Infections
Conditions
Keywords
Skin infection, Daptomycin, Elderly, Gram positive, Complicated skin and soft tissue infections
Brief summary
The purpose of this study is to provide data documenting the efficacy of daptomycin in elderly patients aged ≥ 65 years with complicated Skin and Soft Tissue Infections.
Interventions
DRUGDaptomycin
Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.
DRUGVancomycin or Semi-Synthetic Penicillins (SSPs)
Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients 65 years or older with infection of sufficient severity to require in-patient hospitalization, with parenteral antimicrobial therapy for at least 96 hours. Patients who have a diagnosis of Gram-positive complicated Skin and Soft Tissue Infections (cSSTIs) with or without bacteremia: * Wound infections, * Major abscesses with or without recognized preceding trauma, that require antibiotic therapy in addition to surgical incision and drainage, * Severe carbunculosis, * Infected ulcers (except patients with multiple infected ulcers) associated with: diabetes, vascular insufficiency, pressure (i.e., decubitus ulcers).
Exclusion criteria
Conditions requiring surgery that in and of itself would cure the infection or remove the infected site (e.g., amputation). Minor or superficial skin infections (e.g., furuncles, simple abscesses, acne, impetigo). Cellulitis, including erysipelas, not associated with complicating factors. However, patients with cellulitis associated with more serious infection (e.g., surgical wound, diabetic ulcer, deep tissue) can be enrolled (proportion of these patients will be limited to 30%). Infections for which outcome is difficult to assess: * Perirectal abscess, * Hidradenitis suppurativa, * Gangrene, * Infected human or animal bites, * Multiple infected ulcers at distant sites, * Infected burns (only third degree burn wound or wound area of more than 10 cm diameter), * Conditions requiring emergency surgery including necrotizing fasciitis. Medical conditions: * History of significant allergy or intolerance to Vancomycin or Daptomycin. Hypersensitivity to SSPs penicillins is not an exclusion criterion, * Concomitant clinically suspected or confirmed other site of infection or disorder at study entry that may interfere with the evaluation in this protocol, * Infections associated with a permanent prosthetic device that will not be removed within 24 hours after enrolment, * Known or suspected HIV infection with a CD4+ T-cell count \< 500/μL (HIV testing is not required), * Severe hepatic disease (Child-Pugh Class C) or ALT and/or AST \> 5 times ULN and/ or total bilirubin \> 2 times ULN at screening, * Calculated creatinine clearance by the Cockcroft-Gault equation using actual body weight \< 30 mL/min or any type of dialysis, * Treatment with any investigational agent or device within 30 days of study drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit | Baseline and 7 to 14 days after end of therapy | Success: Clinically significant signs and symptoms associated with the skin infection present at the pre-treatment infection site resolved (cure), or improved without need of further antibacterial therapy. Failure: Persistence or progression of signs and symptoms or development of new clinical signs and symptoms at the infection site, or concomitant antibacterial therapy with activity against isolated organisms, or treatment duration longer than pre-specified, or switch back to intravenous therapy due to relapse, or requirement of a major surgical procedure as adjunct or follow-up therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit | Baseline and 7 to 14 days after end of therapy | Microbiological Success: All infecting Gram-positive pathogens isolated at baseline were eradicated or presumed to be eradicated at the Test-of-Cure (TOC) evaluation and a super infecting pathogen was not isolated either prior to or at the TOC evaluation. Microbiological Failure: Persistence or relapse / re-infection of one or more infecting Gram-positive pathogens or isolation of a super infecting pathogen prior to or at the TOC evaluation. |
| Duration of Treatment (Intravenous) | Up to 28 days | Duration of treatment is the interval from first to last intravenous (i.v.) administration. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days. |
| Duration of Treatment (Intravenous and Oral) | Up to 28 days | Duration of treatment is the interval from first to last intravenous (i.v.) or to last oral administration if patients switched to an oral antibiotic therapy. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days. |
| Number of Patients With Adverse Events, Serious Adverse Events and Death | Continuously from baseline up to 28 days after end of antibiotic treatment. | — |
Countries
Austria, Germany, Italy, Russia, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days.
Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days. | 81 |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days.
Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days. | 39 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 1 | 1 |
| Overall Study | Adverse Event | 3 | 4 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol deviation | 1 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 3 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Daptomycin | Vancomycin or Semi-Synthetic Penicillins (SSPs) | Total |
|---|---|---|---|
| Age Continuous | 74.63 years STANDARD_DEVIATION 6.331 | 75.28 years STANDARD_DEVIATION 5.515 | 74.84 years STANDARD_DEVIATION 6.063 |
| Sex: Female, Male Female | 47 Participants | 26 Participants | 73 Participants |
| Sex: Female, Male Male | 34 Participants | 13 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 80 | 14 / 40 |
| serious Total, serious adverse events | 7 / 80 | 4 / 40 |
Outcome results
Primary
Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit
Success: Clinically significant signs and symptoms associated with the skin infection present at the pre-treatment infection site resolved (cure), or improved without need of further antibacterial therapy. Failure: Persistence or progression of signs and symptoms or development of new clinical signs and symptoms at the infection site, or concomitant antibacterial therapy with activity against isolated organisms, or treatment duration longer than pre-specified, or switch back to intravenous therapy due to relapse, or requirement of a major surgical procedure as adjunct or follow-up therapy.
Time frame: Baseline and 7 to 14 days after end of therapy
Population: The clinically evaluable population was used for the efficacy analysis. It included all patients who met the criteria for complicated skin and soft tissue, had no substantive protocol deviation, had a sponsor clinical response assessment of success or failure at the assessment visit, and had a specified baseline primary site of infection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin | Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit | Success | 65 participants |
| Daptomycin | Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit | Failure | 8 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit | Success | 25 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit | Failure | 5 participants |
Secondary
Duration of Treatment (Intravenous)
Duration of treatment is the interval from first to last intravenous (i.v.) administration. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days.
Time frame: Up to 28 days
Population: The Full Analysis Set (FAS) comprised all patients to whom study treatment had been assigned at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daptomycin | Duration of Treatment (Intravenous) | 7.8 Days | Standard Deviation 3.42 |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Duration of Treatment (Intravenous) | 7.3 Days | Standard Deviation 2.42 |
Secondary
Duration of Treatment (Intravenous and Oral)
Duration of treatment is the interval from first to last intravenous (i.v.) or to last oral administration if patients switched to an oral antibiotic therapy. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days.
Time frame: Up to 28 days
Population: The Full Analysis set (FAS) comprised all patients to whom study treatment had been assigned at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | Duration of Treatment (Intravenous and Oral) | intravenous only | 7.8 Days | Standard Deviation 3.4 |
| Daptomycin | Duration of Treatment (Intravenous and Oral) | intravenous + oral | 8.7 Days | Standard Deviation 4.9 |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Duration of Treatment (Intravenous and Oral) | intravenous only | 7.3 Days | Standard Deviation 2.4 |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Duration of Treatment (Intravenous and Oral) | intravenous + oral | 9.6 Days | Standard Deviation 5.4 |
Secondary
Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit
Microbiological Success: All infecting Gram-positive pathogens isolated at baseline were eradicated or presumed to be eradicated at the Test-of-Cure (TOC) evaluation and a super infecting pathogen was not isolated either prior to or at the TOC evaluation. Microbiological Failure: Persistence or relapse / re-infection of one or more infecting Gram-positive pathogens or isolation of a super infecting pathogen prior to or at the TOC evaluation.
Time frame: Baseline and 7 to 14 days after end of therapy
Population: Population analyzed consisted of patients from the clinically evaluable population who had independent microbiological assessments.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin | Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit | Success | 54 participants |
| Daptomycin | Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit | Failure | 11 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit | Success | 23 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit | Failure | 4 participants |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Death
Time frame: Continuously from baseline up to 28 days after end of antibiotic treatment.
Population: The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events | 50 participants |
| Daptomycin | Number of Patients With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 7 participants |
| Daptomycin | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 0 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events | 26 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 0 participants |
| Vancomycin or Semi-Synthetic Penicillins (SSPs) | Number of Patients With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 4 participants |