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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00729937
First received: August 7, 2008
Last updated: September 12, 2013
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Methicillin-Resistant S.Aureus
Drug: Cephalexin
Drug: Trimethoprim-sulfamethoxazole (TS)
Drug: Clindamycin
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Strategies Using Off-Patent Antibiotics for Methicillin-Resistant Staphylococcus Aureus ("STOP MRSA") - A Phase IIB, Multi-Center, Randomized, Double-Blind Clinical Trial

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Clinical cure at the Test-of-Cure Visit in the per protocol population. [ Time Frame: 7-14 days after the end of therapy (Days 14-21). ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Rates of change of erythema dimensions, composite clinical and microbiological cure, surgical procedures, and invasive/recurrent infections. Infections in household contacts, medication AEs, and time to normal activity and until analgesics are not used. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Enrollment: 2265
Study Start Date: March 2009
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TMP/SMX vs. Clindamycin
Subjects with an acute uncomplicated wound infection will be randomized to receive Trimethoprim/Sulfamethoxazole (TMP/SMX) (4 single strength pills, 80 mg/400 mg each, twice per day, with alternating 1 identical placebo pill, twice per day) or clindamycin (300 mg, four times per day, with 3 placebo pills on alternating doses).
Drug: Trimethoprim-sulfamethoxazole (TS)
4 single strength Trimethoprim/Sulfamethoxazole (TMP/SMX), 80 mg/400 mg each, twice per day.
Drug: Clindamycin
300 mg, four times per day.
Drug: Placebo
Placebo tablet administered orally.
Experimental: Cephalexin and TMP/SMX vs. Cephalexin
Subjects with acute uncomplicated cellulitis will be randomized to receive cephalexin (500 mg, four times per day) and Trimethoprim/Sulfamethoxazole (TMP/SMX) (4 single strength pills, 80 mg/400 mg each, twice per day) or cephalexin (500 mg, four times per day) and placebo (4 pills, twice per day).
Drug: Cephalexin
500 mg, four times per day.
Drug: Trimethoprim-sulfamethoxazole (TS)
4 single strength Trimethoprim/Sulfamethoxazole (TMP/SMX), 80 mg/400 mg each, twice per day.
Drug: Placebo
Placebo tablet administered orally.
Experimental: TMP/SMX vs. Placebo
Subjects with an acute uncomplicated cutaneous abscess will be randomized to receive either Trimethoprim/Sulfamethoxazole (TMP/SMX) (4 single strength pills, 80 mg/400 mg each, twice per day) or 4 placebo pills (twice per day).
Drug: Trimethoprim-sulfamethoxazole (TS)
4 single strength Trimethoprim/Sulfamethoxazole (TMP/SMX), 80 mg/400 mg each, twice per day.
Drug: Placebo
Placebo tablet administered orally.

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).

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00729937

Locations
United States, Arizona
Maricopa Medical Center - Emergency Medicine
Phoenix, Arizona, United States, 85008-4973
United States, California
University of California Los Angeles - Olive View Medical Center
Sylmar, California, United States, 91342-1437
United States, Maryland
Johns Hopkins University at Mount Washington - Emergency Medicine
Baltimore, Maryland, United States, 21209-3652
United States, Missouri
Truman Medical Center - Hospital Hill
Kansas City, Missouri, United States, 64108-2640
United States, Pennsylvania
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140-5103
Sponsors and Collaborators
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00729937     History of Changes
Other Study ID Numbers: 07-0040, HHSN272200700032C
Study First Received: August 7, 2008
Last Updated: September 12, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Methicillin, Staphylococcus aureus, MRSA

Additional relevant MeSH terms:
Anti-Bacterial Agents
Cephalexin
Clindamycin
Clindamycin-2-phosphate
Methicillin
Antibiotics, Antitubercular
Sulfamethoxazole
Trimethoprim
Trimethoprim-Sulfamethoxazole Combination
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Folic Acid Antagonists

ClinicalTrials.gov processed this record on April 16, 2014