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

Official Title: “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”

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.

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. The primary efficacy endpoint for the trial is clinical cure, which is the absence of clinical failure. The secondary objectives are: to estimate the cure rates of CLINDA and of TMP-SMX, and their difference, for limited abscess, cellulitis, or larger abscess: at the End of Treatment (EOT) visit, one month follow-up (OMFU) visit, in children and adults at the TOC visit; and for children versus adults at the TOC visit; to compare rates of adverse events and of adverse events that are treatment limiting between CLINDA and TMP-SMX for limited abscess, cellulitis, or larger abscess: at the TOC visit, EOT visit, and for children and adults separately at the TOC visit; and to estimate rates of adverse events and of adverse events that are treatment limiting for CLINDA and for TMP-SMX for limited abscess, cellulitis, or larger abscess for children, for adults, and the difference between children and adults. Secondary efficacy endpoints are: clinical cure at the EOT visit and clinical cure at the OMFU visit. Study duration will be for 3 years with subject participation duration equal to 6 weeks.

Intervention(s) in this Clinical Trial

• Drug: Clindamycin
  • 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.
• Drug: Placebo
  • Placebo capsules will be identical in appearance to the CLINDA and TMP-SMX. Administered for 10 days.
• Drug: Trimethoprim-sulfamethoxazole (TS)
  • 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.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Limited Abscess
  • Limited abscess (i.e., less than or equal to 5 cm in diameter (or proportionately smaller in size in children depending on age) will be randomized to receive a) TMP-SMX or b) CLINDA or c) placebo.
• Experimental: Cellulitis or Larger Abscess
  • Subjects with cellulitis or abscess greater than 5 cm in diameter (or proportionately smaller size in children depending on age), or with 2 or more sites of skin infection will be randomized to receive a) TMP-SMX or b) CLINDA.

Primary Measures

• Clinical cure, defined as absence of clinical failure.
  • Time Frame: 24-48 hours after enrollment; end of therapy (48 hours after completion of therapy); test of cure (7-10 days after completion of therapy); 1 month follow up.
    Safety Issue?: Yes

Secondary Measures

• Safety outcomes: adverse events; and adverse events that are treatment limiting.
  • Time Frame: 24-48 hours after enrollment; end of therapy (48 hours after completion of therapy); test of cure (7-10 days after completion of therapy); 1 month follow up.
    Safety Issue?: Yes
• Efficacy outcome: clinical cure.
  • Time Frame: Within 48 hours of completion of therapy; 1 month follow up.
    Safety Issue?: No

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:
• 1. Erythema
• 2. Swelling or induration
• 3. Local warmth
• 4. Purulent drainage
• 5. 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:
• 1. Impetigo
• 2. Ecthyma
• 3. Folliculitis
• 4. 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:
• 1. Age 6 - 11 months: < 70 mm Hg
• 2. Age 1 to 8 years: < 80 mm Hg
• 3. Age 9 to 17 years: < 90 mm Hg
• 4. 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:
• 1. Age 6 - 11 months: > 140 BPM
• 2. Age 1 to 8 years: > 120 BPM
• 3. Age 9 to 17 years: > 120 BPM
• 4. 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:
• 1. Age 6 - 11 months: > 38.0 degrees Celsius (100.4 degrees Fahrenheit)
• 2. Age 1 to 8 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit)
• 3. Age 9 to 17 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit)
• 4. 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:
• 1. Periauricular or orbital infection
• 2. Perirectal infection
• 3. Suspected deep space infection of the hand or foot
• 4. Genital infection
• 5. Mastitis
• 6. 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:
• 1. Catheter or catheter site infection within 30 days of placement
• 2. Surgical site infection
• 3. Known or suspected prosthetic device infection
• 4. Suspected Gram-negative or anaerobic pathogen
• 5. Unusual exposure history (e.g., underwater injury, fish-tank exposure, heavy soil exposure, etc)
• 6. 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:
• 1. Diabetes mellitus
• 2. Chronic renal failure, creatinine clearance <30 ml/min
• 3. Renal dialysis within the past 180 days
• 4. 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
• 5. Organ or bone marrow transplantation (ever), immunosuppressive therapy within the past 180 days, severe liver disease
• 6. Other serious underlying disease, as determined by the treating physician or the investigator

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Months

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: National Institute of Allergy and Infectious Diseases (NIAID) NIH

Overall Clinical Trial Officials and Contacts

Overall Contact: Henry Forrest Chambers (415) 206-5437 hchambers@medsfgh.ucsf.edu

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00730028

Study ID Number: 07-0051

ClinicalTrials.gov Identifier: NCT00730028

Health Authority: United States: Federal Government