Abscess, Cellulitis, Systemic Inflammation, Wound Infection
Conditions
Keywords
ABSSSI, Skin Infection, Abscess
Brief summary
The purpose of this Phase 3 trial was to evaluate the efficacy, safety, and tolerability of oritavancin in acute bacterial skin and skin structure infections (ABSSSIs), including those caused by methicillin-resistant staphylococcus aureus (MRSA), and to evaluate the potential economic benefit of oritavancin administered as a single 1200-milligram (mg) intravenous (IV) dose.
Detailed description
This was a Phase 3, multicenter, randomized, double-blind, parallel, comparative efficacy and safety study of single-dose IV oritavancin/IV placebo versus IV vancomycin for 7 to 10 days in adults with ABSSSI suspected or proven to be caused by gram-positive pathogens. Approximately 960 participants were to be randomized at 100 centers globally. In addition, this study characterized the pharmacokinetics (PK) and PK/pharmacodynamics (PD) properties of a single 1200-mg IV dose of oritavancin and evaluated the potential health economic benefits offered by this dosing strategy.
Interventions
Oritavancin was administered as a single IV dose.
DRUGIV Vancomycin
Intravenous vancomycin was administered for a minimum of 7 days and up to a maximum of 10 days.
DRUGPlacebo
Intravenous placebo was administered thereafter, for a minimum of 7 days and up to a maximum of 10 days (oritavancin and placebo).
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
Participants were included in the study if they met all of the following inclusion criteria: 1. Males or females ≥18 years old 2. Diagnosis of ABSSSI suspected or confirmed to be caused by a gram-positive pathogen requiring at least 7 days of IV therapy 3. An ABSSSI included 1 of the following infections: wound infections, cellulitis/erysipelas, major cutaneous abscess 4. ABSSSI must have presented with at least 2 local signs and symptoms and at least 1 sign of systemic inflammation (unless \>70 years of age). 5. Able to give informed consent and willing to comply with all required study procedures
Exclusion criteria
Participants were excluded from the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cessation Of Spread Or Reduction In Size Of Baseline Lesion, Absence Of Fever, And No Rescue Antibiotic Medication At Early Clinical Evaluation (ECE) (48 To 72 Hours) | 48-72 hours after the initiation of study therapy | Clinical response at the ECE visit (48-72 hours following initiation of study drug administration). Early clinical response was defined as a composite outcome based on cessation of spreading or reduction in the size of baseline lesion, absence of fever and no rescue antibiotic medication. A participant was classified as success if all of the following were met: cessation of spread or reduction of the lesion (defined as cessation of spread of the redness, edema, and/or induration or reduction in size \[length, width, and area\] of the redness, edema, and/or induration such that the size of the lesion was less than or equal to the size at baseline); resolution (absence) of fever (temperature \<37.7°Celsius at the last 3 consecutive recordings by the same route of administration taken 4 times per day, for example every 6 hours between 48 and 72 hours); no rescue antibiotic medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator Assessed Clinical Cure Of Treatment With Single-dose IV Oritavancin Compared With IV Vancomycin For 7 To 10 Days At Post-therapy Evaluation (Key Secondary Endpoint) | 7-14 days after end of therapy | Compared the clinical efficacy at the post therapy evaluation of oritavancin and vancomycin based on the Investigator examination of the signs and symptoms of the primary acute bacterial skin and skin structure infection (ABSSSI). Investigator assessment of clinical cure was complete or nearly complete resolution of baseline signs and symptoms of the primary infection such that no further treatment with antibiotics was needed. |
| Number Of Participants With A Lesion Size Reduction ≥20% From Baseline At ECE | 48-72 hours after the initiation of study therapy | Clinical response at the ECE visit (48-72 hours following initiation of study drug administration) based on changes in ABSSSI lesion size measurements from baseline. Participants with a ≥20% reduction in size of baseline lesion were classified a 'success', while those with missing data or those without a reduction in size of baseline lesion ≥20% were classified a 'failure'. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single-Dose 1200 mg Oritavancin Single 1200 mg IV dose of oritavancin diphosphate administered as first infusion followed by IV placebo administered twice daily for a minimum of 7 days and up to a maximum of 10 days. | 475 |
| Vancomycin Intravenous vancomycin, 1 g or 15 mg/kg, administered twice daily for a minimum of 7 days and up to a maximum of 10 days. | 479 |
| Total | 954 |
Baseline characteristics
| Characteristic | Single-Dose 1200 mg Oritavancin | Vancomycin | Total |
|---|---|---|---|
| Age, Continuous | 46.2 years STANDARD_DEVIATION 14.2 | 44.3 years STANDARD_DEVIATION 14.5 | 45.2 years STANDARD_DEVIATION 14.38 |
| Sex: Female, Male Female | 174 Participants | 178 Participants | 352 Participants |
| Sex: Female, Male Male | 301 Participants | 301 Participants | 602 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 473 | 2 / 481 |
| other Total, other adverse events | 323 / 473 | 340 / 481 |
| serious Total, serious adverse events | 35 / 473 | 35 / 481 |
Outcome results
Primary
Cessation Of Spread Or Reduction In Size Of Baseline Lesion, Absence Of Fever, And No Rescue Antibiotic Medication At Early Clinical Evaluation (ECE) (48 To 72 Hours)
Clinical response at the ECE visit (48-72 hours following initiation of study drug administration). Early clinical response was defined as a composite outcome based on cessation of spreading or reduction in the size of baseline lesion, absence of fever and no rescue antibiotic medication. A participant was classified as success if all of the following were met: cessation of spread or reduction of the lesion (defined as cessation of spread of the redness, edema, and/or induration or reduction in size \[length, width, and area\] of the redness, edema, and/or induration such that the size of the lesion was less than or equal to the size at baseline); resolution (absence) of fever (temperature \<37.7°Celsius at the last 3 consecutive recordings by the same route of administration taken 4 times per day, for example every 6 hours between 48 and 72 hours); no rescue antibiotic medication.
Time frame: 48-72 hours after the initiation of study therapy
Population: Modified intent to treat (mITT) population consisting of all participants who were randomized into the trial and received any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single-Dose 1200 mg Oritavancin | Cessation Of Spread Or Reduction In Size Of Baseline Lesion, Absence Of Fever, And No Rescue Antibiotic Medication At Early Clinical Evaluation (ECE) (48 To 72 Hours) | Success | 391 participants |
| Single-Dose 1200 mg Oritavancin | Cessation Of Spread Or Reduction In Size Of Baseline Lesion, Absence Of Fever, And No Rescue Antibiotic Medication At Early Clinical Evaluation (ECE) (48 To 72 Hours) | Failure | 84 participants |
| Vancomycin | Cessation Of Spread Or Reduction In Size Of Baseline Lesion, Absence Of Fever, And No Rescue Antibiotic Medication At Early Clinical Evaluation (ECE) (48 To 72 Hours) | Success | 378 participants |
| Vancomycin | Cessation Of Spread Or Reduction In Size Of Baseline Lesion, Absence Of Fever, And No Rescue Antibiotic Medication At Early Clinical Evaluation (ECE) (48 To 72 Hours) | Failure | 101 participants |
95% CI: [-1.6, 8.4]
Secondary
Investigator Assessed Clinical Cure Of Treatment With Single-dose IV Oritavancin Compared With IV Vancomycin For 7 To 10 Days At Post-therapy Evaluation (Key Secondary Endpoint)
Compared the clinical efficacy at the post therapy evaluation of oritavancin and vancomycin based on the Investigator examination of the signs and symptoms of the primary acute bacterial skin and skin structure infection (ABSSSI). Investigator assessment of clinical cure was complete or nearly complete resolution of baseline signs and symptoms of the primary infection such that no further treatment with antibiotics was needed.
Time frame: 7-14 days after end of therapy
Population: Modified intent to treat (mITT) population consisting of all participants who were randomized into the trial and received any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single-Dose 1200 mg Oritavancin | Investigator Assessed Clinical Cure Of Treatment With Single-dose IV Oritavancin Compared With IV Vancomycin For 7 To 10 Days At Post-therapy Evaluation (Key Secondary Endpoint) | Clinical Cure | 378 participants |
| Single-Dose 1200 mg Oritavancin | Investigator Assessed Clinical Cure Of Treatment With Single-dose IV Oritavancin Compared With IV Vancomycin For 7 To 10 Days At Post-therapy Evaluation (Key Secondary Endpoint) | Clinical Failure | 97 participants |
| Vancomycin | Investigator Assessed Clinical Cure Of Treatment With Single-dose IV Oritavancin Compared With IV Vancomycin For 7 To 10 Days At Post-therapy Evaluation (Key Secondary Endpoint) | Clinical Cure | 383 participants |
| Vancomycin | Investigator Assessed Clinical Cure Of Treatment With Single-dose IV Oritavancin Compared With IV Vancomycin For 7 To 10 Days At Post-therapy Evaluation (Key Secondary Endpoint) | Clinical Failure | 96 participants |
95% CI: [-5.5, 4.7]
Secondary
Number Of Participants With A Lesion Size Reduction ≥20% From Baseline At ECE
Clinical response at the ECE visit (48-72 hours following initiation of study drug administration) based on changes in ABSSSI lesion size measurements from baseline. Participants with a ≥20% reduction in size of baseline lesion were classified a 'success', while those with missing data or those without a reduction in size of baseline lesion ≥20% were classified a 'failure'.
Time frame: 48-72 hours after the initiation of study therapy
Population: Modified intent to treat (mITT) population consisting of all participants who were randomized into the trial and received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single-Dose 1200 mg Oritavancin | Number Of Participants With A Lesion Size Reduction ≥20% From Baseline At ECE | Success | 413 Participants |
| Single-Dose 1200 mg Oritavancin | Number Of Participants With A Lesion Size Reduction ≥20% From Baseline At ECE | Failure | 62 Participants |
| Vancomycin | Number Of Participants With A Lesion Size Reduction ≥20% From Baseline At ECE | Success | 397 Participants |
| Vancomycin | Number Of Participants With A Lesion Size Reduction ≥20% From Baseline At ECE | Failure | 82 Participants |
95% CI: [-0.5, 8.6]