Aprotinin treatment against SARS‐CoV‐2: A randomized phase III study to evaluate the safety and efficacy of a pan‐protease inhibitor for moderate COVID‐19
Francisco Javier Redondo Calvo, Juan Fernando Padín, José Ramón Muñoz‐Rodríguez, Leticia Serrano‐Oviedo, Pilar López‐Juárez, María Lourdes Porras Leal, Francisco Javier González Gasca, Marta Rodríguez Martínez, Raúl Pérez Serrano, Abraham Sánchez Cadena, Natalia Bejarano Ramírez, Constanza Muñoz Hornero, José Ramón Barberá Farré, Inmaculada Domínguez‐Quesada, María A. Sepúlveda Berrocal, María Dolores Villegas Fernández‐Infantes, María Isabel Manrique Romo, A Comino, José Manuel Pérez‐Ortiz, Francisco Javier Gómez‐Romero, ATAC team
Abstract
BACKGROUND: SARS-CoV-2 virus requires host proteases to cleave its spike protein to bind to its ACE2 target through a two-step furin-mediated entry mechanism. Aprotinin is a broad-spectrum protease inhibitor that has been employed as antiviral drug for other human respiratory viruses. Also, it has important anti-inflammatory properties for inhibiting the innate immunity contact system. METHODS: This was a multicentre, double-blind, randomized trial performed in four Spanish hospitals comparing standard treatment versus standard treatment + aprotinin for patients with COVID-19 between 20 May 2020 and 20 October 2021. The primary efficacy outcomes were length of hospital stay and ICU admission. The secondary endpoints were each of the primary efficacy outcomes and a composite of oxygen therapy, analytical parameters and death. Safety outcomes included adverse reactions to treatment during a 30-day follow-up period. Treatment was given for 11 days or till discharge. RESULTS: With almost identical analytical profiles, significant differences were observed in treatment time, which was 2 days lower in the aprotinin group (p = .002), and length of hospital admission, which was 5 days shorter in the aprotinin group (p = .003). The incidence of discharge was 2.19 times higher (HR: 2.188 [1.182-4.047]) in the aprotinin group than in the placebo group (p = .013). In addition, the aprotinin-treated group required less oxygen therapy and had no adverse reactions or side effects. CONCLUSION: Inhaled aprotinin may improve standard treatment and clinical outcomes in hospitalized patients with COVID-19, resulting in a shorter treatment time and hospitalization compared with the placebo group. The administration of aprotinin was safe.