Single-Arm, Multicenter Phase I/II Clinical Trial for the Treatment of Envenomings by Massive Africanized Honey Bee Stings Using the Unique Apilic Antivenom

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Barbosa, Alexandre Naime ^[1] ; Ferreira, Jr., Rui Seabra ^{[1, 2, 3, 4, 5]} ; de Carvalho, Francilene Capel Tavares ^{[2, 3]} ; Schuelter-Trevisol, Fabiana ^{[6, 7]} ; Mendes, Monica Bannwart ^[1] ; Mendonca, Bruna Cavecci ^{[2, 3]} ; Batista, Jose Nixon ^[6] ; Trevisol, Daisson Jose ^{[6, 7]} ; Boyer, Leslie ^[8] ; Chippaux, Jean-Philippe ^{[9, 10]} ; Medolago, Natalia Bronzatto ^[11] ; Cassaro, Claudia Vilalva ^{[2, 3]} ; Carneiro, Marcia Tonin Rigotto ^[11] ; de Oliveira, Ana Paola Piloto ^[11] ; Pimenta, Daniel Carvalho ^{[12, 2]} ; da Cunha, Luis Eduardo Ribeiro ^[13] ; Santos, Lucilene Delazari dos ^{[1, 2, 3, 4, 5]} ; Barraviera, Benedito ^{[1, 2, 3, 4, 5]}

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^[1] UNESP Univ Estadual Paulista, Sao Paulo State Univ, Botucatu Med Sch FMB, Dept Infectol Dermatol Imaging Diag & Radiotherap, Botucatu, SP - Brazil

^[2] UNESP Univ Estadual Paulista, Sao Paulo State Univ, Botucatu Med Sch FMB, Grad Program Trop Dis, Botucatu, SP - Brazil

^[3] UNESP Univ Estadual Paulista, Sao Paulo State Univ, Ctr Study Venoms & Venomous Anim CEVAP, Botucatu, SP - Brazil

^[4] UNESP Univ Estadual Paulista, Sao Paulo State Univ, Ctr Study Venoms & Venomous Anim CEVAP, Grad Program Clin Res, Botucatu, SP - Brazil

^[5] UNESP Univ Estadual Paulista, Sao Paulo State Univ, Botucatu Med Sch FMB, Botucatu, SP - Brazil

^[6] Nossa Senhora Conceicao Hosp, Clin Res Ctr, Tubarao - Brazil

^[7] Univ Southern Santa Catarina Tubarao, Grad Program Hlth Sci, Tubarao - Brazil

^[8] Univ Arizona, Coll Med, VIPER Inst, Tucson, AZ - USA

^[9] Sorbonne Paris Cite, Univ Paris 05, IRD, MERIT, Paris - France

^[10] Inst Pasteur, CRT, Paris - France

^[11] UNESP Univ Estadual Paulista, Sao Paulo State Univ, Botucatu Med Sch, Clin Res Unit UPECLIN, Botucatu, SP - Brazil

^[12] Butantan Inst, Biochem & Biophys Lab, Sao Paulo - Brazil

^[13] Vital Brazil Inst, Antivenom Prod Lab, Rio De Janeiro - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 12, MAR 23 2021.
• Citações Web of Science: 2

Resumo

We evaluated the safety, optimal dose, and preliminary effectiveness of a new-approach Africanized honeybee (Apis mellifera) Antivenom (AAV) in a phase I/II, multicenter, non-randomized, single-arm clinical trial involving 20 participants with multiple stings. Participants received 2 to 10 vials of AAV depending on the number of stings they suffered, or a predefined adjuvant, symptomatic, and complementary treatment. The primary safety endpoint was the occurrence of early adverse reactions within the first 24 h of treatment. Preliminary efficacy based on clinical evolution, including laboratory findings, was assessed at baseline and at various time points over the four following weeks. ELISA assays and mass spectrometry were used to estimate venom pharmacokinetics before, during, and after treatment. Twenty adult participants, i.e., 13 (65%) men and 7 (35%) women, with a median age of 44 years and a mean body surface area of 1.92 m(2) (median = 1.93 m(2)) were recruited. The number of stings ranged from 7 to > 2,000, with a median of 52.5. Symptoms of envenoming were classified as mild, moderate, or severe in 80% (16), 15% (3), and 5% (1) of patients, respectively; patients with mild, moderate, or severe envenoming received 2, 6, and 10 vials of AAV as per the protocol. None of the patients had late reactions (serum sickness) within 30 d of treatment. There was no discontinuation of the protocol due to adverse events, and there were no serious adverse events. One patient had a moderate adverse event, transient itchy skin, and erythroderma. All participants completed the intravenous antivenom infusion within 2 h, and there was no loss to follow-up after discharge. ELISA assays showed venom (melittin and PLA(2)) concentrations varying between 0.25 and 1.479 ng/mL prior to treatment. Venom levels decreased in all patients during the hospitalization period. Surprisingly, in nine cases (45%), despite clinical recovery and the absence of symptoms, venom levels increased again during outpatient care 10 d after discharge. Mass spectrometry showed melittin in eight participants, 30 d after treatment. Considering the promising safety results for this investigational product in the treatment of massive Africanized honeybee attack, and its efficacy, reflected in the clinical improvements and corresponding immediate decrease in blood venom levels, the AAV has shown to be safe for human use. (AU)

• Processo FAPESP: 20/16747-1 - Inovação nos acidentes por abelhas: da prova de conceito ao desenvolvimento de um kit diagnóstico do agravo do acidente
• Beneficiário: Bruna Cavecci Mendonça
• Modalidade de apoio: Bolsas no Brasil - Pesquisa Inovativa em Pequenas Empresas - PIPE
• Processo FAPESP: 20/09819-6 - Inovação nos acidentes por abelhas: da prova de conceito ao desenvolvimento de um kit diagnóstico do agravo do acidente
• Beneficiário: Bruna Cavecci Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa Inovativa em Pequenas Empresas - PIPE