Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3389/fimmu.2021.627541 http://hdl.handle.net/11449/207429 |
Resumo: | Background: Heterologous 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). Methods: A 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. Results: No 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. Conclusions: The 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. |
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Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trialbiological dressingsfibrin gluefibrin sealantfibrin tissue adhesivevaricose ulcerBackground: Heterologous 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). Methods: A 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. Results: No 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. Conclusions: The 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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Department of Infectology Dermatology Imaging Diagnosis and Radiotherapy Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Graduate Program in Nursing Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Graduate Program in Clinical Research Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Graduate Program in Tropical Diseases Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Nursing School of Sagrado Coração University (UNISAGRADO)Clinical Research Unit (UPECLIN) Botucatu Medical School São Paulo State University UNESP – Univ Estadual Paulista)Center for the Study of Venoms and Venomous Animals CEVAP) São Paulo State University (UNESP – Univ Estadual PaulistaDepartment of Infectology Dermatology Imaging Diagnosis and Radiotherapy Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Graduate Program in Nursing Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Graduate Program in Clinical Research Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Graduate Program in Tropical Diseases Botucatu Medical School (FMB) São Paulo State University UNESP – Univ Estadual Paulista)Clinical Research Unit (UPECLIN) Botucatu Medical School São Paulo State University UNESP – Univ Estadual Paulista)Center for the Study of Venoms and Venomous Animals CEVAP) São Paulo State University (UNESP – Univ Estadual PaulistaFAPESP: 2014/13299-7CAPES: 23038.006285/2011-21CNPq: 401170/2013-6CNPq: 458919/2014-4CNPq: 563582/2010-3Universidade Estadual Paulista (Unesp)Nursing School of Sagrado Coração University (UNISAGRADO)Abbade, Luciana P. F. [UNESP]Barraviera, Silvia Regina Catharino Sartori [UNESP]Silvares, Maria Regina Cavariani [UNESP]Lima, Ana Beatriz B. de C. O. [UNESP]Haddad, Gabriela R. [UNESP]Gatti, Márcia A. N.Medolago, Natália Bronzatto [UNESP]Rigotto Carneiro, Márcia Tonin [UNESP]dos Santos, Lucilene Delazari [UNESP]Ferreira, Rui Seabra [UNESP]Barraviera, Benedito [UNESP]2021-06-25T10:55:02Z2021-06-25T10:55:02Z2021-02-23info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fimmu.2021.627541Frontiers in Immunology, v. 12.1664-3224http://hdl.handle.net/11449/20742910.3389/fimmu.2021.6275412-s2.0-85102371843Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengFrontiers in Immunologyinfo:eu-repo/semantics/openAccess2024-08-15T18:46:27Zoai:repositorio.unesp.br:11449/207429Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-15T18:46:27Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
title |
Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
spellingShingle |
Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial Abbade, Luciana P. F. [UNESP] biological dressings fibrin glue fibrin sealant fibrin tissue adhesive varicose ulcer |
title_short |
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_sort |
Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial |
author |
Abbade, Luciana P. F. [UNESP] |
author_facet |
Abbade, Luciana P. F. [UNESP] Barraviera, Silvia Regina Catharino Sartori [UNESP] Silvares, Maria Regina Cavariani [UNESP] Lima, Ana Beatriz B. de C. O. [UNESP] Haddad, Gabriela R. [UNESP] Gatti, Márcia A. N. Medolago, Natália Bronzatto [UNESP] Rigotto Carneiro, Márcia Tonin [UNESP] dos Santos, Lucilene Delazari [UNESP] Ferreira, Rui Seabra [UNESP] Barraviera, Benedito [UNESP] |
author_role |
author |
author2 |
Barraviera, Silvia Regina Catharino Sartori [UNESP] Silvares, Maria Regina Cavariani [UNESP] Lima, Ana Beatriz B. de C. O. [UNESP] Haddad, Gabriela R. [UNESP] Gatti, Márcia A. N. Medolago, Natália Bronzatto [UNESP] Rigotto Carneiro, Márcia Tonin [UNESP] dos Santos, Lucilene Delazari [UNESP] Ferreira, Rui Seabra [UNESP] Barraviera, Benedito [UNESP] |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) Nursing School of Sagrado Coração University (UNISAGRADO) |
dc.contributor.author.fl_str_mv |
Abbade, Luciana P. F. [UNESP] Barraviera, Silvia Regina Catharino Sartori [UNESP] Silvares, Maria Regina Cavariani [UNESP] Lima, Ana Beatriz B. de C. O. [UNESP] Haddad, Gabriela R. [UNESP] Gatti, Márcia A. N. Medolago, Natália Bronzatto [UNESP] Rigotto Carneiro, Márcia Tonin [UNESP] dos Santos, Lucilene Delazari [UNESP] Ferreira, Rui Seabra [UNESP] Barraviera, Benedito [UNESP] |
dc.subject.por.fl_str_mv |
biological dressings fibrin glue fibrin sealant fibrin tissue adhesive varicose ulcer |
topic |
biological dressings fibrin glue fibrin sealant fibrin tissue adhesive varicose ulcer |
description |
Background: Heterologous 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). Methods: A 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. Results: No 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. Conclusions: The 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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-25T10:55:02Z 2021-06-25T10:55:02Z 2021-02-23 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.3389/fimmu.2021.627541 Frontiers in Immunology, v. 12. 1664-3224 http://hdl.handle.net/11449/207429 10.3389/fimmu.2021.627541 2-s2.0-85102371843 |
url |
http://dx.doi.org/10.3389/fimmu.2021.627541 http://hdl.handle.net/11449/207429 |
identifier_str_mv |
Frontiers in Immunology, v. 12. 1664-3224 10.3389/fimmu.2021.627541 2-s2.0-85102371843 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Frontiers in Immunology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808128127094751232 |