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

Impetigo Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00852540
• Other study ID #: 110978
• Status: Completed
• Phase: Phase 3
• First received: February 26, 2009
• Last updated: July 12, 2012
• Start date: April 2009
• Est. completion date: August 2010

Study information

• Verified date: February 2012
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 410
• Est. completion date: August 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Months and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bacterial Infections
• Impetigo
• Secondarily-infected Traumatic Lesions
• Skin Diseases, Infectious
• Skin Infections, Bacterial
• Staphylococcal Infections

Intervention

Drug:
• Retpamulin Ointment, 1%
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.
• Linezolid
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.

Locations

Country	Name	City	State
United States	GSK Investigational Site	Anniston	Alabama
United States	GSK Investigational Site	Atlantis	Florida
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Bakerfield	California
United States	GSK Investigational Site	Bay Pines	Florida
United States	GSK Investigational Site	Bell Gardens	California
United States	GSK Investigational Site	Bentonville	Arkansas
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Brooklyn	New York
United States	GSK Investigational Site	Butte	Montana
United States	GSK Investigational Site	Carlisle	Ohio
United States	GSK Investigational Site	Charlottesville	Virginia
United States	GSK Investigational Site	Colorado Springs	Colorado
United States	GSK Investigational Site	Columbus	Georgia
United States	GSK Investigational Site	Corvallis	Oregon
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Duncanville	Texas
United States	GSK Investigational Site	Fort Lauderdale	Florida
United States	GSK Investigational Site	Ft. Lauderdale	Florida
United States	GSK Investigational Site	Grand Blanc	Michigan
United States	GSK Investigational Site	Gresham	Oregon
United States	GSK Investigational Site	Honolulu	Hawaii
United States	GSK Investigational Site	Honolulu	Hawaii
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Huntington Beach	California
United States	GSK Investigational Site	Jackson	Mississippi
United States	GSK Investigational Site	Jonesboro	Arkansas
United States	GSK Investigational Site	Layton	Utah
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Macon	Georgia
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	New Orleans	Louisiana
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Overland Park	Kansas
United States	GSK Investigational Site	Paragould	Arkansas
United States	GSK Investigational Site	Pensacola	Florida
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Roseville	California
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	St. Petersburg	Florida
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Vero Beach	Florida
United States	GSK Investigational Site	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Stiefel, a GSK Company	GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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)	No