Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers A Randomized Clinical Trial
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 clin...
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| Published in | JAMA network open Vol. 4; no. 9; p. e2122607 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Medical Association
01.09.2021
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| Subjects | |
| Online Access | Get full text |
| ISSN | 2574-3805 2574-3805 |
| DOI | 10.1001/jamanetworkopen.2021.22607 |
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| Abstract | 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.
To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs.
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.
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.
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.
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.
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).
ClinicalTrials.gov Identifier: NCT01898923. |
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| AbstractList | This randomized clinical trial evaluates the wound healing efficacy of topical ON101 cream compared with a standard absorbent dressing in the treatment of patients with chronic diabetic foot ulcers. 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. To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. 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. 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. 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. 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. 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). ClinicalTrials.gov Identifier: NCT01898923. 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.ImportanceDelayed 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.To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs.ObjectiveTo compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs.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.Design, Setting, and ParticipantsThis 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.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.InterventionsTwice-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.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.Main Outcomes and MeasuresThe 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.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.ResultsIn 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.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).Conclusions and RelevanceIn 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).ClinicalTrials.gov Identifier: NCT01898923.Trial RegistrationClinicalTrials.gov Identifier: NCT01898923. 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 cm2present 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 |
| Author | Lin, Pao-Yuan Cazzell, Shawn M. Lin, Ching-Wen Huang, Hsuan-Li Yan, Li Cao, Yemin Li, Qiu Cheng, Nai-Chen Li, Yanbing Tung, Kwang-Yi Huang, Kuo-Feng Perng, Cherng-Kang Xue, Yaoming Chen, Hsin-Han Ma, Yujin Shi, Bimin Huang, Yu-Yao Liu, Chang Ning, Guang Chang, Shun-Cheng |
| AuthorAffiliation | 22 Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People’s Republic of China, Shanghai, China 24 Shanghai Jiao Tong University School of Medicine, Shanghai, China 4 Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan 6 Plastic and Reconstruction Surgery, China Medical University Hospital, Taichung, Taiwan 3 Oneness Biotech Company Limited, Taipei, Taiwan 23 Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai, China 20 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China 7 Plastic Surgery Center, Chi-Mei Medical Center, Tainan, Taiwan 12 Department of Surgery, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan 19 Department of Endocrinology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangdong, China 11 Division of Plastic and Reconstructiv |
| AuthorAffiliation_xml | – name: 14 Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Jiangsu, China – name: 9 Division of Cardiology, Buddhist Tzu Chi General Hospital, Taipei, Taiwan – name: 18 Department of Endocrinology, Nanfang Hospital of Southern Medical University, Guangdong, China – name: 15 Department of Endocrinology, The First Affiliated Hospital of Henan Science and Technology University, Henan, China – name: 8 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan – name: 21 Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Shanghai, China – name: 12 Department of Surgery, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan – name: 10 Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan – name: 13 Department of Endocrinology, The First Affiliated Hospital of Soochow University, Jiangsu, China – name: 2 Department of Medical Nutritional Therapy, Chang Gung Memorial Hospital, Taoyuan City, Taiwan – name: 20 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China – name: 23 Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai, China – name: 7 Plastic Surgery Center, Chi-Mei Medical Center, Tainan, Taiwan – name: 4 Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan – name: 22 Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People’s Republic of China, Shanghai, China – name: 5 Limb Preservation Platform Inc, Fresno, California – name: 16 Department of Vascular Anomalies, Shanghai TCM (Traditional Chinese Medicine)–Integrated Hospital, Shanghai, China – name: 11 Division of Plastic and Reconstructive Surgery, Taipei Veterans General Hospital, Taipei, Taiwan – name: 17 Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China – name: 3 Oneness Biotech Company Limited, Taipei, Taiwan – name: 6 Plastic and Reconstruction Surgery, China Medical University Hospital, Taichung, Taiwan – name: 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan – name: 19 Department of Endocrinology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangdong, China – name: 25 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 – name: 24 Shanghai Jiao Tong University School of Medicine, Shanghai, China – name: 26 Division of Plastic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan |
| Author_xml | – sequence: 1 givenname: Yu-Yao surname: Huang fullname: Huang, Yu-Yao organization: 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 – sequence: 2 givenname: Ching-Wen surname: Lin fullname: Lin, Ching-Wen organization: Oneness Biotech Company Limited, Taipei, Taiwan – sequence: 3 givenname: Nai-Chen surname: Cheng fullname: Cheng, Nai-Chen organization: Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan – sequence: 4 givenname: Shawn M. surname: Cazzell fullname: Cazzell, Shawn M. organization: Limb Preservation Platform Inc, Fresno, California – sequence: 5 givenname: Hsin-Han surname: Chen fullname: Chen, Hsin-Han organization: Plastic and Reconstruction Surgery, China Medical University Hospital, Taichung, Taiwan – sequence: 6 givenname: Kuo-Feng surname: Huang fullname: Huang, Kuo-Feng organization: Plastic Surgery Center, Chi-Mei Medical Center, Tainan, Taiwan – sequence: 7 givenname: Kwang-Yi surname: Tung fullname: Tung, Kwang-Yi organization: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan – sequence: 8 givenname: Hsuan-Li surname: Huang fullname: Huang, Hsuan-Li organization: Division of Cardiology, Buddhist Tzu Chi General Hospital, Taipei, Taiwan – sequence: 9 givenname: Pao-Yuan surname: Lin fullname: Lin, Pao-Yuan organization: Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan – sequence: 10 givenname: Cherng-Kang surname: Perng fullname: Perng, Cherng-Kang organization: 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 – sequence: 11 givenname: Bimin surname: Shi fullname: Shi, Bimin organization: Department of Endocrinology, The First Affiliated Hospital of Soochow University, Jiangsu, China – sequence: 12 givenname: Chang surname: Liu fullname: Liu, Chang organization: Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Jiangsu, China – sequence: 13 givenname: Yujin surname: Ma fullname: Ma, Yujin organization: Department of Endocrinology, The First Affiliated Hospital of Henan Science and Technology University, Henan, China – sequence: 14 givenname: Yemin surname: Cao fullname: Cao, Yemin organization: Department of Vascular Anomalies, Shanghai TCM (Traditional Chinese Medicine)–Integrated Hospital, Shanghai, China – sequence: 15 givenname: Yanbing surname: Li fullname: Li, Yanbing organization: Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China – sequence: 16 givenname: Yaoming surname: Xue fullname: Xue, Yaoming organization: Department of Endocrinology, Nanfang Hospital of Southern Medical University, Guangdong, China – sequence: 17 givenname: Li surname: Yan fullname: Yan, Li organization: Department of Endocrinology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangdong, China – sequence: 18 givenname: Qiu surname: Li fullname: Li, Qiu organization: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China – sequence: 19 givenname: Guang surname: Ning fullname: Ning, Guang organization: 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 – sequence: 20 givenname: Shun-Cheng surname: Chang fullname: Chang, Shun-Cheng organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34477854$$D View this record in MEDLINE/PubMed |
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| DOI | 10.1001/jamanetworkopen.2021.22607 |
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| Snippet | 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... 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... This randomized clinical trial evaluates the wound healing efficacy of topical ON101 cream compared with a standard absorbent dressing in the treatment of... |
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| SubjectTerms | Adult Aged Aged, 80 and over Bandages China Clinical trials Dermatologic Agents - administration & dosage Dermatologic Agents - therapeutic use Diabetes Diabetes and Endocrinology Diabetic Foot - drug therapy Disease-Free Survival Female Foot diseases Hemoglobin Humans Leg ulcers Macrophages Male Middle Aged Online Only Original Investigation Single-Blind Method Taiwan Treatment Outcome United States Wound Healing Young Adult |
| Subtitle | A Randomized Clinical Trial |
| Title | Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers |
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