MRSA Treatment Study Robert Daum, MD,CM Diana Sullivan, RN, BSN Randomized, Double-Blind Trial of Clindamycin, Trimethoprim-Sulfamethoxazole, or Placebo for Uncomplicated Skin and Soft Tissue Infections (uSSTIs) Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) Robert Daum, MD,CM Pediatric Infectious Disease Principal Site Investigator - U of C Three-Center Research Study - UCSF & UCLA Diana Sullivan, RN, BSN Clinical Research Nurse MRSA Treatment Study Robert Daum, MD

Primary Null Hypotheses CLINDA and TMP-SMX will have similar rates of cure in the treatment of the group of patients with cellulitis or larger abscess. After successful surgical drainage, placebo will have a rate of cure similar to that of CLINDA and TMP-SMX in the treatment of the group of patients with limited abscess. MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD Primary Objectives 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. To compare the cure rate of CLINDA, TMP-SMX, and placebo, each in conjunction with surgical drainage for the treatment of patients with limited abscess at the TOC visit. MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD Secondary Objectives To estimate the cure rates of CLINDA and of TMP-SMX, and their difference, for limited abscess, cellulitis, or larger abscess End of treatment and one-month follow-up Children and adults 2. To compare rates of adverse events and of adverse events that are treatment limiting MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD uSSTIs for Enrollment Cellulitis (erysipelas) Abscess (furuncle) + cellulitis Other wounds with cellulitis or abscess (see next slide for exclusion criteria) uSSTI must be evidenced by at least two of the following localized signs or symptoms on the skin for at least 24 hours Erythema Swelling or induration Local warmth Purulent drainage Tenderness or pain upon palpation MRSA Treatment Study Robert Daum, MD

uSSTIs NOT for Enrollment Impetigo or ecthyma Folliculitis Simple boil Other No surgical or catheter sites No immunocompromised host (cancer, diabetes, CRF, HIV+ with CD4 count <200 or <4% in past 180 days, h/o organ transplant or BMT) Third trimester pregnancy Hospitalized (now or within last 14D) Residence of a skilled nursing facility Unstable psychiatric condition ETOH or other drug abuse Concomitant meds: warfarin, phenytoin, methotrexate MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD Treatment Assignment Subjects satisfying simple inclusion criteria will be referred to the study by the Emergency Room physician Research Nurse will obtain informed consent and a child (>7 yrs) assent form RN will perform screening history and physical for CRF’s RN will review full inclusion/exclusion criteria with the subject to confirm eligibility RN will enroll subject into EMMES (online system) Subjects consenting to enrollment, but are found ineligible by exclusion criteria are considered screen failures and removed from the study. MRSA Treatment Study Robert Daum, MD

Stratification Based on Abscess Size Stratify to CLINDA vs TMP-SMX randomization if: No abscess, cellulitis only Two (2) or more sites of skin infection, regardless of type or size Abscess size > 5 cm Abscess size > 4 cm and subject age 1 to 8 years Abscess size > 3 cm and subject age 6 -11 months Stratify to CLINDA vs TMP-SMX vs Placebo randomization if : Abscess size < 5 cm and subject age > 9 years Abscess size < 4 cm and subject age 1 to 8 years Abscess size < 3 cm and subject age 6 -11 months MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD No Hospitalization required, immunocompromised state, significant vital sign abnormalities, other exclusions? Ineligible for study Eligible for study Presence of an abscess? Incision and drainage performed Abscess > 5 cm (lesser size in children depending on age) or 2 sites of infection Placebo CLINDA Antibiotic treatment Randomized 1:1 TMP-SMX Surgical drainage not performed or surgical drainage performed but no purulent material present (i.e., cellulitis without abscess) or cellulitis with non-purulent drainage Yes Cellulitis or Larger Abscess Randomize 1:1 N=524 Limited Abscess Randomize 1:2 N=786 Skin Infection MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD Incision and Drainage The treating physician will evaluate the wound and determine if incision and drainage will be performed as a standard of care procedure. However, the drainage procedure must be completed after RN obtains informed consent and before randomization in order to collect drainage for culture and stratify subjects appropriately MRSA Treatment Study Robert Daum, MD

Incision and Drainage Either surgical incision and drainage OR Drainage by aspiration is acceptable If drainage of the abscess is determined to be inadequate, e.g., there is evidence of deeper infection requiring specialized treatment or hospitalization, the subject will be removed from the study. MRSA Treatment Study Robert Daum, MD

How to Determine Abscess Size Locate this point on the wooden shaft Drained abscess cavity Plane of the skin MRSA Treatment Study Robert Daum, MD

Determination of Abscess Size Purpose: The long axis measurement of the abscess cavity will be used to stratify patients into one of two treatment groups. Procedure Prior to skin prep mark ends of the longest and shortest axis of the area of erythema Collect abscess fluid for culture After I&D probe abscess cavity from its approximate center to the outer edge Locate the radius of this longest axis by placing the thumb along the wooden shaft of the swab at the best estimate of the center of the abscess Break or cut the swab at the point located with the thumb along the swab shaft Measure the length in cm (to the nearest 0.1 cm) of the shaft fragment upon which the cotton swab is present. Multiply this length by 2. This is the abscess size. Record this value in the source document. Measure the longest and shortest axes of the area of erythema surrounding the abscess cavity. Record these results in the source document. MRSA Treatment Study Robert Daum, MD

Randomization Enrollment will be done online using the enrollment module of The EMMES Corporation’s Internet Data Entry System (IDES). There will be six randomization schedules at each site Dose 1 (Morning) Dose 2 (Afternoon) Dose 3 (Evening) TMP-SMX TMP-SMX tablet or suspension Placebo tablet or suspension CLINDA Clindamycin tablet or suspension Placebo MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD Laboratory Studies Microbiological Studies All baseline abscesses will be sent for gram stain and culture Nonsuppurative lesions will also be swabbed and sent for gram stain and culture During any follow-up visits (EOT, OMFU), if there is a lesion it will be swabbed and sent for gram stain and culture. Other Clinical Laboratory Studies These will not be routinely performed, but may be obtained at the discretion of the primary physician or study physician. MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD Adverse Events (AE) An adverse event (AE) is defined as any unfavorable or undesirable effect (sign, symptom, laboratory abnormality, or condition), regardless of causal relationship to study procedures or participation that occurs in a subject while enrolled in this clinical trial. Any medical condition that is present at screening is baseline and only reported as an AE if condition deteriorates. Serious adverse events (SAE’s) are reported to PI, IRB and appropriate outside agencies for follow-up There are two Internal Safety Monitors (ISM) that are available 24/7 to evaluate SAE’s and start the “unblinding process”, if neccesary. The ISM will contact the patient’s primary care physician for further evaluation and treatment. The patient will be discontinued from the study. MRSA Treatment Study Robert Daum, MD

Subjects Discontinuing Study Medication before EOT Will be evaluated for clinical cure or failure. If additional antimicrobial therapy is required, subjects will complete evaluations outlined in Termination of Study Protocol (TOSP) visit. Subjects who will undergo TOSP visit: Those requiring hospitalization Subjects withdrawing themselves from the protocol A site investigator withdrawing the subject from the protocol Subjects deemed clinical failures prior to EOT Subjects requiring additional therapy will be referred to a primary physician for treatment. MRSA Treatment Study Robert Daum, MD

Summary The MRSA treatment study is funded by the National Institutes of Health (NIH) and will be ongoing for 3 years. Our goal is to enroll 175 adults and 200 children at U of C, a total of 1300 from all three sites. CA-MRSA is emerging across the globe, infecting otherwise healthy individuals. There is little consensus on how the infections should be treated. Even though Clindamycin and Bactrim are widely used for uSSTI’s, they are not FDA approved for CA-MRSA. The outcome of this clinical trial will directly influence treatment of uSSTI’s in the future. MRSA Treatment Study Robert Daum, MD

A physician or Nurse will be on call 24/7 in case of adverse events Research Nurses Contact Information Diana Sullivan, RN, BSN Tracey Silverstein, RN, BSN Pager: 188-7234 1-877-MRSA-CENTER (call 24/7) RN will work primarily a 12 hour Day shift schedule (830am-830pm) Monday through Friday A physician or Nurse will be on call 24/7 in case of adverse events MRSA Treatment Study Robert Daum, MD

MRSA Treatment Study Robert Daum, MD