stay (LOS) | 193.5 hours | Standard Deviation 119.72 |
Secondary
Microbiological Response
Documented or presumed eradication or persistence
Time frame: up to 14 days (End Of Treatment visit) and 7-14 days after last dose (Test Of Cure visit)
Population: MITT population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Delafloxacin | Microbiological Response | TOC Visit | Eradicated | 94 Participants |
| Delafloxacin | Microbiological Response | TOC Visit | Persisted | 11 Participants |
| Delafloxacin | Microbiological Response | EOT Visit | Eradicated | 80 Participants |
| Delafloxacin | Microbiological Response | EOT Visit | Persisted | 25 Participants |
| Best Available Therapy | Microbiological Response | EOT Visit | Persisted | 38 Participants |
| Best Available Therapy | Microbiological Response | TOC Visit | Eradicated | 81 Participants |
| Best Available Therapy | Microbiological Response | EOT Visit | Eradicated | 64 Participants |
| Best Available Therapy | Microbiological Response | TOC Visit | Persisted | 21 Participants |
Secondary
Number of Participants Eligible to Switch to Oral Formulation According to Blinded Observer's Assessment
Blinded assessment based on patient stabilization and ability to tolerate OS diet. In particular, the following details had to be met: Systolic blood pressure normal/not clinically significant abnormal No infection related tachycardia Afebrile status; body temperature \<38°C for at least 24 hours\* WBC count normalized/not clinically significant abnormal Patient able to tolerate PO diet/to take PO treatment and no GI absorption problem The measure counts only the participants eligible to switch, without taking into account the actually switched. Indeed, only linezolid in the BAT has an equivalent oral formulation suitable for the switch.
Time frame: up to 14 days
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delafloxacin | Number of Participants Eligible to Switch to Oral Formulation According to Blinded Observer's Assessment | 129 Participants |
| Best Available Therapy | Number of Participants Eligible to Switch to Oral Formulation According to Blinded Observer's Assessment | 129 Participants |