Antibiotic Tumescent For Chronic Wounds

Non-healing Wound Clinical Trial

— TAI  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06327113
• Other study ID #: IRB#23-001248
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 25, 2024
• Est. completion date: March 25, 2028

Study information

• Verified date: March 2024
• Source: University of California, Los Angeles
• Contact: Andrew Vardanian, MD
• Phone: 310-825-8927
• Email: avardanian[@]mednet.ucla.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Chronic non-healing wounds are becoming an increasingly more common problem. Eligible, consenting patients with chronic leg wounds 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.

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 TAI. Secondary Objectives 1. To evaluate wound size or closure. 2. To evaluate chronic-wound-related pain. 3. To evaluate Quality of Life (QoL). 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: March 25, 2028
• Est. primary completion date: March 25, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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

1. One or more full thickness ulcers on the lower extremity with a surface area exceeding 0.5 cm^2 (50 mm^2) and less than 10 cm^2 after debridement (full thickness means extending through the epidermis and dermis but not involving tendon, bone or joint capsule).

2. Presence of a chronic wound (including venous ulcer, arterial ulcer, pressure ulcer, diabetic foot ulcer, ischemic ulcer) that has existed for >4 weeks at Visit 1.

3. Documentation that the wound has been treated at least 2 times at the wound care center.

4. Documentation that the wound area has not decreased by more than 50% in 4 weeks.

5. 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.
• 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:

1. Condoms (male or female) with or without a spermicidal agent

2. Diaphragm or cervical cap with spermicide

3. Intrauterine device (IUD)

4. Tubal ligation

5. 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.

1. 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.

2. Clinically severe wound at high risk for amputation as determined by the Medical Director.

• Cellulitis or acute infection as determined by:

1. Significant wound erythema, induration, warmth, presence of pus, or tenderness, determined by PI or medical director = 2 cm radially from wound margin.

2. 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:

1. 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.

2. Unstable cardiovascular or other high-risk general medical condition making participation in the study a significant risk to the participant, per medical director determination.

3. Laboratory evidence of severe metabolic, renal, hepatic, endocrine, hematologic disorder per medical director determination.

4. Recent trauma complicated by significant bone, nerve, or vascular damage.

5. 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.

Related Conditions & MeSH terms

• Non-healing Wound
• Wounds and Injuries

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of California, Los Angeles

References & Publications (15)

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. — View Citation

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. — View Citation

Boeni R. Safety of tumescent liposuction under local anesthesia in a series of 4,380 patients. Dermatology. 2011;222(3):278-81. doi: 10.1159/000327375. Epub 2011 May 24. — View Citation

Coerper S, Beckert S, Kuper MA, Jekov M, Konigsrainer A. Fifty percent area reduction after 4 weeks of treatment is a reliable indicator for healing--analysis of a single-center cohort of 704 diabetic patients. J Diabetes Complications. 2009 Jan-Feb;23(1):49-53. doi: 10.1016/j.jdiacomp.2008.02.001. Epub 2008 Apr 3. — View Citation

Durand BARN, Pouget C, Magnan C, Molle V, Lavigne JP, Dunyach-Remy C. Bacterial Interactions in the Context of Chronic Wound Biofilm: A Review. Microorganisms. 2022 Jul 25;10(8):1500. doi: 10.3390/microorganisms10081500. — View Citation

Harb G, Lebel F, Battikha J, Thackara JW. Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaluronidase (rHuPH20) versus intravenous ceftriaxone administration in adult volunteers. Curr Med Res Opin. 2010 Feb;26(2):279-88. doi: 10.1185/03007990903432900. — View Citation

Kim H, Park H, Lee SJ. Effective method for drug injection into subcutaneous tissue. Sci Rep. 2017 Aug 29;7(1):9613. doi: 10.1038/s41598-017-10110-w. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: Infect Drug Resist. 2017 Aug 16;10 :247. — View Citation

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. — View Citation

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. — View Citation

Okuma K, Iwakawa K, Turnidge JD, Grubb WB, Bell JM, O'Brien FG, Coombs GW, Pearman JW, Tenover FC, Kapi M, Tiensasitorn C, Ito T, Hiramatsu K. Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community. J Clin Microbiol. 2002 Nov;40(11):4289-94. doi: 10.1128/JCM.40.11.4289-4294.2002. — View Citation

Scali C, Kunimoto B. An update on chronic wounds and the role of biofilms. J Cutan Med Surg. 2013 Nov-Dec;17(6):371-6. doi: 10.2310/7750.2013.12129. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Objectives - Assess the number of chronic wound-related complications (increased wound sizes, infections, dermatitis).	Record the number and severity of chronic-wound-related complications.; difference in wound size,; incidence and degree of infection; occurrence of dermatitis.; Difference in wound quality via visual inspection (granulation tissue, tissue necrosis, exudate, drainage).	From enrollment through 6 month visit.
Other	Exploratory Objectives - Assess the number of clinical signs of infection in participants.	Record number and severity of clinical signs of infection.; cellulitis via visual inspection and exam,; pus via visual inspection and exam,; fever via visual inspection and exam,; abscess via visual inspection and exam.	From enrollment through 6 month visit.
Other	Exploratory Objectives - Determine the species of pathogenic bacteria present in wound.	Species of pathogenic bacteria will be determined with a wound culture.	From enrollment through 6 month visit.
Primary	Primary Objective - Assess the rate of occurrence and severity of adverse events and their relationship to TAI	Adverse events will be tabulated by treatment group and will include the number of participants for whom the event occurred, the rate of occurrence, and the relationship to TAI. The severity of adverse events will be measured by the adverse event severity scale (1-4; Mild; Moderate; Severe; Life-threatening). The relationship of the adverse event to the study drug will be assessed by the likelihood of the relationship (Definitely; Probably; Possibly; Unrelated). Frequency of adverse events that result in discontinuation of the investigative treatment will be quantified.	From enrollment through 6 month visit.
Secondary	Secondary Objective - To evaluate wound size and closure.	Wound closure will be determined by the clinical practitioner at time of wound assessment at clinic follow up. If wound is not closed, wound size will be measured with a device that scans the wound and determines its area in cm^2. If wound is closed the wound size will be returned as 0 cm^2.	From enrollment through 6 month visit or until wound is closed.
Secondary	Secondary Objective - Chronic-wound-related pain	Chronic wound-related pain will me be measured with a pain assessment administered every visit. The pain assessment is the PEG-3 Pain Screening Tool which consists of 3 questions; The PEG-3 answer scale ranges from 0 to 10 for each question, where 0 corresponds to no pain and 10 represents the worst pain. A combined score is generated by summing the answer to each question.	From enrollment through 6 month visit.
Secondary	Secondary Objective - Rating Quality of life	Quality of Life (QoL) will be measured with a QoL assessment administered at every visit.; The QoL assessment is the WOUND-QOL-14 QUESTIONNAIRE which consists of 14 questions. Answers to each item are coded with numbers (0='not at all', 1='a little', 2='moderately', 3='quite a lot', to 4='very much') and summed or averaged to generate a global score. A higher score denotes a lower QoL.	From enrollment through 6 month visit.

External Links

•   UCLA Center for Wound Healing & Limb Preservation