A phase 2 randomized, double-blinded, placebo-controlled, multicenter trial evaluating the efficacy and safety of raloxifene for patients with mild to moderate COVID-19

Abstract

Background: Current available therapeutic options for Coronavirus Disease-2019 (COVID-19) are primarily focused on treating hospitalized patients, and there is a lack of oral therapeutic options to treat mild to moderate outpatient COVID-19 and prevent clinical progression. Raloxifene was found as a promising molecule to treat COVID-19 due to its activity to modulate the replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and act as an immunomodulator to decrease proinflammatory cytokines.

Methods: This was a phase 2 multicenter, randomized, placebo-controlled trial to evaluate the efficacy and safety of raloxifene in adult patients with mild to moderate COVID-19 between October 2020 to June 2021 in five centers located in Italy. This was a planned 2/3 adaptive study, but due to operational difficulties, the study was discontinued during the phase 2 study segment. Participants were randomized 1:1:1 to receive oral placebo, raloxifene 60 mg, or raloxifene 120 mg by self-administration for a maximum of two weeks. The primary outcomes were the proportion of patients with undetectable SARS-CoV-2 via nasopharyngeal swabs at day 7 and the proportion of patients who did not require supplemental oxygen therapy or mechanical ventilation on day 14. Safety was assessed. The trial is registered (EudraCT 2021-002,476-39, and ClinicalTrials.gov: NCT05172050).

Findings: A total of 68 participants were enrolled and randomized to placebo (n = 21), raloxifene 60 mg (n = 24), and raloxifene 120 mg (n = 23). The proportion of participants with undetectable SARS-CoV-2 after seven days of treatment with raloxifene 60 mg [36.8%, 7/19 vs. 0.0%, 0/14] and 120 mg [22.2%, 4/18 vs. 0.0%, 0/14] was better compared to placebo, [risk difference (RD) = 0·37 (95% C.I.:0·09-0·59)] and [RD = 0·22 (95% C.I.: -0·03-0·45)], respectively. There was no evidence of effect for requirement of supplemental oxygen and/or mechanical ventilation with effects for raloxifene 60 mg and raloxifene 120 mg over placebo, [RD = 0·09 (95% C.I.: -0·22-0·37)], and [RD = 0·03 (95% C.I.: -0·28-0·33)], respectively. Raloxifene was well tolerated at both doses, and there was no evidence of any difference in the occurrence of serious adverse events.

Interpretation: Raloxifene showed evidence of effect in the primary virologic endpoint in the treatment of early mild to moderate COVID-19 patients shortening the time of viral shedding. The safety profile was consistent with that reported for other indications. Raloxifene may represent a promising pharmacological option to prevent or mitigate COVID-19 disease progression.

Funding: The study was funded by Dompé Farmaceutici SpA and supported by the funds from the European Commission - Health and Consumers Directorate General, for the Action under the Emergency Support Instrument- Grant to support clinical testing of repurposed medicines to treat SARS-COV-2 patients (PPPA-ESI-CTRM-2020-SI2.837140), and by the COVID-2020-12,371,675 Ricerca finalizzata and line 1 Ricerca Corrente COVID both funded by Italian Ministry of Health.

Keywords: COVID-19; Estrogen; Raloxifene; SARS-CoV-2; Selective estrogen receptor modulator (SERM).

Conflict of interest statement

Marcello Allegretti, Giovanni Goisis, Maria De Pizzol, Flavio Mantelli, Carolina Marsiglia, Giuseppe Terpolilli and Andrea R. Beccari are full time Dompé Farmaceutici SpA employees. Elizabeth Marie Gavioli is a full time employee of Dompe, U.S., Inc. Emanuele Pivetta declared a loan from the Butterfly network for ultrasound machines for research purpose. Emanuele Nicastri declared training fees and medical boards of Gilead Science, SOBI, Eli Lilly, and Roche. Andrea Rosario Beccari declared EP20173318.5 compounds for the treatment of COVID-19. Elena Torri, Franco Marinangeli, Francesco Reggiani, Francesco Vaia, Giuseppe Fiorentino, Scorzolini Laura and Serena Vettori have not declared any conflict of interest.

© 2022 The Author(s).

Figures

Figure 1

Trial profile. All consented patients were eligible to be enrolled in the trial. The Safety (SAF) and the Full Analysis Set (FAS) populations consist of all randomized patients who received at least one dose of the investigational product. The SAF population was analyzed according to the actual treatment received, while the FAS population according to ITT principle, i.e. by treatment allocation. AE: Adverse Event.

Figure 2

Endpoint analysis of raloxifene population The primary virological endpoint was the proportion of patients with undetectable SARS-CoV-2 at Day 7 and the primary clinical endpoint was the proportion of patients not requiring oxygen therapy and/or mechanical ventilation at Day 14 within the FAS population. The figure depicts raloxifene 120 mg as the black bar, raloxifene 60 mg as the dark gray bar, and placebo as the light gray color bar. Undetectable was defined as the proportion of participants with undetectable SARS-CoV-2 infection by an approved molecular polymerase chain reaction (PCR) test. Evaluable was defined as the number of participants that were included within the analysis at that time point. Reasons for discontinuing treatment are provided in Fig. 1. All p-values are descriptive in nature with significance defined as a p-value