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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), poses an unprecedented threat for global health. Even in the context of intensified vaccine rollout, identifying efficacious therapeutics remains a priority in case of severe forms of COVID-19. During the early phases of the pandemic, efforts were addressed at investigating repurposed therapeutic agents with antiviral and/or immuno-modulating properties, culminating in a broad multi-arm international trial (WHO SOLIDARITY) testing, among others, Interferon β−1a (IFNβ−1a) [
], is associated with higher risk of severe COVID-19.
Based on this rationale, between 2020 and 2021, in concomitance with the Solidarity and the ACTT-3 trials, we conducted a single-center, randomized, controlled, open-label, phase 2 clinical trial to evaluate efficacy and safety and antiviral activity of IFNβ−1a in hospitalized patients with COVID-19 radiologically diagnosed pneumonia (INTERCOP study, NCT04449380; EudraCT 2020–002,458–25).
]. People aged 18 years or older, diagnosed at the Emergency Department of San Raffaele Hospital (Milan, Italy) with COVID-19 by RT-PCR and pneumonia by chest radiography or computed tomography, with a clinical status of non-severe disease as defined by categories 3 and 4 of a 7-point clinical severity ordinal scale, were considered for enrolment. The scale consisted of the following: 1) not hospitalized, with resumption of normal activities; 2) not hospitalized, but unable to resume normal activities; 3) hospitalized, not requiring supplemental oxygen; 4) hospitalized, requiring supplemental oxygen; 5) hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6) hospitalized, requiring ECMO, invasive mechanical ventilation, or both; 7) death.
The protocol and consent documents were approved by the Ethics Committees of the San Raffaele Hospital, Milan and of the Lazzaro Spallanzani Institute for Infectious Diseases, Rome, Italy (the national center oversighting COVID-19 clinical trials in Italy) and by the Italian Medicines Agency (AIFA). All patients or their legally authorized representative provided written informed consent. The trial has been conducted in compliance with the principles of the Declaration of Helsinki.
Eligible patients were randomly assigned 2:1 to either receive interferon IFNβ−1a (Rebif®, Merck Serono, Rome, Italy), 44 micrograms 3-times per week for two weeks, at least 48 h apart in addition to standard of care, or standard of care alone. The experimental drug was administered over a maximum range of 14 days or until negative conversion of nasal swab.
The primary outcome measure was the time to negative conversion of nasopharyngeal swabs for SARS-CoV-2, defined as the date of the first negative, confirmed, nasal swab. Nasopharyngeal swabs were taken every other day from baseline until day 15, then at day 21 and at day 29, as per protocol. The full set of the secondary and exploratory outcomes is reported in the Protocol [
Efficacy and safety were evaluated up to day 29. Evaluation was performed during hospitalization and, in case of discharge in the meanwhile, in a dedicated outpatient clinic at weekly intervals. In patients still positive for SARS-CoV-2 infection at day 29, additional nasopharyngeal swabs were offered as extra-follow-up tests and included in the analyses.
Albeit unplanned, an interim analysis was requested by the Principal Investigator at the end of the second epidemic wave and in coincidence with the publication of the interim results of the Solidarity Trial showing no significant clinical effects of IFNβ−1a in COVID-19 patients.
The trial was prematurely terminated for futility: 53 patients (44% of the planned cohort) were recruited at the time of trial termination: median age was 67 yr (IQR 51–80), 32 were male, 50 (94%) with no oxygen supplementation and 3 (6%) on low flow oxygen at baseline. There were 4 deaths (7.5% of the total cohort): 2 (5.7%) in the IFNβ−1a intervention and 2 (11.1%) in the control arm. Median time to negative conversion of nasopharyngeal swabs (primary outcome of the study) was 23 and 20 days in the intervention and control arms, respectively (p = 0.19; hazard ratio for negative conversion 0.63 [95% CI 0.32–1.26]) (Fig. 1). No significant differences emerged in the secondary outcomes. Overall, adverse events occurred in 28 (82%) and 6 (33%) patients in the intervention and control arms, respectively, being fever the most commonly event reported.
In conclusion, subcutaneous IFNβ−1a does not reduce the duration of infection of SARS-CoV-2 and does not ameliorate the clinical course of COVID-19.
INTERCOP study group Collaborators: Luigi Di Filippo, Nicola Farina, Luigi Nocera, Nicola Clementi, Benedetta Sposito, Diego Palumbo, Francesco De Cobelli, Patrizia Rovere-Querini, Marco Bregni, Fabio Ciceri, Moreno Tresoldi, Antonella Castagna, Andrea Giustina, Massimo Clementi, Sofia Sisti, Marco Tonelli, Giordano Vitali, Sabina Martinenghi, Giuseppe Di Lucca, Junaid Mushtaq, Renato Pennella, Stefania Del Rosso.
Merck Serono (Rome, Italy), a division of Merck KGaA, Darmstadt, Germany, provided the experimental medicinal product Rebif® free of charge. The company had no role in the study design, conduct, data analysis and interpretation.
This work was supported by IRCCS Ospedale San Raffaele with internal funds dedicated to COVID-19.
Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results.