MRSA Treatment Study Robert Daum, MD 1 MRSA Treatment Study Robert Daum, MD,CM Pediatric Infectious Disease Principal Site Investigator - U of C Three-Center

MRSA Treatment Study Robert Daum, MD

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MRSA Treatment Study

QuickTime™ and a decompressor

are needed to see this picture.Robert Daum, MD,CMPediatric Infectious Disease

Principal Site Investigator - U of CThree-Center Research Study - UCSF & UCLA

Diana Sullivan, RN, BSNClinical Research Nurse

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)


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are needed to see this picture.

Primary Null Hypotheses

1. CLINDA and TMP-SMX will have similar rates of cure in the treatment of the group of patients with cellulitis or larger abscess.

2. 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.


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Primary Objectives

1. 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.

2. 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.


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Secondary Objectives

1. 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


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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


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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


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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.


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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


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No

Hospitalization required, immunocompromised state, significant vital sign abnormalities, other exclusions?

Ineligible for studyEligible 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 treatmentRandomized 1:1

TMP-SMX

CLINDA 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

No

Yes

YesNo

YesCellulitis or Larger AbscessRandomize 1:1

N=524

Limited AbscessRandomize 1:2

N=786

Skin Infection


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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


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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.


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How to Determine Abscess Size

Locate this point on the wooden shaft

Drained abscess cavity

Plane of the skin


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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.


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Randomization

Dose 1 (Morning)

Dose 2 (Afternoon)

Dose 3 (Evening)

TMP-SMX TMP-SMX tablet or suspension

Placebo tablet or suspension

TMP-SMX tablet or

suspension

CLINDA Clindamycin tablet or

suspension

Clindamycin tablet or

suspension

Clindamycin tablet or

suspension

Placebo Placebo tablet or suspension



• 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


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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.


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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.


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• 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.

Subjects Discontinuing Study Medication before EOT


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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.


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Research Nurses Contact Information

Diana Sullivan, RN, BSN

Tracey Silverstein, RN, BSNPager: 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

Documents

MRSA Treatment Study Robert Daum, MD 1 MRSA Treatment Study Robert Daum, MD,CM Pediatric Infectious Disease Principal Site Investigator - U of C Three-Center