Improved Wound Healing by Direct Cold Atmospheric Plasma Once or Twice a Week: A Randomized Controlled Trial on Chronic Venous Leg Ulcers

Objective: This study compared the effect of two frequencies of direct cold atmospheric plasma (direct-CAP) treatment with standard of care (SOC) alone on healing of venous leg ulcers (VLUs). Approach: Open-label, randomized controlled trial (ClinicalTrials.gov: NCT04922463) on chronic VLUs at two home care organizations in the Netherlands. All three groups received SOC for 12 weeks or until healing. Additionally, treatment groups received direct-CAP once (1x direct-CAP) or twice (2x direct-CAP) a week, at specialized wound care facilities and the patients' residences. Primary outcome was percentage of wounds healed. Secondary outcomes included wound area reduction and adverse events. Results: 46 patients were randomly allocated to receive SOC only (n=15), SOC + direct-CAP once a week (n=17) or SOC + direct-CAP twice a week (n=14). A higher percentage of wounds healed within 12 weeks in the treatment groups: 53.3% (1x direct-CAP, p=0.16) and 61.5% (2x direct-CAP, p=0.08) vs 25.0% (control). The largest wound area reduction was obtained with 2x direct-CAP (95.2%, p=0.07), followed by 1x direct-CAP (63.9%, p=0.58), vs control (52.8%). Absolute wound area reduced significantly compared with baseline in both treatment groups (p≤0.001), not in control (p=0.11). No device-related serious adverse events occurred. Innovation: Direct-CAP applied once or twice a week could substantially improve wound healing of VLUs in primary care. Conclusion: Together with other clinical safety and efficacy data, these results support the integration of direct-CAP as a valuable therapy for complex wounds.