Strategies Using Off-Patent Antibiotics for Methicillin Resistant S. Aureus "STOP MRSA"

Condition(s) targeted: Staphylococcal Infection

Intervention: Cephalexin (Drug); Clindamycin (Drug); Placebo (Other); Trimethoprim-sulfamethoxazole (Drug)

Phase: Phase 2/Phase 3

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

The purpose of this study is to determine the optimal outpatient treatment strategy of uncomplicated skin and soft tissue infection (SSTI) in areas of the United States where the prevalence of Community-Acquired Methicillin-Resistant Staphylococcus (S.) aureus (CA-MRSA) is high. Infection with the S. aureus bacteria that is resistant to antibiotics is a cause of SSTIs. Three oral antibiotics will be tested for off patent treatment. Patients will receive Trimethoprim/Sulfamethoxazole (TMP/SMX), placebo (substance containing no medication), clindamycin, or cephalexin or some combination of these. The study population will include 2,235 volunteers, children 13 years of age and over and adults presenting to 5 large urban Emergency Departments. Therapy for acute uncomplicated SSTIs, including abscess, infected wound, and cellulitis will start on the day of enrollment. Participants may be involved in study related procedures for about 9 weeks.

Official title: Strategies Using Off-Patent Antibiotics for Methicillin-Resistant Staphylococcus Aureus ("STOP MRSA") - A Phase IIB, Multi-Center, Randomized, Double-Blind Clinical Trial

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

Primary outcome: Number of Participants With Clinical Cure as of the Test-of-Cure (TOC) Visit in the Per Protocol Population

Secondary outcome:

Number of Participants With Clinical Cure as of the TOC Visit in the Intent to Treat Population

Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the On-therapy Visit in the Per Protocol Population

Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the On-therapy Visit in the Intent to Treat Population

Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the End-of-therapy Visit in the Per Protocol Population

Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the End-of-therapy Visit in the Intent to Treat Population

Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the TOC Visit in the Per Protocol Population

Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the TOC Visit in the Intent to Treat Population

Number of Participants by Composite Clinical Outcome at the TOC Visit in the Per Protocol Population

Number of Participants With Each Microbiological Outcome at the TOC Visit in the Per Protocol Population

Number of Participants Requiring Surgical Intervention Through the TOC Visit in the Per Protocol Population

Number of Participants Requiring Surgical Intervention Through the TOC Visit in the Intent to Treat Population

Number of Participants Requiring Surgical Intervention Through the Extended Follow-up Visit (EFV) in the Per Protocol Population

Number of Participants Requiring Surgical Intervention Through the Extended Follow-up Visit (EFV) in the Intent to Treat Population

Number of Participants With Development of an Invasive Infection Through the TOC Visit in the Per Protocol Population

Number of Participants With Development of an Invasive Infection Through the TOC Visit in the Intent to Treat Population

Number of Participants With Development of an Invasive Infection Through the EFV Visit in the Per Protocol Population

Number of Participants With Development of an Invasive Infection Through the EFV Visit in the Intent to Treat Population

Number of Participants Who Developed a Recurrent Infection at the Original Infection Site Through the TOC Visit in the Per Protocol Population

Number of Participants Who Developed a Recurrent Infection at the Original Infection Site Through the TOC Visit in the Intent to Treat Population

Number of Participants Who Developed a Recurrent Infection at the Original Infection Site Through the EFV Visit in the Per Protocol Population

Number of Participants Who Developed a Recurrent Infection at the Original Infection Site Through the EFV Visit in the Intent to Treat Population

Number of Participants With Infections in Household Contacts Through the TOC Visit in the Per Protocol Population

Number of Participants With Infections in Household Contacts Through the TOC Visit in the Intent to Treat Population

Number of Participants With Infections in Household Contacts Through the EFV Visit in the Per Protocol Population

Number of Participants With Infections in Household Contacts Through the EFV Visit in the Intent to Treat Population

Number of Participants With Adverse Events Considered Associated With the Study Product by MedDRA System Organ Class

Mean Days Missed From Normal Activities in the Per Protocol Population

Mean Days Missed From Normal Activities in the Intent to Treat Population

Number of Participants Reporting 1-14 Days of Analgesic Use in the Per Protocol Population

Number of Participants Reporting 1-14 Days of Analgesic Use in the Intent to Treat Population

Detailed description: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged as a cause of skin and soft-tissue infection (SSTI). In the current era of increasing CA-MRSA infections, the outpatient management of SSTIs has not been well studied. This will be a clinical trial to evaluate oral off-patent antibiotics for outpatient treatment of patients with any of the 3 main types of acute uncomplicated SSTI, i. e., abscesses, infected wounds, and cellulitis. Upon enrollment, subjects will be stratified by type of infection, and then randomized to various treatments. Subjects with an acute uncomplicated cutaneous abscess receiving incision and drainage (I&D) will be treated with Trimethoprim/Sulfamethoxazole (TMP/SMX) or placebo to determine whether the addition of an antibiotic with activity against CA-MRSA is more clinically efficacious than I&D alone. Subjects with an acute wound infection will be treated with TMP/SMX or clindamycin to determine if clindamycin, an antibiotic with activity against CA-MRSA, methicillin-susceptible Staphylococcus aureus (MSSA), and streptococci is more clinically efficacious than TMP/SMX, an antibiotic with activity against CA-MRSA and MSSA. Subjects with acute cellulitis will be treated with cephalexin/TMP/SMX or cephalexin/placebo to determine if cephalexin/TMP/SMX is more clinically efficacious than cephalexin alone. The primary objectives for each type of SSTI studied are to compare the cure rates in the per protocol (PP) population. Secondary objectives provide additional means of assessment for the clinical efficacy of the employed interventions and resolution of the infection and include describing microbiological cure, change in the dimension of erythema, composite cure, surgical procedures, invasive and recurrent infections, infections in household contacts, and time to normal activity and until analgesics are no longer used at various times in the PP/ modified intent-to-treat (mITT) populations. This is a multi-center, randomized, double-blind clinical trial in which subjects will be stratified by the type of infection and then randomized to various 7-day oral antibiotic treatments, including placebo-controlled and comparative designs. The study population will include children 13 years of age and over and adults, who weigh greater than or equal to 40 kg presenting to 5 large urban emergency departments. Therapy will start on the day of enrollment. Subjects will be evaluated upon enrollment, at 2-3 days after enrollment (OTV), at 1-3 days after the end-of-therapy (EOT), at 7-14 days after the end-of-therapy (TOC), and at 6-8 weeks after the end-of-therapy (EFV).

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Adult or child 13 years of age and older (who weighs greater than or equal to 40 kg);

- Have a skin and soft tissue infection (SSTI) with all three local findings of

erythema (> 2 cm across the lesion or from a discrete wound edge), tenderness, and swelling/induration. Fever, leukocytosis, and lymphangitis will be noted, but are not enrollment criteria. SSTI with these local findings will be further categorized and defined as one of:

1. Abscess - a fluctuant and/or indurated lesion, or findings of a fluid-filled

cavity on soft tissue ultrasound evaluation that, when opened reveals purulent material, receiving incision and drainage (I&D) (considered standard care for abscess) and having a minimum diameter (along any axis) of at least 2 cm (measured from the borders of induration, if a fluctuant lesion, or borders of the abscess cavity on ultrasound, if not fluctuant). Note: Although I&D of an abscess is considered standard care (i. e., patients will receive I&D whether or not they are enrolled in the study), the procedure may be performed after enrollment into the study so that prior measurements of the area of erythema and swelling/induration can be obtained unless it is an occult abscess in which the I&D will be performed prior to enrollment to verify infection type and ensure correct classification of the subject.

2. Infected Wound - a wound (defined as any apparent break in the skin) with any

apparent drainage limited in depth to only involving skin and subcutaneous tissue, including sutured cutaneous wounds not involving intra-abdominal surgeries contaminated with bacterial or bowel contents (e. g., colon surgery and empyema drainage), and

3. Cellulitis - an area of erythema without the presence of a wound with drainage

or abscess; Cellulitis associated with an abscess will be categorized as an abscess. Cellulitis associated with an infected wound will be classified as an infected wound. Patients with cellulitis and an abscess less than 2 cm will be excluded. Infected wound associated with an abscess that may require I&D, will be classified as an infected wound.

- Have the infected lesion for 7 days or less duration;

- Are to receive outpatient treatment at enrollment/baseline;

- Express willingness and ability to be contacted and return for re-evaluation

according to the study protocol;

- Provide written informed consent (and for subjects ages 13-17, consent from their

guardian and assent);

- Negative pregnancy test for subjects who are women of childbearing potential.

Exclusion Criteria:

- Severe allergy or reaction to study drug or drugs similar to the study drug relevant

to whichever study sub-trial the subject would be assigned to (e. g., patients with severe or life-threatening penicillin allergies, allergy to any cephalosporin, clindamycin, or sulfonamides, or any other drug containing sulfur such as thiazides, furosemide, and oral sulfonylureas);

- Concomitant treatment (i. e., while on study drug therapy) with coumadin, phenytoin,

or methotrexate, or suspected G-6-PD or folic acid deficiency;

- Expected inability to swallow or absorb the study drug (assessed by patient history);

- Pregnancy, nursing, or expectation of becoming pregnant while on study drug;

- Perirectal (within 5 cm of anus), perineal non-skin lesions (i. e., mucosal), or

paronychial location of infection. Scrotal and labial abscesses will not be excluded.

- An infection due to a mammalian bite;

- Treatment with a study drug relevant to their infection type, or another systemic

antibiotic in the previous 48 hours (i. e., before screening/baseline) unless associated with treatment failure which is defined as a patient who has been on prior (non study drug) antibiotics for at least 72 hours and failed.

- Expected concurrent treatment with a topical antibiotic or another systemic

antibiotic up to Test-of-Cure Visit (TOC) (note: if patient was using a topical antibiotic previously, they can still be enrolled if they agree to stop using it);

- Immunodeficiency [e. g., absolute neutrophil count <500/mm^3, chronic

immunosuppressive drugs, active chemotherapy, or known acquired immunodeficiency syndrome (AIDS) (CD4 count <200 or AIDS-defining illness within the last year) assessed by patient history]. Note: patients who had prior AIDS-defining illness or CD4 count <200 in the past may be enrolled if most recent CD4 count >200;

- Burn or active chronic skin condition (e. g., including rash or eczema) related to the

skin and soft-tissue infection (SSTI) at screening/baseline;

- Infection related to currently indwelling device (e. g., intravenous line), excepting

sutures associated with qualifying infected wounds which will be removed upon enrollment;

- Infection for which prior cultures reveal in vitro resistance of a pathogen to a

study drug in the previous month prior to screening/baseline;

- Known or suspected osteomyelitis or septic arthritis;

- Infection related to diabetic foot, decubitus, or ischemic ulcer;

- Known severe renal insufficiency (creatinine clearance < 50 mL/min) calculated by

measurement of serum creatinine if patient provides this history or based on past studies at baseline/enrollment;

- Prior enrollment in this study within 12 weeks;

- Another active infection of another organ system (e. g., pneumonia) or more than one

active (i. e., currently on antibiotic treatment and/or requiring I&D) SSTI site (e. g., a site noncontiguous with the infection under study). Note: Minor folliculitis at secondary site is not an exclusion;

- Presence of an abscess that has completely drained, either spontaneously or by a

healthcare provider prior to enrollment;

- An infected wound or cellulitis that has been surgically explored (>1 cm incision)

and does not reveal an abscess. Cellulitis that has been needled, minimally incised (less than or equal to 1 cm) or punch biopsied and no purulent drainage found can still be enrolled;

- Currently incarcerated in a detention facility or in police custody (note: patients

wearing a monitoring device can be enrolled) at baseline/screening;

- For patients with an infected wound, history of C. difficile infection,

pseudomembranous colitis, or active diarrhea at baseline/screening;

- For patients with an infected wound, severe liver disease based on patient history;

- An intravenous (IV) drug user in the last month with current presence of fever;

- Current residence in a nursing home or other long term care facility at

baseline/screening;

- Expected use of other investigational drug or vaccine while on study drug;

- For patients with an abscess, cardiac conditions associated with the highest risk of

adverse outcome from endocarditis for which prophylaxis is reasonable, including patients with prosthetic cardiac valve or prosthetic material used for cardiac valve repair, history of previous infective endocarditis, congenital heart disease (excluding mitral valve prolapse), and history of cardiac transplantation recipients who develop cardiac valvulopathy;

- Presence of an organic foreign body, e. g., wood (note: subjects with embedded

non-organic materials, e. g., metal or glass, that can be completely removed can still be enrolled if physician is certain there is no foreign body left).

Maricopa Medical Center - Emergency Medicine, Phoenix, Arizona 85008-4973, United States

University of California Los Angeles - Olive View Medical Center, Sylmar, California 91342-1437, United States

Johns Hopkins University at Mount Washington - Emergency Medicine, Baltimore, Maryland 21209-3652, United States

Truman Medical Center - Hospital Hill, Kansas City, Missouri 64108-2640, United States

Temple University Hospital, Philadelphia, Pennsylvania 19140-5103, United States

Starting date: April 2009
Last updated: January 29, 2015