Marginal Ulcer Healing With Low-Thermal Argon Plasma Endoscopic Treatment (AMULET)

Christopher C. Thompson, MD, MSc

Status: Begins enrollment in 1 month

Conditions: Vomiting; Roux-en-y Anastomosis Site; Nausea; Ulcer; Marginal Ulcer (Peptic) or Erosion; GastroIntestinal Bleeding; Dysphagia; Ulcer Gastrojejunal; Ulcer Gastrointestinal; Marginal Ulcer; Ulcer, Gastric; Abdominal Pain

Treatments: Other: Standard of Care Ulcer Treatment (typically PPI Administration); Procedure: Low Thermal Plasma (LTP) Treatment

Study type: Interventional

Funder types: Other

Identifiers

NCT06543316

2024P002124

Details and patient eligibility

About

The objective of the study is to investigate the treatment of marginal ulcers with Low Thermal plasma in an endoscopic setting. By a treatment of the ulcerated areas with argon plasma with low power settings (~ 1 W) we hypothesize that the size of the ulcers will shrink, and the healing is accelerated compared to standard of care alone. Patients will benefit from this minimally invasive approach compared to a much more invasive surgical approach that comes with higher risks and hospital stay length time. From a societal and scientific perspective, this study aims to extend the well-documented clinical benefits of plasma technology - from external wound healing to internal ulcer treatment - within an endoscopic framework. The success of this study could pave the way for broader applications of LTP in the treatment of other endoscopically accessible conditions such as peptic ulcers, duodenal ulcers and esophageal ulcers. This advancement has the potential not only to improve patient outcomes through less invasive methods, but also to position LTP as a cornerstone in the future of gastroenterological wound management strategies.

Full description

Gastric bypass surgery, specifically Roux-en-Y gastric bypass (RYGB), is the second most common bariatric procedure performed worldwide (29.3%) after sleeve gastrectomy (55.4%). Despite its success in reducing obesity-related conditions, RYGB is associated with the development of marginal ulcers (MUs)-internal wounds at the gastrojejunal anastomosis prone to poor healing. The incidence of MUs in patients post-RYGB ranges widely, reported at 0.6% to 25% in the U.S., with some estimates as high as 34% worldwide due to asymptomatic cases that go undetected unless investigated endoscopically. These ulcers can become chronic and persisting over time, significantly complicating post-surgical outcomes and increasing the risk of severe complications like perforation, which necessitates urgent surgical intervention in approximately 1-2% of cases.

The current standard of care for MUs involves prolonged use of proton pump inhibitors (PPIs), which reduce gastric acidity to promote ulcer healing. However, this approach addresses only one aspect of MU pathophysiology and is limited by several shortcomings. It is often insufficient in preventing recurrence and carries risks of significant side effects, including increased risk of infection, electrolyte imbalances, and potential kidney disease, particularly with long-term use. Standard therapy is 8 weeks high-dose treatment, and a lifelong PPI therapy is considered if success is seen with medical management. For those not responding to 8 weeks of therapy, most advocate for continued PPI treatment with serial endoscopic evaluation, even up to 2 years out from initial diagnosis. Given these challenges, there is an evident need for alternative treatments that can more effectively target the underlying causes of MUs and reduce the reliance on PPIs.

Low-thermal or low-temperature plasma (LTP) represents a significant advance in accelerated wound healing technologies. As the fourth state of matter, physical plasma is used in the field of plasma medicine to treat a variety of medical conditions at atmospheric pressure and temperatures close to body temperature (typically between 20°C and 50°C). Over the past 10 to 15 years, wound healing has been a primary clinical application for LTP, with extensive use demonstrating its clinical efficacy in the treatment of chronic and poorly healing wounds.

The mechanisms by which LTP facilitates wound healing include oxygenation of tissues, activation of growth factors, improvement of microcirculation, reduction of bacterial load in wounds, and devitalization of senescent cells. These effects are primarily achieved by the ionization of argon gas and the generation of reactive oxygen and nitrogen species (RONS) in the gas phase. Clinically, LTP has been applied to a variety of wound types, including pressure ulcers, chronic wounds, and acute wounds, and has demonstrated effectiveness across a range of wound sizes and stages. LTP treatments are particularly noted for their ability to transform chronic wounds into actively healing wounds, thereby altering the physiological state of the wound.

Several studies have rigorously evaluated the safety profile of LTP and confirmed that it does not pose mutagenic or carcinogenic risks. Long-term evaluations have shown no evidence of tumor formation or abnormal tissue architecture in gas plasma-treated animal models, even after extended periods corresponding to 60 human-equivalent years. Patient follow-up studies using advanced imaging techniques have further confirmed the absence of abnormal healing responses, supporting the absence of adverse long-term effects.

Currently, the most common low-thermal plasma sources used to treat external wounds are PlasmaJets and Dielectric Barrier Discharge (DBD) plasma sources. However, the physical dimensions of these devices limit their use in endoscopic applications. This has limited the availability of LTP for the treatment of internal wounds and ulcers.

Argon plasma coagulation (APC) is a technology that has been used in endoscopy for more than three decades. It has demonstrated clinical safety and efficacy in many areas, including bleeding management (e.g., bleeding ulcers), ablation of cancerous tissue, and precise treatment in sensitive areas. It is primarily used in endoscopic procedures with flexible probes, but also in laparoscopic and open surgery settings. The flexible probes are available in various diameters, 1.5 mm, 2.3 mm and 3.2 mm.

APC works by ionizing argon gas with a high-frequency alternating current passed through an electrode. This ionized gas forms a physical plasma that is applied to tissue. Depending on the mode and effect setting, the plasma can be adjusted in power from as low as 1 W to as high as 120 W. At higher power settings (5 W and above), the plasma exhibits a more pronounced thermal effect due to increased current flow through the tissue, facilitating effective coagulation. Conversely, at lower settings below 5 W, a low-thermal plasma effect is achieved, minimizing tissue coagulation through dynamic application and avoiding prolonged exposure to a single spot. As with PlasmaJets and Dielectric Barrier Discharge (DBD) plasma sources, the effectiveness of low-thermal argon plasma is primarily due to the high energy and voltage that generate reactive oxygen and nitrogen species (RONS).

Enrollment: 100 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Subjects aged 18 years and above, inclusive of both males and females.
• Patients with a history of Roux-en-Y gastric bypass (RYGB) presenting symptoms indicative of marginal ulcers (MUs) such as abdominal pain, nausea, vomiting, gastrointestinal bleeding, or dysphagia.
• Subjects must be scheduled for an EGD for the evaluation of these symptoms.
• Marginal ulcers confirmed during the initial EGD.
• Willingness to adhere to the SOC treatment, which includes PPIs.
• Subjects able to tolerate repeated endoscopic procedures.
• Capacity for providing informed consent and understanding of study requirements.
• Willingness and ability to attend required follow-up assessments at 4 weeks (+/- 1 week) and 8 weeks (+/- 2 weeks).

Exclusion criteria

• Inability to provide informed consent.
• Unwillingness to undergo repeated endoscopies.
• Inability or unwillingness to comply with the SOC.
• Current use of systemic antibiotics.
• Any condition deemed by the investigator to compromise the safety of undergoing an endoscopic procedure.
• Pregnancy, lactation, or absence of reliable contraception in women of childbearing potential.
• Current enrollment in another investigational trial with potential to interfere with this study's endpoint analyses.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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100 participants in 2 patient groups

Low Thermal Plasma (LTP)

Active Comparator group

Description:

Patients randomized to this group will receive LTP treatment of the ulcer in addition to SOC (PPI administration).

Treatment:

Procedure: Low Thermal Plasma (LTP) Treatment

Other: Standard of Care Ulcer Treatment (typically PPI Administration)

Standard of Care (SOC) PPI Administration

Active Comparator group

Description:

Patients randomized to this group will receive only the SOC treatment (PPI administration).

Treatment:

Other: Standard of Care Ulcer Treatment (typically PPI Administration)