Safety and Tolerability Study of Antimicrobial TheraGauze for Skin Abscess
Condition: Furunculosis
MeSH terms: Furunculosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The goal of this study is to demonstrate safety and tolerability of a novel antimicrobial
      wound dressing, Antimicrobial TheraGauze. The unique microvillous structure of TheraGauze is
      ideal for the development of an antimicrobial wound dressing. In vitro testing has
      demonstrated that tobramycin is an ideal compound for integration into TheraGauze providing
      excellent killing of MRSA and other organisms that commonly cause wound infections.
      Tobramycin is a non-absorbable aminoglycoside that will be contained solely to the wound bed
      preventing any potential for systemic toxicities. In vivo testing of tobramycin-impregnated
      TheraGauze used in mouse wound models has confirmed no systemic absorption of tobramycin as
      demonstrated by undetectable blood levels. TheraGauze has been commercially available for 10
      years as a wound dressing. Tobramycin has been available for many years as a topical
      antibiotic as eyedrops and as an inhaled antibiotic for patients with cystic fibrosis,
      demonstrating excellent safety in both cases.

      This Phase I trial will test Antimicrobial TheraGauze (ATG) as an antimicrobial wound packing
      for patients presenting to an Emergency Department with skin abscess (furunculosis). Subjects
      will either receive ATG or standard of care wound packing (cotton wick or iodoform wick).
      Subjects will return to the ED in 2 days for wound packing removal and reassessment of their
      wounds and symptomatology. A final followup will be performed by a physician and study
      coordinator in an outpatient setting on day 7.
    

Detailed description: 
      Primary Endpoint. The primary endpoint of the study is to evaluate the safety of and identify
      side effects of TheraGauze/tobramycin wound packing compared with standard of care management
      for cutaneous abscesses requiring incision and drainage.

      Methods.

      Design:

      This is a proof-of-concept, prospective, randomized clinical trial for safety of
      TheraGauze-tobramycin in adult subjects who present to Emergency Department settings for care
      of skin abscess requiring incision and drainage. A control, standard of care, arm is included
      to provide some data with respect to the side effect profile of current furunculosis
      management for comparison.

      Two arms are proposed for this study:

        1. Incision + TheraGauze+tobramycin packing (no systemic antibiotics)

        2. Incision + standard iodoform wick or plain cotton wick packing (± p.o. antibiotics)

      Anti-microbial TheraGauze (saturated tobramycin solution at 3 mg/ml) will be packed into the
      drained wounds of the subjects in the study arm. The control arm will receive current
      standard of care wound packing with a choice of iodoform wick or plain cotton wick, based on
      the preference of the ED physician. After packing, the wound excess TheraGauze or wick will
      be cut away. The ED physicians have the option to prescribe an oral antibiotic or not,
      according to their preference. The following oral antibiotic choices are available for
      subjects in the control arm only:

        -  Bactrim (TMP/SMX)

        -  Vibramycin (doxycycline)

        -  Cleocin (clindamycin) Antibiotics will be purchased by subjects from their local
           pharmacy.

      TheraGauze-tobramycin. We plan to use TheraGauze saturated with tobramycin at 3 mg/ml, the
      same dose used in the ophthalmic preparations (e.g., Tobrex) and much smaller concentration
      than the concentration in tobramycin bone cement (50 - 60 mg/ml). The decades of efficacy and
      safety with tobramycin eye drops justifies using the 3 mg/ml concentration. In vitro testing
      with TheraGauze/tobramycin (0.9 mg/ml), shows excellent broad-spectrum antibacterial activity
      against Gram-negative and Gram-positive bacterial pathogens including all clinical MRSA
      strains tested (Echague, Hair et al. 2010). We expect that >85% of the cutaneous abscesses
      (furuncles) will be infected with MRSA (Demos, McLeod et al. 2012). Additionally, tobramycin
      is a non-absorbable antibiotic and thus an excellent choice for achieving local antimicrobial
      activity with minimal risk of systemic side effects, which it is why it is the most common
      antibiotic bone cement.

      The TheraGauze/tobramycin wound packing will be placed after the incision and drainage of the
      abscess and removed at the day 3 (± 1) follow up visit in the Emergency Department.
      TheraGauze/tobramycin will only be placed in the wound a single time.

      Methods:

      Study Population:

      Subjects from the Hampton Roads region of southeastern Virginia will be recruited from the
      hospital emergency department site staffed by EVMS physicians at Sentara Norfolk General
      Hospital.

      Study Size:

      We anticipate screening 200 patients in order to enroll and randomize 100 subjects. Subjects
      will be randomized 2:1 to the TheraGauze+tobramycin or iodoform wick/ plain cotton wick,
      respectively. We anticipate 50 participants completing the study. The 50% retention rate is
      typical for emergency department populations.

      Recruitment and Retention:

      Subjects who present to Emergency Department setting for care of skin abscess requiring
      incision and drainage will be approached by on-site Study Coordinators for enrollment. Upon
      meeting eligibility criteria and willingness to participate, subjects/LARs will provide
      informed consent. A medical information release will be obtained from the subject so that
      outcomes data can be collected related to additional unscheduled visits or adverse events
      cared for outside the emergency department setting.

      Women and minority participation:

      Adults up to 65 years of age will be enrolled regardless of gender and minority status as
      long as they are fluent in English.

      Randomization:

      A study subject identification number will be assigned. Subjects will then be sequentially
      randomized to one of two treatment arms upon enrollment in a 2:1 ratio, using a prepared
      list.

      Study Treatments

      Visit 1 - Day 1:

        -  Informed consent will be obtained from subject.

        -  Review of Eligibility Criteria (Inclusion/Exclusion)

        -  Randomization to Treatment Arm

        -  Contact Information to include phone number(s), address, primary care provider will be
           collected.

        -  Treatment and discharge with instructions to return to the ED for revaluation per
           routine care. The typical schedule is for the patients to return to the ED 2 days after
           initial wound care (Study Day 3 ±1).

      The following information will be collected and recorded on a hard copy Case Report Form at
      this visit.

        -  Subject ID number

        -  Demographics

        -  Medical history

        -  Characteristics of symptoms and history

        -  Abscess characteristics

        -  Procedure information

        -  Laboratory Assessments - Per standard clinical care the abscess contents will be sent
           for routine Gram stain, bacterial culture and susceptibility testing.

        -  If patient is to receive iodoform wick/plain cotton wick then the care provider will
           have the option of prescribing a p.o. antibiotic, as is frequently done in these
           clinical settings.

      Visit 2 - Day 3 ±1: (ED)

      Subjects' wound status will be evaluated. The following information will be collected:

        -  Questions about infection

        -  Bacterial burden in wound bed - Wound culture performed using quantitative methods for
           culturing wound base (Gardner, Frantz et al. 2006).

        -  Wound assessment

        -  Schedule follow-up visit in EVMS Clinical Research Unit in 5 ± 1 days

      Visit 3 - Day 7 ± 1: (EVMS Clinical Research Unit):

      Follow up on subjects' wound status. The following information will be collected:

        -  Questions about infection

        -  Wound assessment

      Statistical Analysis Plan The data will be analyzed using SAS 9.4 software. All statistical
      tests will be two-sided with a significance level of 0.05. Patients who withdraw while on
      treatment will be included in the data analysis for each time point before withdrawal.
      Baseline and follow-up measurements of safety, tolerability, numbers of pathogenic bacteria,
      wound infection persistence or worsening, and gross effects on the rate of wound healing will
      be summarized using descriptive statistics such as mean, median, standard deviation,
      interquartile range, frequency, and percentage where appropriate. Normality assessments for
      the continuous variables will be completed using Shapiro-Wilk tests and stem-and-leaf plots.

      Tests of equivalence between the TheraGauze + tobramycin and standard iodoform wick packing
      treatment groups will establish statistical significance if the two-sided 90% confidence
      interval for the difference falls within the limits (-δ, δ), where δ is the margin of
      clinically accepted difference. This analysis will determine whether the outcomes are
      equivalent between the TheraGauze+tobramycin and standard iodoform wick packing treatment
      groups.

      Protection of Human Subjects:

      This research involves the recruitment, enrollment and management of human subjects
      participating in research. Adults up to age 65 years at enrollment are being studied because
      adults commonly suffer skin abscesses. Study oversight by the investigators will assure
      compliance with all regulatory requirements for Institutional Review Board approval prior to
      the initiation of the study, and will obtain annual re-approval for study activities.

      Potential risks and benefits to subjects and procedures to mitigate risks:

        -  Physical/Medical

           o Serious/Adverse Events - will be reported to EVMS IRB

        -  Confidentiality/PHI o All PHI will be maintained in an encrypted and password protected
           electronic file.

      ASSESSMENT OF SAFETY Subjects must be seen by a physician or an appropriately trained
      healthcare professional at every study visit, and the evaluation must be documented.

      Adverse Events. An AE is any untoward medical occurrence in a clinical investigation subject
      administered a pharmaceutical product and which does not necessarily have to have a causal
      relationship with this treatment. An AE can therefore be any unfavorable and unintended sign
      (including an abnormal laboratory finding, for example), symptom, or disease temporally
      associated with the use of a medicinal product, whether or not considered related to the
      medicinal product.

      Causality Assessment. For all AEs, the PI will provide an assessment of causal relationship
      to the study drug. Causal relationship must be assessed by answering the following question:
      Is there a reasonable possibility the study drug caused the event?

      Adverse Reaction. An AE assessed as likely having a causal relationship with the intervention
      (i.e., TheraGauze/tobramycin). Specifically focusing on local-toxicity adverse reactions, we
      will evaluate for increasing redness, increasing pain or a new rash at the site of the packed
      wound. Increasing pain or redness could be due to progression of the infection
      (cellulitis/abscess) or local toxicity or reaction to the tobramycin in the
      TheraGauze/tobramycin packing. This will be assessed by an Investigator. Increasing purulent
      drainage or the identification of new areas of fluctuance requiring an additional incision
      and drainage procedure will be assessed as progression of the infection rather than evidence
      of local toxicity or reaction to the tobramycin.

      Severity Assessment. The PI must provide an assessment of the severity of each AE by
      recording a severity rating, which will be assessed as described below. Severity, which is a
      description of the intensity of manifestation of the AE, is distinct from seriousness, which
      implies a subject outcome or AE-required treatment measure associated with a threat to life
      or functionality.

      Guidelines for Adverse Event Severity Assessments Mild. Minor awareness of signs or symptoms
      that are easily tolerated without specific medical intervention. Moderate. Discomfort that
      interferes with usual activities and may require minimal intervention.

      Severe. Significant signs or symptoms that are incapacitating with an inability to work or
      perform routine activities and/or that require medical intervention.

      Serious Adverse Events. An SAE is any untoward medical occurrence that at any dose: is life
      threatening, requires in-patient hospitalization or prolongation of existing hospitalization,
      results in persistent or significant disability/incapacity. Important medical events may be
      considered serious when, based on appropriate medical judgment, they may jeopardize the
      subject and may require medical or surgical intervention to prevent one of the outcomes
      listed in this definition. If a serious and unexpected AE occurs for which there is evidence
      suggesting a causal relationship between the drug and the event the event must be reported as
      a serious and unexpected suspected adverse reaction. SAE will be reported to the local IRB
      and the FDA within 5 calendar days.

      Stopping Rules. Adverse reactions, including local-toxicity adverse reactions, or SAEs will
      lead to immediate return to the SNGH ED for assessment and removal of the
      TheraGauze/tobramycin wound packing. The investigator will assess the need for treatment of
      the adverse reaction or SAE and, if necessary, either treat or refer for treatment, as
      appropriate. The subject will continue with their scheduled follow up: Day 3 visit in the ED,
      Day 6 phone follow up, and Day7 visit in the EVMS Clinical Research Unit.
    

Intervention name(s): Antimicrobial TheraGauze
Intervention type(s): Biological
Intervention description(s): In the intervention arm: Antimicrobial TheraGauze, tobramycin impregnated TheraGauze, will be used to pack the wound cavity after incision and drainage of the skin abscess.
In the comparator arm: Standard wound packing, plain cotton wick or iodoform gauze - at the discretion of the provider will be used to pack the wound cavity after incision and drainage of the skin abscess.
Intervention MeSH terms: Anti-Infective Agents; Anti-Bacterial Agents
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment