Antibiotic Tumescent For Chronic Wounds

Official title

A Phase 2 Randomized Study Comparing Subcutaneous Tumescent Antibiotic Administration With Standard of Care for the Treatment of Chronic Wounds

Overview

Chronic non-healing wounds are becoming an increasingly more common problem. Eligible, consenting patients with chronic wounds in the lower extremities, upper extremities or trunk, will either continue to the standard of care or will be randomized to the treatment cohort where antibiotic solution will be injected in the area around the wound. All patients will continue standard wound care as dictated by the wound care clinic. Subjects of both the control and treatment will have approximately 6 study specific visits that may or may not coincide with previously schedule wound care clinic visits. As these specified visits wound size and healing will be documented and patients will complete surveys. The study will conclude for the subject after approximately 6 months. Again, these patients may continue standard wound care but will no longer have study obligations.

Detailed description

Foot ulcers develop in 9.1-26 million people with diabetes annually worldwide. Up to 1% of people in industrialized countries will suffer from a leg ulcer. Numbers of pressure and venous ulcers are rising at rates of 6-7% annually, diabetic ulcers rising at 9%. In the United States, chronic wounds affect 6.5 million patients and over $25 billion dollars are spent annually on chronic wound care. Medicare spending on pressure and arterial ulcers in 2014 was $3696 and $9015 per patient. Diabetic limb complications are more costly than breast cancer.

Attempts to treat chronic wounds have included 1) debridement, 2) specialized dressings, 3) compression bandages, 4) negative pressure devices, 5) topical growth factors and pharmaceuticals, 6) skin grafts and skin substitutes, 7) hyperbaric oxygen therapy and 8) amputation. There is no study that examines the utility of tumescent antibiotic injections (TAI) into a wound. TAI is a relatively simple, cost-effective procedure using known, drugs with a well characterized safety profile, and used in a new way to address this large unmet need.

Our group has published work in this area showing appropriate design, feasibility and safety in a large animal model. The investigators have shown that direct antibiotic delivery through tumescent injections can achieve high antibiotic concentrations directly in skin and soft tissue for sufficient time to kill bacteria. Simultaneously, total antibiotic doses can be kept low, minimizing systemic toxicity. In particular, even antibiotic resistant strains of pathogenic microorganisms may be susceptible due to the high local concentration of antimicrobial agent. Tumescent injections can more effectively deliver antibiotic to compromised body regions with impaired circulation compared to intramuscular or intravenous drug delivery.

Primary Objective

1\. To assess the safety of tumescent antibiotic injections.

Secondary Objectives

1. To evaluate wound size or closure. 2. To evaluate chronic-wound-related pain. 3. To evaluate Quality of Life.

Exploratory Objectives

1. Assess the number of chronic wound-related complications (increased wound sizes, infections, dermatitis). 2. Assess the number of clinical signs of infection in participants. 3. Determine the species of pathogenic bacteria present in wound.

Screening: up to 1 week. Treatment: TAI will take 1 day. Standard wound care will be ongoing until the wound closes, as it would in a wound care center.

Follow-up:

Once weekly (+/-1 week) for 2 weeks, followed by Biweekly (+/-1week) for 4 more weeks. There will also be a 3 month (+/- 2 weeks) and 6 month (+/- 4 weeks) follow up visits. Total duration of participant participation is up to approximately 1 year. Total duration of the study for recruitment and completion of visits is expected to be up to two years.

Interventions

• Drug CeFAZolin Injectable Solution
  One gram Cefazolin reconstituted in 100 mL 0.9% Sodium Chloride (normal saline)

Primary outcome measures

• Primary Objective - Assess the rate of occurrence and severity of adverse events and their relationship to TAI [Time frame: From enrollment through 6 month visit.]

Secondary outcome measures (3)

• Secondary Objective - To evaluate wound size and closure. [Time frame: From enrollment through 6 month visit or until wound is closed.]
• Secondary Objective - Chronic-wound-related pain [Time frame: From enrollment through 6 month visit.]
• Secondary Objective - Rating Quality of life [Time frame: From enrollment through 6 month visit.]

Eligibility criteria

Inclusion criteria

• Male or female ≥18 years of age.
• Must have:

• One or more full thickness ulcers on the lower extremity, upper extremity (excluding the hands) or trunk with a surface area exceeding 0.5 cm\^2 (50 mm\^2) and less than 30 cm\^2 (6\*5 cm) after debridement (full thickness means extending through the epidermis and dermis but not involving tendon, bone or joint capsule).
• Presence of a chronic wound (including venous ulcer, arterial ulcer, below knee pressure ulcer, diabetic foot ulcer, ischemic ulcer) that has existed for >4 weeks at Visit 1.
• Documentation that the wound has been treated at least 2 times at the wound care center.
• Documentation that the wound area has not decreased by more than 50% in 4 weeks.
• Willing to provide written informed consent (and assent when applicable) obtained from participant or participant's legal representative and ability for participant to comply with the requirements of the study.
• Adequate perfusion as demonstrated by TcPO2≥40 mm Hg, ABI ≥ 0.7, or great toe pressure≥50 mm Hg, or palpable pulses of the lower extremity such as dorsalis pedis and/or posterior tibial artery or palpable radial artery in the upper extremity.
• In the opinion of the investigator, participants must be considered reliable, willing, and able to give signed informed consent in English and sign the informed consent form.
• For participants of reproductive potential, two of the following forms of contraception are required between visits 1-4 (total of 3-6 weeks), one of which must be a barrier method:

• Condoms (male or female) with or without a spermicidal agent
• Diaphragm or cervical cap with spermicide
• Intrauterine device (IUD)
• Tubal ligation
• Hormone-based contraceptive such as oral birth control pills

Exclusion criteria

• Participants with limb threatening infection, extensive cellulitis (≥2 cm radially beyond the borders of the wound), lymphangitis, fasciitis, deep tissue infection, abscess, pus, osteomyelitis, or other evidence of local or systemic complications of infection.

• Wound size/surface area, duration, severity, or location outside of INCLUSION criteria Note: Consideration will be given to minor variation, if deemed appropriate by the medical director, and authorized.
• Clinically severe wound at high risk for amputation as determined by the Medical Director.
• All pressure ulcers except below knee pressure ulcers.
• Cellulitis or acute infection as determined by:

• Significant wound erythema, induration, warmth, presence of pus, or tenderness, determined by PI or medical director ≥ 2 cm radially from wound margin.
• Fever with electronic temp >100.4°F (>38°C)
• Following enrollment, if wound culture returns positive for Pseudomonas.
• Participants with symptoms of systemic infection or uncontrolled diabetes mellitus (e.g., severe hyperglycemia, ketoacidosis, azotemia).
• Participants who are allergic or have shown hypersensitivity to penicillin, cefazolin, other beta-lactams, the cephalosporin group of antibiotics, lidocaine, or to local anesthetics of the amide type.
• Participants requiring intravenous antimicrobials during the study period for any infection, including diabetic foot ulcer. Mild localized infection that would be treated on an outpatient basis could be approved by Medical Director authorization.
• Participants who are currently treated by dialysis, awaiting dialysis, or who have an estimated glomerular filtration rate of ≤ 30 mL/min/1.73 m\^2.
• Participants who are expected to be unable to care for their ulcer because of hospitalization, vacation, disability, etc., during the study period.
• Participants with known active alcohol or substance abuse within the 6 months preceding study entry.
• Participants who are receiving systemic corticosteroids (in a dose equivalent to ≥20 mg of prednisone per day), biologic therapy, immunosuppressants, , radiation therapy, or cytotoxic agents, unless approved by medical director authorization
• Participants who require treatment for a primary or metastatic malignancy (other than squamous or basal cell carcinoma of the skin, not involving the wound site).
• Participants with acquired immune deficiency syndrome (AIDS) or known human immunodeficiency virus (HIV) positivity.
• Participants with other conditions considered by the investigator to be reasons for disqualification that may jeopardize participant safety or interfere with the objectives of the trial (e.g., acute illness or exacerbation of chronic illness, lack of motivation, history of poor compliance).
• Women who are breastfeeding, pregnant, or attempting to become pregnant.
• Active acute medically unstable condition defined by:

• Diabetes Mellitus Type 1 or 2, with A1C greater than 9.5. Consideration to HbA1c higher than 9.5 - 10.0% after consultation with the medical director or PI.
• Unstable cardiovascular or other high-risk general medical condition making participation in the study a significant risk to the participant, per medical director determination.
• Laboratory evidence of severe metabolic, renal, hepatic, endocrine, hematologic disorder per medical director determination.
• Recent trauma complicated by significant bone, nerve, or vascular damage.
• Sickle Cell Disease.
• Participant is enrolled/participating in another study or does not agree to refrain from participating in another study while enrolled in this study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of California, Los Angeles — Los Angeles

Publications

• Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017 Jun 15;376(24):2367-2375. doi: 10.1056/NEJMra1615439. No abstract available. PMID 28614678
• O'Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev. 2012 Nov 14;11(11):CD000265. doi: 10.1002/14651858.CD000265.pub3. PMID 23152202
• Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes. Front Physiol. 2018 May 1;9:419. doi: 10.3389/fphys.2018.00419. eCollection 2018. PMID 29765329
• Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009 Nov-Dec;17(6):763-71. doi: 10.1111/j.1524-475X.2009.00543.x. PMID 19903300
• Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haught R, Nusgart M, Cartwright D. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value Health. 2018 Jan;21(1):27-32. doi: 10.1016/j.jval.2017.07.007. Epub 2017 Sep 19. PMID 29304937
• Barshes NR, Sigireddi M, Wrobel JS, Mahankali A, Robbins JM, Kougias P, Armstrong DG. The system of care for the diabetic foot: objectives, outcomes, and opportunities. Diabet Foot Ankle. 2013 Oct 10;4. doi: 10.3402/dfa.v4i0.21847. PMID 24130936
• Koulakis JP, Rouch J, Huynh N, Wu HH, Dunn JCY, Putterman S. Tumescent Injections in Subcutaneous Pig Tissue Disperse Fluids Volumetrically and Maintain Elevated Local Concentrations of Additives for Several Hours, Suggesting a Treatment for Drug Resistant Wounds. Pharm Res. 2020 Feb 10;37(3):51. doi: 10.1007/s11095-020-2769-2. PMID 32043171
• Nicolau DP, Silberg BN. Cefazolin potency against methicillin-resistant Staphylococcus aureus: a microbiologic assessment in support of a novel drug delivery system for skin and skin structure infections. Infect Drug Resist. 2017 Jul 26;10:227-230. doi: 10.2147/IDR.S134497. eCollection 2017. PMID 28794647

Identifiers

NCT: NCT06327113 · IRB#23-001248

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗