Retapamulin Versus Linezolid in the Treatment of SITL and Impetigo Due to MRSA

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to provide further evidence of the clinical and bacteriological efficacy of retapamulin in the treatment of subjects with SITL or impetigo due to MRSA. Subjects aged 2 months and older will be treated with either topical retapamulin for 5 days or oral linezolid for 10 days. The primary endpoint is the clinical response at follow-up (7-9 days after the end of therapy) in subjects who have a MRSA infection at baseline. The primary population is the per-protocol MRSA population. It is anticipated that approximately 500 subjects may be enrolled in order to obtain approximately 105 subjects who have a baseline MRSA infection.

Detailed Description
-----------------
This is a prospective, randomized, double-blind, double dummy, multicenter, comparative study in subjects 2 months of age and older with SITL (including secondarily-infected lacerations, sutured wounds and abrasions) or impetigo (bullous and non-bullous) due to MRSA. 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. Subjects with impetigo can have up to 10 lesions and the infected lesion(s) must not be more than 100 cm2 in area (or up to a maximum of 2% total body surface area for subjects <18 years of age), must not require surgical intervention and must be able to be appropriately treated with a topical antibiotic. There are five study visits occurring over a 17-19 day period. At the baseline visit (Visit 1, day 1), subjects will be randomized to receive retapamulin (plus oral placebo) or linezolid (plus placebo ointment) in a 2:1 ratio. Retapamulin is applied twice daily for 5 days, and linezolid is dosed, depending on subject age, either twice or three times daily for 10 days. The on-therapy, end of therapy and follow-up visits are staggered due to the difference in duration of the treatment regimens. Subjects will be monitored and clinically evaluated at all postbaseline visits. Randomization will be center-based and stratified by age (<5 years, ≥5 to <12 years, ≥12 years), 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.

Official Title
-----------------
A Randomized, Double-Blind, Double Dummy, Comparative, Multicenter Study to Assess the Safety and Efficacy of Topical Retapamulin Ointment, 1%, Versus Oral Linezolid in the Treatment of Secondarily-Infected Traumatic Lesions and Impetigo Due to Methicillin-Resistant Staphylococcus Aureus

Conditions
-----------------
Skin Infections, Bacterial

Intervention / Treatment
-----------------
* Drug: Retpamulin Ointment, 1%
* Drug: Linezolid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 2 months of age or older diagnosis of secondarily-infected traumatic lesion (SITL) or impetigo (bullous or non-bullous) negative urine pregnancy test (females of childbearing potential) total skin infection rating scale (SIRS) score of at least 8, which must include a pus/exudate score of at least 3 subject or parent/legal guardian willing and able to comply with protocol written informed, dated consent, and written assent (if applicable) Exclusion Criteria: previous hypersensitivity to pleuromutilins or oxazolidinones phenylketonuria or known hypersensitivity to aspartame secondarily-infected animal/human bite, or puncture wound abscess chronic ulcerative lesion underlying skin disease (eg, eczematous dermatitis) with secondary infection systemic signs and symptoms of infection skin infection not appropriate for treatment by a topical antibiotic (eg, extensive cellulitis, furunculosis) subject requires surgical intervention for infection prior to study or likely will during the study receipt of systemic antibacterial or steroid, or application of any topical therapeutic agent directly to wound within 24 hours of entry into the study subject currently receiving adrenergic agents subject currently receiving serotonergic agents history of pseudomembranous colitis known, pre-existing myelosuppression, history of myelosuppression with linezolid use, or receiving a medication that produces bone marrow suppression history of siezures history of severe renal failure and undergoing dialysis serious underlying disease that could be imminently life-threatening pregnant, breast feeding or planning a pregnancy, or not using accepted method of contraception (females of childbearing potential or <1 year post-menopausal) use of another investigational drug within 30 days prior to entry into this study previously enrolled in this study fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency (for subjects <12 years of age receiving linezolid suspension)

Ages Eligible for Study
-----------------
Minimum Age: 2 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Retapamulin<br> | Drug: Retpamulin Ointment, 1%<br>* Topical retapamulin (SB-275833) ointment, 1% (w/w), and placebo ointment, will be provided as approximately 10 grams of an off-white smooth ointment in collapsible aluminum tubes with reverse-taper puncture-tip caps. Retapamulin or placebo ointment will be applied twice daily for 5 days.<br>|
| Active Comparator: Linezolid<br> | Drug: Linezolid<br>* Adult and adolescent (=>12 years of age) subjects will receive one 600mg linezolid tablet (overencapsulated), or one placebo capsule, twice daily for 10 days. Pediatric subjects aged 5-11 years will receive 10mg/kg body weight of a 100mg/5mL oral linezolid suspension, or placebo suspension, twice daily for 10 days. Pediatric subjects <5 years of age will receive 10mg/kg of a 100mg/5mL oral linezolid suspension, or placebo suspension, three times daily for 10 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Clinical Response at Follow-up Who Had Methicillin-resistant Staphlococcus Aureus (MRSA) as a Baseline Pathogen | Follow-up is defined as 7-9 days post-therapy: Day 12-14 for retapamulin; Day 17-19 for linezolid. Clinical success at follow-up was defined as the resolution of clinically meaningful signs and symptoms of infection recorded at baseline, including a pus/exudate skin infection rating scale (SIRS) score of 0. The SIRS is used by the investigator to evaluate infected lesions. Scores on the SIRS range from 0 (absent) to 6 (severe). | 7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Microbiological Response (MR) at Follow-up (FU) Who Had MRSA as a Baseline Pathogen (BP) | MR was defined as microbiological success if, (1) for participants (par.) whose clinical outcome at end of therapy (EOT) was clinical success (CS)/improvement, the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and absent at FU, or the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and par. was a CS such that no culture was obtained due to lack of culturable material secondary to adequate clinical response; or (2) a pathogen not previously identified at baseline was isolated at FU in a par. identified at FU as a CS. | 7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid | 
| Number of Participants With Clinical Response at Follow-up | Follow-up is defined as 7-9 days post-therapy: Day 12-14 for retapamulin; Day 17-19 for linezolid. Clinical success at follow-up was defined as the resolution of clinically meaningful signs and symptoms of infection recorded at baseline, including a pus/exudate skin infection rating scale (SIRS) score of 0. The SIRS is used by the investigator to evaluate infected lesions. Scores on the SIRS range from 0 (absent) to 6 (severe). | 7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid | 
| Number of Participants Who Achieved Microbiological Response (MR) at Follow-up (FU) Who Had a Baseline Pathogen (BP) | MR was defined as microbiological success if, (1) for participants (par.) whose clinical outcome at end of therapy (EOT) was clinical success (CS)/improvement, the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and absent at FU, or the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and par. was a CS such that no culture was obtained due to lack of culturable material secondary to adequate clinical response; or (2) a pathogen not previously identified at baseline was isolated at FU in a par. identified at FU as a CS. | 7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid | 
| Number of Participants With the Indicated Clinical Outcome at the End of Therapy Who Had MRSA as a Baseline Pathogen | Clinical improvement is defined as improvement of signs/symptoms of infection recorded at baseline (BL) to such an extent that no further antimicrobial therapy is necessary. Clinical failure (CF) is defined as insufficient improvement/deterioration of signs/symptoms of the infection recorded at BL, such that additional antibiotic therapy is required. Unable to determine (UTD) is defined as refusal to consent to a clinical examination, lost to follow-up. Participants who are CF/Unable to Determine at end of therapy are considered such at follow-up as well. | 2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid | 
| Number of Participants With the Indicated Microbiological Outcome at the End of Therapy Who Had MRSA as a Baseline (BL) Pathogen | Eradication is the elimination of BL pathogens. Presumed eradication and presumed improvement are clinical outcomes of success or improvement, respectively, such that no culture was obtained due to lack of culturable material, secondary to adequate clinical response, and is documented in the electronic Case Report Form. Persistence is defined as BL pathogens still being present. Presumed persistence is defined as a participant that is a clinical failure with no obtained culture. Unable to determine was used if no determination of BL pathogen microbiological response could be made. | 2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid | 
| Number of Participants With the Indicated Clinical Outcome at the End of Therapy | Clinical improvement is defined as improvement of signs/symptoms of infection recorded at baseline (BL) to such an extent that no further antimicrobial therapy is necessary. Clinical failure (CF) is defined as insufficient improvement/deterioration of signs/symptoms of the infection recorded at BL, such that additional antibiotic therapy is required. Unable to determine (UTD) is defined as refusal to consent to a clinical examination, lost to follow-up. Participants who are CF/Unable to Determine at end of therapy are considered such at follow-up as well. | 2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid | 
| Number of Baseline Pathogens With the Indicated Microbiological Outcome at the End of Therapy | Eradication is the elimination of BL pathogens. Presumed eradication and presumed improvement are clinical outcomes of success or improvement, respectively, such that no culture was obtained due to lack of culturable material, secondary to adequate clinical response, and is documented in the electronic Case Report Form. Persistence is defined as BL pathogens still being present. Presumed persistence is defined as a participant that is a clinical failure with no obtained culture. Unable to determine was used if no determination of BL pathogen microbiological response could be made. | 2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid | 
| Number of Participants With Therapeutic Response at Follow-up | Therapeutic response is defined as the combined clinical and microbiological response. Therapeutic response iss a measure of the overall efficacy response, and a therapeutic success refers to participants who had been deemed both a clinical success and a microbiological success. All other combinations (other than clinical success + microbiological success) were deemed failures for therapeutic response. | 7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid | 
| Mean Scores on the Skin Infection Rating Scale at Visits 1, 2, 3, 4, and 5 | The investigator evaluated skin infections by grading the infected lesion for exudate (a fluid that leaks out of blood vessels into surrounding tissue)/pus, crusting, erythema (redness of the skin)/ inflammation (E/I), tissue warmth, tissue edema (swelling), itching, and pain, according to the Skin Infection Rating Scale. All parameters were graded on a scale of 0 (absent) to 6 (severe). The total score is calculated by summing the individual scores from the 7 parameters; the total score ranges from 0 to 42. | Visits 1 (Day 1), 2 (Day 3-4), 3 (Day 7-9), 4 (Day 12-14), and 5 (Day 17-19) | 
| Mean Wound Size at Visits 1, 2, 3, 4, and 5 | Lesion sized was measured in centimeters squared at Visits 1, 2, 3, 4, and 5. | Visits 1 (Day 1), 2 (Day 3-4), 3 (Day 7-9), 4 (Day 12-14), and 5 (Day 17-19) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
impetigo, methicillin-resistant Staphylococcus aureus, linezolid, secondarily-infected traumatic lesion, uncomplicated skin infection, retapamulin