Skin Infections, Bacterial
Conditions
Keywords
infection, retapamulin, secondarily-infected traumatic lesions, placebo
Brief summary
The purpose of Study TOC110977 is to demonstrate clinical superiority of Retapamulin ointment, 1%, over placebo in patients with secondarily-infected traumatic lesions, which includes secondarily-infected lacerations, abrasions and sutured wounds. Subjects 2 months of age and older will be treated with topical retapamulin or placebo ointment twice daily for 5 days. The primary endpoint of this study is the clinical response at follow-up (Day 12-14; 7-9 days after the end of therapy) in the intent-to-treat clinical population.
Detailed description
This is a prospective, multicenter, double-blind, placebo-controlled parallel group study in subjects aged 2 months and older with SITL, including secondarily-infected lacerations, sutured wounds or abrasions. A laceration or sutured wound cannot exceed 10 cm in length with surrounding erythema not extending more than 2 cm from the edge of the lesion. Abrasions cannot exceed 100 cm2 in total area, or up to a maximum of 2% total body surface area for subjects \<18 years of age, with surrounding erythema not extending more than 2 cm from the edge of the abrasion. There are four study visits occurring over a 12-14 day period. At the Baseline visit (Visit 1, Day 1), subjects will be randomized to receive retapamulin or placebo ointment in a 2:1 (retapamulin:placebo) ratio. The 2:1 randomization is included to minimize the number of subjects exposed to treatment with placebo. Both active treatment and placebo will be dosed topically twice daily (BID) for 5 days. All subjects will receive a telephone call from the investigator or appropriate designee appointed by the investigator on Day 2. The subject will be interviewed to determine if there is any evidence of worsening infection. Subjects who are thought to be worsening will be instructed to come in to the clinic for an assessment. Subjects will be monitored and clinically evaluated at the On-therapy (Days 3-4), End of Therapy (Days 7-9), and Follow-up (Days 12-14) visits. Randomization will be center-based and performed using an appropriate Interactive Voice Response System (IVRS), an automated telephone system. The block size will remain confidential. Subjects are considered to have completed the study if they meet all inclusion/exclusion criteria, are considered compliant with study medication, and attend all study visits as defined by the protocol.
Interventions
Provided as approximately 10 grams of an off-white smooth ointment in collapsible aluminum tubes with reverse taper puncture tip caps.
DRUGPlacebo ointment
Provided as approximately 10 grams of an off-white smooth ointment in collapsible aluminum tubes with reverse taper puncture tip caps.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* subject is aged 2 months or older * subject has secondarily-infected traumatic lesion (laceration, sutured wound or abrasion) * negative urine pregnancy test * subject has total skin infection rating scale score of at least 8, including pus/exudate score of at least 3 * subject and/or parent/legal guardian is willing and able to comply with protocol * subject or parent/legal guardian has given written informed consent or assent as applicable
Exclusion criteria
* previous hypersensitivity to pleuromutilin * secondarily-infected animal/human bite or puncture wound * subject has an abscess * chronic ulcerative lesion * underlying skin disease * systemic signs and symptoms of infection * infection not appropriately treated with topical antibiotic * infection requires surgical intervention prior to or during study * subject received systemic antibacterial or steroid, or topical therapeutic agent within 24 hours of entry into study * serious underlying disease * subject pregnant, breast feeding or planning a pregnancy, or unacceptable method of contraception * other investigational drug within 30 days of study entry * subject previously enrolled in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Primary Efficacy Population | Days 12-14 | Clinical Success at follow-up was defined as Resolution of clinically meaningful signs and symptoms of infection recorded at baseline including a pus/exudate Skin Infection Rating Scale (SIRS) score of 0. Clinical response at follow-up was classified as Clinical Failure for all other cases. The SIRS consists of seven items (pus/exudates, crusting, erythema/inflammation, tissue warmth, tissue edema, itching and pain). Each item has a score ranging from 0 to 6 (0=absent, 6=severe). The SIRS total score was calculated as the sum of the scores of all 7 SIRS items. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Intent-to-Treat Bacteriology (ITTB) Subset of the Primary Efficacy Population | Days 12-14 | Clinical Success at follow-up was defined as Resolution of clinically meaningful signs and symptoms of infection recorded at baseline including a pus/exudate Skin Infection Rating Scale (SIRS) score of 0. Clinical response at follow-up was classified as Clinical Failure for all other cases. The SIRS consists of seven items (pus/exudates, crusting, erythema/inflammation, tissue warmth, tissue edema, itching and pain). Each item has a score ranging from 0 to 6 (0=absent, 6=severe). The SIRS total score was calculated as the sum of the scores of all 7 SIRS items. |
| Number of Participants With Microbiological Success and Failure at Follow-up (7-9 Days Post Therapy) | Days 12-14 | The by pathogen microbiological outcome was determined by comparing the baseline culture results to those at follow-up. The by subject microbiological response was Microbiological Success if the microbiological outcomes for all baseline pathogens (bps) belong to Eradication (elimination of bps), Presumed Eradication (clinical outcome was success; no culture was obtained due to lack of culturable material), or Colonization (previously unidentified pathogen is identified at end of therapy in participant who is resolved/improved); otherwise, response was Microbiological Failure. |
| Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Days 7-9 | Clinical outcome is determined by the investigator based on signs and symptoms (S/S) at the end of therapy evaluation. The 4 clincal outcome categories are: clinical success, resolution of clinically meaningful S/S of infection recorded at baseline (BL), including a pus/exudates score of 0; clinical improvement, improvement of S/S of infection recorded at BL to such an extent that no further antimicrobial therapy is necessary; clinical failure, insufficient improvement of deterioration of S/S of infection recorded at BL such that additional antibiotic therapy is required; unable to determine. |
| Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Days 7-9 | The by pathogen microbiological outcome was determined by comparing the baseline culture results to those at follow-up. The results presented below pooled all baseline pathogens (bps). Eradication: elimination of bps. Presumed Eradication: clinical outcome was success; no culture was obtained due to lack of culturable material. Presumed Improvement: clinical outcome was improvement such that no culture was obtained due to lack of culturable material. Persistence: bps still present. Presumed persistence: clinical failure and no culture was obtained. |
| Number of Participants With Therapeutic Success and Failure at Follow-up (7-9 Days Post Therapy) | Follow-up (Days 12-14) | Therapeutic Success (Succ) was referred to as both Clinical Succ and Microbiological (Micro) Succ at Follow-up. Clinical Succ was the Resolution of baseline signs/symptoms of infection with a pus score of 0. A participant was Micro Succ if the micro outcome for all baseline pathogens (bps) belonged to Eradication (elimination of bps), Presumed Eradication (clinical outcome is success; no culturable material), or Colonization (new pathogen is identified at end of therapy in participants who are resolved/improved). All other combinations were deemed Therapeutic Failures. |
Countries
Argentina, Brazil, India, South Africa, United States
Participant flow
Pre-assignment details
A total of 508 participants were randomized. One participant did not receive treatment; thus, no data were collected for this participant. Only 507 participants were included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Retapamulin Topical retapamulin ointment, 1% twice daily for 5 days | 343 |
| Placebo Matching placebo | 164 |
| Total | 507 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Lack of Efficacy | 10 | 15 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Retapamulin |
|---|---|---|---|
| Age, Continuous | 28.6 years STANDARD_DEVIATION 18.32 | 31.3 years STANDARD_DEVIATION 18.7 | 32.6 years STANDARD_DEVIATION 18.77 |
| Race/Ethnicity, Customized African American/African Heritage | 71 participants | 215 participants | 144 participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 3 participants | 12 participants | 9 participants |
| Race/Ethnicity, Customized Asian - Central / South Asian Heritage | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 2 participants | 6 participants | 4 participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 15 participants | 48 participants | 33 participants |
| Race/Ethnicity, Customized Mixed Race | 9 participants | 28 participants | 19 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 61 participants | 193 participants | 132 participants |
| Sex: Female, Male Female | 63 Participants | 207 Participants | 144 Participants |
| Sex: Female, Male Male | 101 Participants | 300 Participants | 199 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 342 | 4 / 165 |
| serious Total, serious adverse events | 1 / 342 | 1 / 165 |
Outcome results
Primary
Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Primary Efficacy Population
Clinical Success at follow-up was defined as Resolution of clinically meaningful signs and symptoms of infection recorded at baseline including a pus/exudate Skin Infection Rating Scale (SIRS) score of 0. Clinical response at follow-up was classified as Clinical Failure for all other cases. The SIRS consists of seven items (pus/exudates, crusting, erythema/inflammation, tissue warmth, tissue edema, itching and pain). Each item has a score ranging from 0 to 6 (0=absent, 6=severe). The SIRS total score was calculated as the sum of the scores of all 7 SIRS items.
Time frame: Days 12-14
Population: Primary Efficacy Population: ITTC participants (par.) with baseline pus/exudate \>=3 who were enrolled under the original protocol with data captured under eCRF V1 and who were enrolled under protocol amendments with data captured under eCRF V2; ITTC (Intent-to-treat Clinical): all randomized par. who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Retapamulin | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Primary Efficacy Population | Clinical Success | 184 participants |
| Retapamulin | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Primary Efficacy Population | Clinical Failure | 62 participants |
| Placebo | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Primary Efficacy Population | Clinical Success | 75 participants |
| Placebo | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Primary Efficacy Population | Clinical Failure | 38 participants |
p-value: 0.09895% CI: [-1.6, 18.4]Chi-squared
Secondary
Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy)
The by pathogen microbiological outcome was determined by comparing the baseline culture results to those at follow-up. The results presented below pooled all baseline pathogens (bps). Eradication: elimination of bps. Presumed Eradication: clinical outcome was success; no culture was obtained due to lack of culturable material. Presumed Improvement: clinical outcome was improvement such that no culture was obtained due to lack of culturable material. Persistence: bps still present. Presumed persistence: clinical failure and no culture was obtained.
Time frame: Days 7-9
Population: ITTB subset of Primary Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Retapamulin | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Presumed Eradication | 137 baseline pathogens |
| Retapamulin | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Persistence | 3 baseline pathogens |
| Retapamulin | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Presumed Improvement | 94 baseline pathogens |
| Retapamulin | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Presumed Persistence | 5 baseline pathogens |
| Retapamulin | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Eradication | 4 baseline pathogens |
| Placebo | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Presumed Persistence | 8 baseline pathogens |
| Placebo | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Eradication | 5 baseline pathogens |
| Placebo | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Presumed Eradication | 49 baseline pathogens |
| Placebo | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Presumed Improvement | 35 baseline pathogens |
| Placebo | Number of Baseline Pathogens With the Indicated Microbiological Outcome at End of Therapy (2-4 Days Post Therapy) | Persistence | 13 baseline pathogens |
Secondary
Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Intent-to-Treat Bacteriology (ITTB) Subset of the Primary Efficacy Population
Clinical Success at follow-up was defined as Resolution of clinically meaningful signs and symptoms of infection recorded at baseline including a pus/exudate Skin Infection Rating Scale (SIRS) score of 0. Clinical response at follow-up was classified as Clinical Failure for all other cases. The SIRS consists of seven items (pus/exudates, crusting, erythema/inflammation, tissue warmth, tissue edema, itching and pain). Each item has a score ranging from 0 to 6 (0=absent, 6=severe). The SIRS total score was calculated as the sum of the scores of all 7 SIRS items.
Time frame: Days 12-14
Population: ITTB subset of Primary Efficacy Population: participants in the Primary Efficacy Population (see analysis population description in the Primary Outcome section) who had at least one pathogen isolated at the baseline visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Retapamulin | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Intent-to-Treat Bacteriology (ITTB) Subset of the Primary Efficacy Population | Clinical Success | 139 participants |
| Retapamulin | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Intent-to-Treat Bacteriology (ITTB) Subset of the Primary Efficacy Population | Clinical Failure | 43 participants |
| Placebo | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Intent-to-Treat Bacteriology (ITTB) Subset of the Primary Efficacy Population | Clinical Success | 54 participants |
| Placebo | Number of Participants With Clinical Success and Failure at Follow-up (7-9 Days Post Therapy) for the Intent-to-Treat Bacteriology (ITTB) Subset of the Primary Efficacy Population | Clinical Failure | 30 participants |
p-value: 0.0495% CI: [0.6, 23.6]Chi-squared
Secondary
Number of Participants With Microbiological Success and Failure at Follow-up (7-9 Days Post Therapy)
The by pathogen microbiological outcome was determined by comparing the baseline culture results to those at follow-up. The by subject microbiological response was Microbiological Success if the microbiological outcomes for all baseline pathogens (bps) belong to Eradication (elimination of bps), Presumed Eradication (clinical outcome was success; no culture was obtained due to lack of culturable material), or Colonization (previously unidentified pathogen is identified at end of therapy in participant who is resolved/improved); otherwise, response was Microbiological Failure.
Time frame: Days 12-14
Population: ITTB subset of Primary Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Retapamulin | Number of Participants With Microbiological Success and Failure at Follow-up (7-9 Days Post Therapy) | Microbiological Success | 139 participants |
| Retapamulin | Number of Participants With Microbiological Success and Failure at Follow-up (7-9 Days Post Therapy) | Microbiological Failure | 43 participants |
| Placebo | Number of Participants With Microbiological Success and Failure at Follow-up (7-9 Days Post Therapy) | Microbiological Success | 54 participants |
| Placebo | Number of Participants With Microbiological Success and Failure at Follow-up (7-9 Days Post Therapy) | Microbiological Failure | 30 participants |
p-value: 0.0495% CI: [0.6, 23.6]Chi-squared
Secondary
Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy)
Clinical outcome is determined by the investigator based on signs and symptoms (S/S) at the end of therapy evaluation. The 4 clincal outcome categories are: clinical success, resolution of clinically meaningful S/S of infection recorded at baseline (BL), including a pus/exudates score of 0; clinical improvement, improvement of S/S of infection recorded at BL to such an extent that no further antimicrobial therapy is necessary; clinical failure, insufficient improvement of deterioration of S/S of infection recorded at BL such that additional antibiotic therapy is required; unable to determine.
Time frame: Days 7-9
Population: Primary Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Retapamulin | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Clinical Success | 130 participants |
| Retapamulin | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Clinical Improvement | 102 participants |
| Retapamulin | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Clinical Failure | 11 participants |
| Retapamulin | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Unable to Determine | 3 participants |
| Placebo | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Unable to Determine | 2 participants |
| Placebo | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Clinical Success | 52 participants |
| Placebo | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Clinical Failure | 14 participants |
| Placebo | Number of Participants With the Indicated Clinical Outcome at End of Therapy (2-4 Days Post Therapy) | Clinical Improvement | 45 participants |
Secondary
Number of Participants With Therapeutic Success and Failure at Follow-up (7-9 Days Post Therapy)
Therapeutic Success (Succ) was referred to as both Clinical Succ and Microbiological (Micro) Succ at Follow-up. Clinical Succ was the Resolution of baseline signs/symptoms of infection with a pus score of 0. A participant was Micro Succ if the micro outcome for all baseline pathogens (bps) belonged to Eradication (elimination of bps), Presumed Eradication (clinical outcome is success; no culturable material), or Colonization (new pathogen is identified at end of therapy in participants who are resolved/improved). All other combinations were deemed Therapeutic Failures.
Time frame: Follow-up (Days 12-14)
Population: ITTB subset of Primary Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Retapamulin | Number of Participants With Therapeutic Success and Failure at Follow-up (7-9 Days Post Therapy) | Success | 139 participants |
| Retapamulin | Number of Participants With Therapeutic Success and Failure at Follow-up (7-9 Days Post Therapy) | Failure | 43 participants |
| Placebo | Number of Participants With Therapeutic Success and Failure at Follow-up (7-9 Days Post Therapy) | Success | 54 participants |
| Placebo | Number of Participants With Therapeutic Success and Failure at Follow-up (7-9 Days Post Therapy) | Failure | 30 participants |