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

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.

Keywords: COVID-19; SARS-CoV-2; antivirus; aprotinin; clinical trial; inhalation therapy; pneumonia; protease inhibitor.

FIGURE 1

Study design flow chart. ^aThe rash appeared right after the first administration, and the patient received practically no medication at all. ^bThese patients were effectively excluded after randomization because in the interval between randomization and the start of treatment, they no longer met the inclusion criteria (more or less severity than stated in the inclusion criteria: oxygen saturation >90% with oxygen therapy using nasal spectacles at 2–3 L/min). ^cThey were excluded because treatment administration was delayed due to the unavailability to supply the nebulizer to one of the participating hospitals. In no case, technical problems were reported with the nebulizer used. ^dThe patient was initially included on suspicion of COVID‐19 and then excluded after negative PCR

FIGURE 2

Treatment and admission time box‐plot between placebo and aprotinin groups

FIGURE 3

Kaplan–Meier model of length of hospital stay in the placebo and aprotinin‐treated groups

FIGURE 4

Daily evolution of oxygen therapy during treatment in the placebo and aprotinin‐treated groups. This figure shows the frequency of the different types of devices used each day during the study period and the percentage of StO₂ achieved with the application of these devices. The chi‐squared test was applied to compare between groups for each day. VMK: Ventimask, O₂ Reservoir: oxygen mask reservoir bag, StO₂: skeletal muscle oxygen saturation