tetano
Editor, Senior Moderator
EClinicalMedicine
. 2022 Jun;48:101450.
doi: 10.1016/j.eclinm.2022.101450. Epub 2022 May 12.
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[SUP] 1 [/SUP], Franco Marinangeli[SUP] 2 [/SUP], Emanuele Pivetta[SUP] 3 [/SUP], Elena Torri[SUP] 4 [/SUP], Francesco Reggiani[SUP] 5 [/SUP], Giuseppe Fiorentino[SUP] 6 [/SUP], Laura Scorzolini[SUP] 1 [/SUP], Serena Vettori[SUP] 6 [/SUP], Carolina Marsiglia[SUP] 7 [/SUP], Elizabeth Marie Gavioli[SUP] 8 [/SUP], Andrea R Beccari[SUP] 9 [/SUP], Giuseppe Terpolilli[SUP] 10 [/SUP], Maria De Pizzol[SUP] 10 [/SUP], Giovanni Goisis[SUP] 10 [/SUP], Flavio Mantelli[SUP] 7 [/SUP], Francesco Vaia[SUP] 1 [/SUP], Marcello Allegretti[SUP] 7 [/SUP], Raloxifene Territorial Health COVID19 STUDY GROUP
Affiliations
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).
. 2022 Jun;48:101450.
doi: 10.1016/j.eclinm.2022.101450. Epub 2022 May 12.
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[SUP] 1 [/SUP], Franco Marinangeli[SUP] 2 [/SUP], Emanuele Pivetta[SUP] 3 [/SUP], Elena Torri[SUP] 4 [/SUP], Francesco Reggiani[SUP] 5 [/SUP], Giuseppe Fiorentino[SUP] 6 [/SUP], Laura Scorzolini[SUP] 1 [/SUP], Serena Vettori[SUP] 6 [/SUP], Carolina Marsiglia[SUP] 7 [/SUP], Elizabeth Marie Gavioli[SUP] 8 [/SUP], Andrea R Beccari[SUP] 9 [/SUP], Giuseppe Terpolilli[SUP] 10 [/SUP], Maria De Pizzol[SUP] 10 [/SUP], Giovanni Goisis[SUP] 10 [/SUP], Flavio Mantelli[SUP] 7 [/SUP], Francesco Vaia[SUP] 1 [/SUP], Marcello Allegretti[SUP] 7 [/SUP], Raloxifene Territorial Health COVID19 STUDY GROUP
Affiliations
- PMID: 35582123
- PMCID: PMC9098200
- DOI: 10.1016/j.eclinm.2022.101450
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).