Treatment of Chronic Venous Ulcers With Heterologous Fibrin Sealant: A Phase I/II Clinical Trial

Detalhes bibliográficos
Autor(a) principal: Abbade, Luciana P. F. [UNESP]
Data de Publicação: 2021
Outros Autores: 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]
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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spelling 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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