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
Emanuele Nicastri, Franco Marinangeli, Emanuele Pivetta, Elena Torri, Francesco Reggiani, Giuseppe Fiorentino, Laura Scorzolini, Serena Vettori, Carolina Marsiglia, Elizabeth Marie Gavioli, Andrea R Beccari, Giuseppe Terpolilli, Maria De Pizzol, Giovanni Goisis, Flavio Mantelli, Francesco Vaia, Marcello Allegretti
eClinicalMedicine, doi:10.1016/j.eclinm.2022.101450
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 (2020-003936-25 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.
Muscle or body aches 10 (52¢6% Table 1 : Patient baseline characteristics − FAS/SAF population. Data are presented for the FAS as number, proportion (%) with 95% exact C.I. or mean § SD (standard deviation) Sp02:Oxygen Saturation. * All centers were located in Italy. a Anticoagulants included heparin and enoxaparin. 1 Antibiotics include pencillins, fluroquinolones, and macrolides. x Corticosteroids included dexamethasone and prednisone,This clinical trial was impacted due to the COVID-19 pandemic, and experienced operational difficulties for patient enrollment. The following modifications were made to the original patient population to increase patient recruitment: inclusion of additional centers, lowering the age of the inclusion criteria from 50 to 40 years of age, increasing the time window of SARS-CoV-2 positive results from 7 to 10 days, and deleting a time cut-off of when initial COVID-19 related symptoms were experienced by patients (fever, dyspnea, headache, cough, dysgeusia, conjunctivitis, vomiting, diarrhea, anosmia, muscle or body aches or other symptoms). Any adverse event (Grade ≥3) Adverse Events of Special Interest (AESI) All data are presented as number of patients, proportion (%) with 95% exact C.I. Abbreviations: TEAE: treatment-emergent adverse events, TESAE: Treatment-emergent serious adverse events. Venous
Declaration of interests
Supplementary materials Supplementary material associated with this article can be found in the online version at..
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"source": "Crossref",
"subject": [
"General Medicine"
],
"subtitle": [],
"title": "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",
"type": "journal-article",
"volume": "48"
}
