Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial
BackgroundHeterologous fibrin sealant (HFS) consists of a fibrinogen-rich cryoprecipitate extracted from Bubalus bubalis buffalo blood and a thrombin-like enzyme purified from Crotalus durissus terrificus snake venom. This study evaluated the safety and immunogenicity of HFS, estimated the best dose...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.627541/full |
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| author | Luciana P. F. Abbade Luciana P. F. Abbade Luciana P. F. Abbade Silvia Regina Catharino Sartori Barraviera Silvia Regina Catharino Sartori Barraviera Maria Regina Cavariani Silvares Ana Beatriz B. de C. O. Lima Gabriela R. Haddad Márcia A. N. Gatti Natália Bronzatto Medolago Márcia Tonin Rigotto Carneiro Lucilene Delazari dos Santos Lucilene Delazari dos Santos Lucilene Delazari dos Santos Rui Seabra Ferreira Rui Seabra Ferreira Rui Seabra Ferreira Benedito Barraviera Benedito Barraviera Benedito Barraviera Benedito Barraviera |
| author_facet | Luciana P. F. Abbade Luciana P. F. Abbade Luciana P. F. Abbade Silvia Regina Catharino Sartori Barraviera Silvia Regina Catharino Sartori Barraviera Maria Regina Cavariani Silvares Ana Beatriz B. de C. O. Lima Gabriela R. Haddad Márcia A. N. Gatti Natália Bronzatto Medolago Márcia Tonin Rigotto Carneiro Lucilene Delazari dos Santos Lucilene Delazari dos Santos Lucilene Delazari dos Santos Rui Seabra Ferreira Rui Seabra Ferreira Rui Seabra Ferreira Benedito Barraviera Benedito Barraviera Benedito Barraviera Benedito Barraviera |
| author_sort | Luciana P. F. Abbade |
| collection | DOAJ |
| description | BackgroundHeterologous fibrin sealant (HFS) consists of a fibrinogen-rich cryoprecipitate extracted from Bubalus bubalis buffalo blood and a thrombin-like enzyme purified from Crotalus durissus terrificus snake venom. This study evaluated the safety and immunogenicity of HFS, estimated the best dose, and assessed its preliminary efficacy in the treatment of chronic venous ulcers (CVU).MethodsA phase I/II non-randomized, single-arm clinical trial was performed on 31 participants, accounting for a total of 69 active CVUs. All ulcers were treated with HFS, essential fatty acid, and Unna boot for 12 weeks. The outcomes assessed were: (1) primary safety, immunogenicity analyses, and confirmation of the lowest safe dose; (2) secondary promising efficacy by analyzing the healing process. Immunogenicity was evaluated using the serum-neutralizing (IgM and IgG) and non-neutralizing (IgA and IgE) antibody techniques against the product. The immuno-detection of IgE class antibodies was assessed using dot-blot assay before and at the end of treatment. Positive samples on dot-blot assays were subsequently analyzed by western blotting to verify the results.ResultsNo severe systemic adverse events related to the use of HFS were observed. Local adverse events potentially related to treatment include ulcer pain (52%), peri-ulcer maceration (16%), peri-ulcer pruritus (12%), critical colonization (8%), peri-ulcer eczema (4%), the opening of new ulcers (4%), and increased ulcerated area 4%). Neutralizing and non-neutralizing antibodies did not show significant deviations at any of the evaluated time points. Blot assays showed that all patients presented negative immunological reactions, either before or after treatment, with the thrombin-like enzyme component. In addition, two participants showed a positive immunological reaction to the cryoprecipitate component, while another two were positive before and during treatment. Regarding the secondary outcomes of preliminary efficacy, a total healing and significant reduction of the area was observed in 47.5 and 22%, respectively. A qualitative improvement was observed in the wound beds of unhealed ulcers.ConclusionsThe investigational HFS bioproduct proved to be safe and non-immunogenic with a good preliminary efficacy for the treatment of CVU, according to the protocol and doses proposed. A multicentric phase III clinical trial will be necessary to verify these findings. |
| first_indexed | 2024-12-17T07:40:50Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T07:40:50Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-ed4d9626039045008fd67b0d3d1225892022-12-21T21:58:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.627541627541Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical TrialLuciana P. F. Abbade0Luciana P. F. Abbade1Luciana P. F. Abbade2Silvia Regina Catharino Sartori Barraviera3Silvia Regina Catharino Sartori Barraviera4Maria Regina Cavariani Silvares5Ana Beatriz B. de C. O. Lima6Gabriela R. Haddad7Márcia A. N. Gatti8Natália Bronzatto Medolago9Márcia Tonin Rigotto Carneiro10Lucilene Delazari dos Santos11Lucilene Delazari dos Santos12Lucilene Delazari dos Santos13Rui Seabra Ferreira14Rui Seabra Ferreira15Rui Seabra Ferreira16Benedito Barraviera17Benedito Barraviera18Benedito Barraviera19Benedito Barraviera20Department of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Nursing, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Clinical Research, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilDepartment of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Tropical Diseases, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilDepartment of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilDepartment of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilDepartment of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilNursing School of Sagrado Coração University (UNISAGRADO), Bauru, BrazilClinical Research Unit (UPECLIN), Botucatu Medical School, São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilClinical Research Unit (UPECLIN), Botucatu Medical School, São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Clinical Research, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Tropical Diseases, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilCenter for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Clinical Research, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Tropical Diseases, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilCenter for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilDepartment of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Clinical Research, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilGraduate Program in Tropical Diseases, Botucatu Medical School (FMB), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilCenter for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, BrazilBackgroundHeterologous fibrin sealant (HFS) consists of a fibrinogen-rich cryoprecipitate extracted from Bubalus bubalis buffalo blood and a thrombin-like enzyme purified from Crotalus durissus terrificus snake venom. This study evaluated the safety and immunogenicity of HFS, estimated the best dose, and assessed its preliminary efficacy in the treatment of chronic venous ulcers (CVU).MethodsA phase I/II non-randomized, single-arm clinical trial was performed on 31 participants, accounting for a total of 69 active CVUs. All ulcers were treated with HFS, essential fatty acid, and Unna boot for 12 weeks. The outcomes assessed were: (1) primary safety, immunogenicity analyses, and confirmation of the lowest safe dose; (2) secondary promising efficacy by analyzing the healing process. Immunogenicity was evaluated using the serum-neutralizing (IgM and IgG) and non-neutralizing (IgA and IgE) antibody techniques against the product. The immuno-detection of IgE class antibodies was assessed using dot-blot assay before and at the end of treatment. Positive samples on dot-blot assays were subsequently analyzed by western blotting to verify the results.ResultsNo severe systemic adverse events related to the use of HFS were observed. Local adverse events potentially related to treatment include ulcer pain (52%), peri-ulcer maceration (16%), peri-ulcer pruritus (12%), critical colonization (8%), peri-ulcer eczema (4%), the opening of new ulcers (4%), and increased ulcerated area 4%). Neutralizing and non-neutralizing antibodies did not show significant deviations at any of the evaluated time points. Blot assays showed that all patients presented negative immunological reactions, either before or after treatment, with the thrombin-like enzyme component. In addition, two participants showed a positive immunological reaction to the cryoprecipitate component, while another two were positive before and during treatment. Regarding the secondary outcomes of preliminary efficacy, a total healing and significant reduction of the area was observed in 47.5 and 22%, respectively. A qualitative improvement was observed in the wound beds of unhealed ulcers.ConclusionsThe investigational HFS bioproduct proved to be safe and non-immunogenic with a good preliminary efficacy for the treatment of CVU, according to the protocol and doses proposed. A multicentric phase III clinical trial will be necessary to verify these findings.https://www.frontiersin.org/articles/10.3389/fimmu.2021.627541/fullvaricose ulcerbiological dressingsfibrin tissue adhesivefibrin gluefibrin sealant |
| spellingShingle | Luciana P. F. Abbade Luciana P. F. Abbade Luciana P. F. Abbade Silvia Regina Catharino Sartori Barraviera Silvia Regina Catharino Sartori Barraviera Maria Regina Cavariani Silvares Ana Beatriz B. de C. O. Lima Gabriela R. Haddad Márcia A. N. Gatti Natália Bronzatto Medolago Márcia Tonin Rigotto Carneiro Lucilene Delazari dos Santos Lucilene Delazari dos Santos Lucilene Delazari dos Santos Rui Seabra Ferreira Rui Seabra Ferreira Rui Seabra Ferreira Benedito Barraviera Benedito Barraviera Benedito Barraviera Benedito Barraviera Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial Frontiers in Immunology varicose ulcer biological dressings fibrin tissue adhesive fibrin glue fibrin sealant |
| title | Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
| title_full | Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
| title_fullStr | Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
| title_full_unstemmed | Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
| title_short | Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
| title_sort | treatment of chronic venous ulcers with heterologous fibrin sealant a phase i ii clinical trial |
| topic | varicose ulcer biological dressings fibrin tissue adhesive fibrin glue fibrin sealant |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.627541/full |
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