Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant Staphylococcus Aureus

Study Overview
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Brief Summary
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The purpose of this clinical trial is to evaluate 2 different antibiotics, drugs that fight bacteria, [clindamycin (CLINDA) and trimethoprim-sulfamethoxazole (TMP-SMX)] and wound care for the outpatient management of uncomplicated skin and soft tissue infections (uSSTIs) in children and adults. The study will occur in areas where community associated methicillin-resistant Staphylococcus (S.) aureus are common. S. aureus is a type of bacteria. A total of 1310 volunteers, greater than or equal to 6 months of age and adults 85 years or younger, non-immunocompromised, with uSSTIs (in particular abscess and/or cellulitis) will be enrolled in this study. Subjects will be treated with one of the following: CLINDA, TMP-SMX, or placebo (contains no medication). Volunteers will be grouped based on the presence of cellulitis or abscess, whether the abscess can be surgically drained, and its size. The subject participation duration for this study is about 6 weeks.

Detailed Description
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Clinical practice in the treatment of community-onset skin and soft tissue infections (SSTI) has not kept pace with the emergence of methicillin-resistant Staphylococcus aureus (MRSA) in the community. This clinical trial will evaluate clindamycin (CLINDA) and trimethoprim-sulfamethoxazole (TMP-SMX) and wound care for the outpatient management of uncomplicated skin and soft tissue infection (uSSTI) in 3 metropolitan areas, Chicago, Los Angeles, and San Francisco, cities with high prevalence of community acquired (CA)-MRSA. This is a phase IIb multicenter, stratified, randomized, double-blind trial in which enrolled subjects with abscess or cellulitis will be treated with CLINDA, TMP-SMX, or placebo. Participants will include 1310 non-immunocompromised out-patients age 6 months to 85 years with SSTIs not requiring hospital admission. Subjects will undergo a screening/baseline evaluation, including determination of presence and size of abscess and/or presence of cellulitis. Subjects will then be randomized to receive treatment with either CLINDA, TMP-SMX, or placebo depending on whether they have: a larger drainable abscess, defined as greater than 5 cm in diameter in adults and as greater than 3 cm in diameter for ages 6-11 months, greater than 4 cm for ages 1-8 years, and greater than 5 cm for age 9 years and older; a limited drainable abscess, defined as less than or equal to 5 cm for adults and as less than or equal to 3 cm for ages 6-11 months, less than or equal to 4 cm for ages 1-8 years, and less than or equal to 5 cm for age 9 years and older; or cellulitis or erysipelas only. If the diameter of the abscess greater than 5 cm (smaller for children depending on age) or 2 or more sites of skin infection are present the subject will be randomized (1:1) to 10 days of therapy with TMP-SMX or CLINDA. If the diameter of the abscess less than or equal to 5 cm (smaller for children depending on age) then the subject will be randomized (1:1:1) to TMP-SMX, CLINDA or placebo for 10 days. Subjects with cellulitis or erysipelas only will be randomized (1:1) to TMP-SMX or CLINDA for 10 days. Subjects will be provided study drug, instructed in its use, and scheduled for 4 follow-up visits including: wound check (24-48 hours after enrollment); end of therapy (48 hours after completion of therapy); test of cure (7-10 days after completion of therapy); and a final visit at one month after completion of therapy. The primary objectives of this study are: to compare the cure rate of CLINDA to that of TMP-SMX for the treatment of patients with cellulitis or larger abscess at the Test of Cure (TOC) visit and to compare the cure rate of CLINDA, TMP-SMX, and placebo, each in conjunction with surgical drainage for the treatment of subjects with limited abscess at the TOC visit.

Official Title
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Randomized, Double-Blind Trial of Clindamycin, Trimethoprim-Sulfamethoxazole, or Placebo for Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant Staphylococcus Aureus

Conditions
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Staphylococcal Infection

Intervention / Treatment
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* Drug: Trimethoprim-sulfamethoxazole
* Other: Placebo
* Drug: Clindamycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6 months to 85 years. Able to complete the informed consent process or, if a minor, a parent or guardian who is able to complete the informed consent process; an assent form also will be completed for children age 7 and older. Willing and able to complete the study protocol, study-related activities, and visits. Diagnosis of uncomplicated skin and soft tissue infection (uSSTI), either cellulitis (defined as an inflammation of skin and associated skin structures) or abscess (defined as a circumscribed collection of pus), evidenced by at least 2 of the following localized signs or symptoms on the skin for at least 24 hours: Erythema Swelling or induration Local warmth Purulent drainage Tenderness to palpation or pain Able to take oral antibiotic therapy, either in pill or suspension form. Exclusion Criteria: Hospital in-patient. Hospitalization within the prior 14 days. Residence in a long-term skilled nursing facility. Requirement for hospitalization for skin infection or other condition. Previous enrollment in this protocol. Participation in another clinical trial within the previous 30 days. Superficial skin infection only, including: Impetigo Ecthyma Folliculitis Infections that have a high cure rate after surgical incision alone (such as isolated furunculosis) or after topical or local measures Unstable psychiatric or psychological condition rendering the subject unlikely to be cooperative or to complete study requirements. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with the adherence or subject compliance with study requirements. Systolic blood pressure > 180 mm Hg. Systolic blood pressure (SBP) less than an age-specific critical value: Age 6 - 11 months: < 70 mm Hg Age 1 to 8 years: < 80 mm Hg Age 9 to 17 years: < 90 mm Hg Age greater than or equal to 18 years: < 90 mm Hg Heart rate less than 45 beats per minute (BPM). Heart rate greater than an age-specific critical value: Age 6 - 11 months: > 140 BPM Age 1 to 8 years: > 120 BPM Age 9 to 17 years: > 120 BPM Age greater than or equal to 18 years: > 120 BPM. Oral temperature (or equivalent rectal, tympanic membrane, axillary) less than 35.5 degrees Celsius (95.9 degrees Fahrenheit). Oral temperature (or equivalent rectal, tympanic membrane, axillary) greater than age-specific critical value: Age 6 - 11 months: > 38.0 degrees Celsius (100.4 degrees Fahrenheit) Age 1 to 8 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit) Age 9 to 17 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit) Age greater than or equal to 18 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit). Documented human or witnessed animal bite in the past 30 days at the site of infection. Systemic antibacterial therapy with antistaphylococcal activity within the prior 14 days. The following concomitant medications: warfarin, phenytoin, methotrexate, rosiglitazone or sulfonylureas and systemically administered antibacterial agents with activity against staphylococci. Diagnosed or suspected disseminated or severe Staphylococcus aureus or group A streptococcal (GAS) infection, including lymphangitic spread of skin infection, septicemia, bacteremia, pneumonia, endocarditis, osteomyelitis, septic arthritis, gangrene, necrotizing fasciitis, myositis, or other serious infections. Infection at an anatomical skin site requiring specialized management or specialized antimicrobial therapy, including: Periauricular or orbital infection Perirectal infection Suspected deep space infection of the hand or foot Genital infection Mastitis Bursitis Radiographic evidence or suspicion of gas in the tissue or foreign body infection (note: radiography is not required for screening and can be performed at the discretion of the treating physician). Gastrointestinal symptoms such as nausea, vomiting, or diarrhea of a severity that would preclude consumption of oral antibiotics. Hypersensitivity or history of allergic reaction to study drug. History of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Third trimester pregnancy: pregnant women must have gestational age estimated by an objective means, e.g. ultrasound, fundal height, and women who are within 4 weeks of the third trimester of pregnancy, defined as week 27 of pregnancy, are not eligible. Currently breast feeding. Severe or morbid obesity with a body mass index (BMI) >40 kg/m^2. Complicated skin or soft tissue infection, such as: Catheter or catheter site infection within 30 days of placement Surgical site infection Known or suspected prosthetic device infection Suspected Gram-negative or anaerobic pathogen Unusual exposure history (e.g., underwater injury, fish-tank exposure, heavy soil exposure, etc) Infection at the site of an area of underlying skin disease such as chronic eczema, psoriasis, atopic dermatitis, or chronic venous stasis History of underlying immunocompromising condition or immunodeficiency, for example: Diabetes mellitus Chronic renal failure, creatinine clearance <30 ml/min Renal dialysis within the past 180 days Human immunodeficiency virus (HIV)-positive with either cluster of differentiation (CD)4 count <200 or <4 percent CD4 in the past 180 days or HIV-positive and no documented CD4 count in the past 4 months Organ or bone marrow transplantation (ever), immunosuppressive therapy within the past 180 days, severe liver disease Other serious underlying disease, as determined by the treating physician or the investigator

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Limited Abscess<br>Limited abscess with or without cellulitis less than or equal to 5 cm in diameter will be randomized to receive a 10-day course a) TMP-SMX 160/800 mg twice daily for adults; 8-10 mg/kg of TMP, 40-50 mg/kg of SMX twice daily for children; or b) CLINDA 300 mg three times daily for adults; 25-30 mg/kg/day divided three times daily for children; or c) placebo two capsules three times daily. | Drug: Trimethoprim-sulfamethoxazole<br>* Trimethoprim-sulfamethoxazole (TMP-SMX) will be administered orally at a dose of 160 mg TMP and 800 mg SMX (as 2 single strength over encapsulated tablets) twice daily (adult or child > 40 kg dose) or 8-10 mg TMP, 40-50 mg SMX per kg daily, divided into 2 daily doses (child < 40 kg dose). Study drug will be administered for 10 days.<br>Other: Placebo<br>* Placebo capsules will be identical in appearance to the CLINDA and TMP-SMX. Administered 3 times daily for 10 days.<br>Drug: Clindamycin<br>* CLINDA (adult dose of 300 mg three times daily; pediatric dose of 25-30 mg/kg/day divided three times daily up to a maximum dose of 900 mg/day). Study drug will be administered for 10 days.<br>|
| Experimental: Cellulitis or Larger Abscess<br>Subjects with cellulitis only or abscess > 5 cm in diameter, or with 2 or more sites of skin infection will be randomized to receive a 10-day course a) TMP-SMX 160/800 mg twice daily for adults; 8-10 mg/kg of TMP, 40-50 mg/kg of SMX twice daily for children; or b) CLINDA300 mg three times daily for adults; 25-30 mg/kg/day divided three times daily for children. | Drug: Trimethoprim-sulfamethoxazole<br>* Trimethoprim-sulfamethoxazole (TMP-SMX) will be administered orally at a dose of 160 mg TMP and 800 mg SMX (as 2 single strength over encapsulated tablets) twice daily (adult or child > 40 kg dose) or 8-10 mg TMP, 40-50 mg SMX per kg daily, divided into 2 daily doses (child < 40 kg dose). Study drug will be administered for 10 days.<br>Drug: Clindamycin<br>* CLINDA (adult dose of 300 mg three times daily; pediatric dose of 25-30 mg/kg/day divided three times daily up to a maximum dose of 900 mg/day). Study drug will be administered for 10 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Cure, Defined as Absence of Clinical Failure, in the Evaluable Population. | Clinical failure is defined as the occurence of any of the following: Lack of resolution at the Test of Cure (TOC) visit in any or all of the following: erythema, tenderness, purulent drainage, swelling, and local warmth. Erythema or tenderness that was considered due the surgical therapy itself (incision and drainage), was not considered to be indicative of clinical failure. Occurrence of a SSTI at another site other than the site(s) under study. Intolerance of study medication or a treatment-limiting adverse reaction necessitating discontinuation of study drug within the first 48 hours. Administration of other antimicrobial therapy for treatment of a SSTI at any time through the TOC visit. Unplanned surgical procedure for the infection under study at any time through the TOC visit. Hospitalization for treatment of active or invasive infection at any time through the TOC visit. | Test of cure (TOC) (7-10 days after completion of therapy) | 
| Percentage of Participants Achieving Clinical Cure, Defined as Absence of Clinical Failure, in the Intent-to-Treat (ITT) Population. | Clinical failure is defined as the occurence of any of the following: Lack of resolution at the Test of Cure (TOC) visit in any or all of the following: erythema, tenderness, purulent drainage, swelling, and local warmth. Erythema or tenderness that was considered due the surgical therapy itself (incision and drainage), was not considered to be indicative of clinical failure. Occurrence of a SSTI at another site other than the site(s) under study. Intolerance of study medication or a treatment-limiting adverse reaction necessitating discontinuation of study drug within the first 48 hours. Administration of other antimicrobial therapy for treatment of a SSTI at any time through the TOC visit. Unplanned surgical procedure for the infection under study at any time through the TOC visit. Hospitalization for treatment of active or invasive infection at any time through the TOC visit. | Test of cure (TOC) (7-10 days after completion of therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Adverse Events. | Subjects were issued a Memory Aid to record symptoms for 10 days post product administration. At study visits, the staff reviewed the memory aid and elicited as much information as possible about any reported symptoms. Occurrence of adverse events was solicited in the memory aid and during study visits. Reported symptoms, both solicited and unsolicited, were recorded as Adverse Events. | End of Treatment (EOT) (48 hours after completion of therapy); Test of Cure (TOC) (7-10 days after completion of therapy); One Month Follow-up Visit (OMFU) | 
| Number of Participants Reporting Adverse Events That Are Treatment Limiting. | Participants were issued a Memory Aid to record symptoms for 10 days post product administration. At study visits, the staff reviewed the memory aid and elicited as much information as possible about any reported symptoms. Occurrence of adverse events was solicited in the memory aid and during study visits. Reported symptoms, both solicited and unsolicited, were recorded as Adverse Events. For these results, adverse events that resulted in discontinuation of study treatment for the participant were considered treatment limiting. | End of Treatment (EOT) (48 hours after completion of therapy); Test of Cure (TOC) (7-10 days after completion of therapy); One Month Follow-up Visit (OMFU) | 
| Percentage of Participants Achieving Clinical Cure at the End of Treatment (EOT) Visit for the Evaluable Population. | Measures of clinical cure and clinical failure are the same as those defined for the primary efficacy outcome measure. | EOT visit within 48 hours of completion of therapy | 
| Percentage of Participants Achieving Clinical Cure at the End of Treatment (EOT) Visit for the Intent-to-Treat (ITT) Population. | Measures of clinical cure and clinical failure are the same as those defined for the primary efficacy outcome measure. | EOT visit within 48 hours of completion of therapy | 
| Percentage of Participants Achieving Clinical Cure at the One Month Follow-up (OMFU) Visit for the Evaluable Population. | Measures of clinical cure and clinical failure are the same as those defined for the primary efficacy outcome measure, with one addition. At the OMFU, relapse (the return of the original infection after initial improvement) or recurrence (return of skin infection at original site after cure of original infection) of SSTI was scored as clinical failure. | OMFU visit | 
| Percentage of Participants Achieving Clinical Cure at the One Month Follow-up (OMFU) Visit for the Intent-to-Treat (ITT) Population. | Measures of clinical cure and clinical failure are the same as those defined for the primary efficacy outcome measure, with one addition. At the OMFU, relapse (the return of the original infection after initial improvement) or recurrence (return of skin infection at original site after cure of original infection) of SSTI was scored as clinical failure. | OMFU visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methicillin-resistant Staphylococcus aureus (MRSA), cellulitis, abscess, children, elderly