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Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan. Department of Medical Nutritional Therapy, Chang Gung Memorial Hospital, Taoyuan City, Taiwan. Oneness Biotech Company Limited, Taipei, Taiwan. Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. Limb Preservation Platform Inc, Fresno, California. Plastic and Reconstruction Surgery, China Medical University Hospital, Taichung, Taiwan. Plastic Surgery Center, Chi-Mei Medical Center, Tainan, Taiwan. Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan. Division of Cardiology, Buddhist Tzu Chi General Hospital, Taipei, Taiwan. Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Division of Plastic and Reconstructive Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Department of Surgery, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan. Department of Endocrinology, The First Affiliated Hospital of Soochow University, Jiangsu, China. Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Jiangsu, China. Department of Endocrinology, The First Affiliated Hospital of Henan Science and Technology University, Henan, China. Department of Vascular Anomalies, Shanghai TCM (Traditional Chinese Medicine)-Integrated Hospital, Shanghai, China. Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China. Department of Endocrinology, Nanfang Hospital of Southern Medical University, Guangdong, China. Department of Endocrinology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangdong, China. Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China. Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Shanghai, China. Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People's Republic of China, Shanghai, China. Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai, China. Shanghai Jiao Tong University School of Medicine, Shanghai, China. Division of Plastic Surgery, Department of Surgery, Integrated Burn and Wound Care Center, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan. Division of Plastic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

JAMA network open. 2021;(9):e2122607
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Abstract

IMPORTANCE Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. OBJECTIVE To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. DESIGN, SETTING, AND PARTICIPANTS This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. INTERVENTIONS Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. MAIN OUTCOMES AND MEASURES The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. RESULTS In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. CONCLUSIONS AND RELEVANCE In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01898923.

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MeSH terms : Diabetic Foot