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

Phase 3

Completed

Conditions: Skin Infections, Bacterial

Interventions: Drug: Retpamulin Ointment, 1%
Drug: Linezolid

Registration Number: NCT00852540

Lead Sponsor: Stiefel, a GSK Company

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 410

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Retapamulin	Retpamulin Ointment, 1%	-
Linezolid	Linezolid	-

Primary Outcome Measures

Name	Time	Method
Number of Participants Achieving Clinical Response at Follow-up Who Had Methicillin-resistant Staphlococcus Aureus (MRSA) as a Baseline Pathogen	7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid	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).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Clinical Response at Follow-up	7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid	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).
Number of Participants With the Indicated Clinical Outcome at the End of Therapy	2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid	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.
Number of Baseline Pathogens With the Indicated Microbiological Outcome at the End of Therapy	2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid	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.
Number of Participants Who Achieved Microbiological Response (MR) at Follow-up (FU) Who Had a Baseline Pathogen (BP)	7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid	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."
Number of Participants Achieving Microbiological Response (MR) at Follow-up (FU) Who Had MRSA as a Baseline Pathogen (BP)	7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid	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."
Number of Participants With the Indicated Clinical Outcome at the End of Therapy Who Had MRSA as a Baseline Pathogen	2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid	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.
Number of Participants With the Indicated Microbiological Outcome at the End of Therapy Who Had MRSA as a Baseline (BL) Pathogen	2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid	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.
Mean Scores on the Skin Infection Rating Scale 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)	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.
Mean Wound Size 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)	Lesion sized was measured in centimeters squared at Visits 1, 2, 3, 4, and 5.
Number of Participants With Therapeutic Response at Follow-up	7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid	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.