Skin Diseases, Infectious, Soft Tissue Infections
Conditions
Keywords
Complicated Skin and Soft Tissue Infections. Daptomycin, Vancomycin, Teicoplanin, Complicated skin and soft tissue infections
Brief summary
This study evaluated the efficacy and safety of daptomycin compared to vancomycin or teicoplanin for the treatment of complicated skin and soft tissue infections
Interventions
DRUGDaptomycin
4 mg/kg intravenous once daily
DRUGVancomycin
1 g intravenous twice daily
DRUGTeicoplanin
400 mg intravenous once daily following a loading dose of 400 mg administered at 0, 12, 24 hours on day one.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with a diagnosis of cSSTI * Infection known or suspected (based on Gram's stain) to be due, at least partially, to Gram-positive bacteria. * Hospitalised subjects with clinical evidence of at least one of the following:I infected ulcers , major abscess. deep or extensive cellulitis, post-surgical / post-traumatic wound infection * Presence of at least two of the following: drainage and/or discharge from the infection site, redness, swelling and/or hardened skin, heat and/or localised warmth, pain and/or tenderness to touch, presence of pus.
Exclusion criteria
* cSSTIs of the following categories: * Infected burns, * Severely impaired arterial blood supply (such that the likelihood of amputation of the infected anatomical site is likely), * Decubitus ulcers, * Infected diabetic foot ulcers associated with osteomyelitis, * Infected human or animal bites, superficial infections or abscesses in an anatomic site, such as the rectal area, where the risk of anaerobic or Gram-negative pathogen involvement is high (e.g. perirectal abscess), * Necrotising fasciitis or gangrene, * cSSTI expected to require more than 14 days of intravenous antimicrobial therapy, * Skin and/or skin structure infection that can be treated by surgery alone, * Infections associated with a permanent prosthetic device that will not be removed within 2 days of study randomisation * Subjects with documented bacteraemia at Baseline or those with shock or hypotension * Concomitant clinically suspected or confirmed other site of infection or disorder at study entry that may interfere with the evaluations in this protocol * Treatment with vancomycin or teicoplanin within the past 48 hours, unless administered for less than 24 hours. * Subjects admitted to the hospital for conditions associated with rhabdomyolysis or those with an infection due to an organism known prior to study entry to be resistant to daptomycin, vancomycin or teicoplanin. * Previously diagnosed disease of immune function. Human Immunodeficiency Virus (HIV) infected subjects without Acquired Immune Deficiency Syndrome (AIDS) may be enrolled. * Subjects receiving oral steroids or receiving immunosuppressant drugs after organ transplant. * Absence of purulent material for initial culture and Gram's stain. Subjects with cellulitis may be enrolled in the absence of purulent material, provided that infection with a Gram-positive organism is suspected. * Subjects who have received more than 48 hours of any systemic antibiotic or topical antibiotic at the infection site with activity against Gram-positive pathogens, unless there is clinical evidence of treatment failure OR documented resistance in the identified Gram-positive pathogen to the previous antibiotic therapy. * cSSTI suspected or documented as being due exclusively to Gram-negative or anaerobic organisms based on epidemiology or on direct examination of a Gram-stained specimen. * Subjects diagnosed with pneumonia or those with severe renal impairment or hepatic disease * Previous history of hearing loss. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Success as Measured by Comparing the Participants Signs and Symptoms at the Test of Cure (TOC) Visit to Those Recorded at Study Baseline in the Clinically Evaluable Population. | Baseline to TOC Visit (7-14 days after end of treatment) up to 4 weeks | Success: Total resolution of clinically significant signs and symptoms of the infection site (cure) or improvement to such a level that no further antibacterial therapy was required (improvement). Failure: Persistence or progression of signs and symptoms after at least 3 days of study therapy, or development of new signs and symptoms at the infection site, or concomitant or additional antibacterial therapy with documented activity against isolated organisms, or a treatment duration greater than 14 days, or requirement of a major surgical procedure as adjunct or follow-up therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Microbiological Efficacy Measured by the Number of Participants Achieving Bacteriological Eradication of Gram-positive Baseline Pathogens at the TOC Visit. | Baseline to TOC Visit (7-14 days after end of treatment) up to 4 weeks | Microbiological Success: All infecting Gram-positive pathogens isolated at baseline were eradicated at the TOC evaluation and a superinfecting pathogen was not isolated either prior to or at the TOC evaluation. Microbiological Failure: Persistence of one or more infecting Gram-positive pathogens or isolation of a superinfecting pathogen prior to or at the TOC evaluation. |
Participant flow
Recruitment details
194 participants were randomized; 5 participants were not exposed to study drug by mistake; therefore, only 189 participants received study drug.
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin Daptomycin 4 mg/kg intravenous (i.v.) once daily | 97 |
| Pooled Comparator Vancomycin 1 g intravenous (i.v.) twice daily or Teicoplanin 400 mg i.v. once daily following a loading dose of 400 mg administered at 0, 12 and 24 hours on day one. | 92 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reasons | 1 | 0 |
| Overall Study | Adverse Event | 3 | 8 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Inappropriate enrollment | 2 | 1 |
| Overall Study | Lack of Efficacy | 6 | 5 |
| Overall Study | Lost to Follow-up | 6 | 6 |
| Overall Study | Protocol discontinuation criteria met | 1 | 2 |
| Overall Study | Protocol Violation | 3 | 2 |
| Overall Study | Unable to classify | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Daptomycin | Pooled Comparator | Total |
|---|---|---|---|
| Age, Customized < 65 years | 62 Participants | 61 Participants | 123 Participants |
| Age, Customized >=65 years | 35 Participants | 31 Participants | 66 Participants |
| Sex: Female, Male Female | 36 Participants | 41 Participants | 77 Participants |
| Sex: Female, Male Male | 61 Participants | 51 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 97 | 25 / 92 |
| serious Total, serious adverse events | 17 / 97 | 16 / 92 |
Outcome results
Primary
Clinical Success as Measured by Comparing the Participants Signs and Symptoms at the Test of Cure (TOC) Visit to Those Recorded at Study Baseline in the Clinically Evaluable Population.
Success: Total resolution of clinically significant signs and symptoms of the infection site (cure) or improvement to such a level that no further antibacterial therapy was required (improvement). Failure: Persistence or progression of signs and symptoms after at least 3 days of study therapy, or development of new signs and symptoms at the infection site, or concomitant or additional antibacterial therapy with documented activity against isolated organisms, or a treatment duration greater than 14 days, or requirement of a major surgical procedure as adjunct or follow-up therapy.
Time frame: Baseline to TOC Visit (7-14 days after end of treatment) up to 4 weeks
Population: The clinically evaluable population was used for the efficacy analysis. It included all patients who met the criteria for cSSTI as listed in the Protocol, 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 | Clinical Success as Measured by Comparing the Participants Signs and Symptoms at the Test of Cure (TOC) Visit to Those Recorded at Study Baseline in the Clinically Evaluable Population. | Clinical Success | 53 Participants |
| Daptomycin | Clinical Success as Measured by Comparing the Participants Signs and Symptoms at the Test of Cure (TOC) Visit to Those Recorded at Study Baseline in the Clinically Evaluable Population. | Clinical Failure | 5 Participants |
| Pooled Comparator | Clinical Success as Measured by Comparing the Participants Signs and Symptoms at the Test of Cure (TOC) Visit to Those Recorded at Study Baseline in the Clinically Evaluable Population. | Clinical Success | 41 Participants |
| Pooled Comparator | Clinical Success as Measured by Comparing the Participants Signs and Symptoms at the Test of Cure (TOC) Visit to Those Recorded at Study Baseline in the Clinically Evaluable Population. | Clinical Failure | 6 Participants |
Secondary
Microbiological Efficacy Measured by the Number of Participants Achieving Bacteriological Eradication of Gram-positive Baseline Pathogens at the TOC Visit.
Microbiological Success: All infecting Gram-positive pathogens isolated at baseline were eradicated at the TOC evaluation and a superinfecting pathogen was not isolated either prior to or at the TOC evaluation. Microbiological Failure: Persistence of one or more infecting Gram-positive pathogens or isolation of a superinfecting pathogen prior to or at the TOC evaluation.
Time frame: Baseline to TOC Visit (7-14 days after end of treatment) up to 4 weeks
Population: Population analyzed consisted of patients from the clinically evaluable population who had microbiological assessments.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin | Microbiological Efficacy Measured by the Number of Participants Achieving Bacteriological Eradication of Gram-positive Baseline Pathogens at the TOC Visit. | Microbiological Success | 56 Participants |
| Daptomycin | Microbiological Efficacy Measured by the Number of Participants Achieving Bacteriological Eradication of Gram-positive Baseline Pathogens at the TOC Visit. | Microbiological Failure | 1 Participants |
| Pooled Comparator | Microbiological Efficacy Measured by the Number of Participants Achieving Bacteriological Eradication of Gram-positive Baseline Pathogens at the TOC Visit. | Microbiological Success | 39 Participants |
| Pooled Comparator | Microbiological Efficacy Measured by the Number of Participants Achieving Bacteriological Eradication of Gram-positive Baseline Pathogens at the TOC Visit. | Microbiological Failure | 4 Participants |