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The total number of non-serious adverse events was 42 in each the two groups. Conclusions: The combined use of methylprednisolone endometriosis org plus tacrolimus, in addition to the SoC, did not endometriosis org improve endometriosis org time endometriosis org clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19.

Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors.

It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19.

In December 2019, a new type of human coronavirus (SARS-CoV-2), causing an emerging diseases (COVID-19), was first recognized in China and spread globally (1, 2).

The COVID-19 was declared a pandemic by the WHO on March 12, 2020 (3), and it continues to spread worldwide, causing considerable morbimortality and economic damage. SARS-CoV-2 has evolved some mechanisms endometriosis org disturb host-immune response.

In fact, impaired interferon (IFN) signature in early stages leads to a persistent blood viral load and a later hyper-inflammatory response that has been related with a worse COVID-19 outcome (4, 5).

Accordingly, antiviral followed by anti-inflammatory drugs have been recommended (6). While some immunosuppressive treatments could be potentially harmful, others have been suggested for treating the disproportionate inflammation triggered by the SARS-CoV-2 infection endometriosis org. Due to the lack of evidence-based treatments, a large number of patients received off-label and compassionate therapies, based on their in vitro antiviral or immunomodulatory properties.

The repurposing of older drugs was the initial main strategy given their proven safety profile (11). Today, RCTs are still needed in order to provide evidence-based effective and safe therapies for COVID-19 management (12). Our hypothesis was that methylprednisolone pulses plus tacrolimus could be an effective and safe drug combination for endometriosis org COVID-19 patients.

Accordingly, given the health emergency due to endometriosis org rapid spread of SARS-CoV-2 worldwide, we conducted a proof-of-concept study in a randomized, single-center, open-label clinical trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC), vs.

SoC alone, in severe COVID-19 patients with lung injury and systemic hyperinflammatory syndrome. The rationale for the current RCT was based on the fact that corticosteroids, such as methylprednisolone, are a pillar in the treatment of multiple inflammatory diseases, with several mechanisms of action impacting both the innate and adaptive arms of immunity.

Regarding tacrolimus, the reason for its use was based on both the anti-inflammatory and anti-viral actions of calcineurin inhibitors (CNIs). In this respect, severe COVID-19 disease presents a similar clinical and cytokine profile to other disorders like secondary hemophagocytic lymphohistiocytosis (14), where CNIs play a central role in endometriosis org treatment (15).

Additionally, several human coronavirus replication depends on immunophilin pathways, which can be inhibited by CNIs in cell culture (16, 17). Based on these two mechanisms, it has been suggested that CNIs could be used to treat COVID-19 (18).

In endometriosis org, recent non-randomized studies suggest endometriosis org cyclosporine could reduce mortality, mainly in patients with moderate to severe COVID-19 (19, 20). Our study is the first RCT assessing the effect of corticosteroids plus a CNI (tacrolimus) in hospitalized patients with severe Endometriosis org. They are low-cost drugs with a well-known safety profile that could be produced on a large scale if they were effective at treating COVID-19.

TACROVID was a pragmatic, randomized (1:1) with parallel-groups, open-label, single-center, phase II clinical trial to evaluate the efficacy and safety of endometriosis org pulses and tacrolimus plus SoC, Trifarotene Cream (Aklief)- FDA. The TACROVID trial was conducted at Hospital Universitari de Bellvitge (HUB), a 750-bed tertiary care public hospital endometriosis org adults in Barcelona endometriosis org, Spain).

In March 2020, the HUB's Ethical Committee for Drug Research and the Spanish Agency for Drugs and Health Products approved the protocol and informed consent form (ICF). The trial registration numbers are NCT04341038 and EudraCT 2020-001445-39.

All patients (or a legal representative if patients were unable) had to provide ICF prior to initiation of the trial procedures.

The protocol is available endometriosis org (21). Patients were included in the trial if they met all the inclusion criteria endometriosis org none of the exclusion criteria. After obtaining the ICF, patients were randomized using the RedCap, a secure web application endometriosis org building and managing electronic case report forms (eCRF).

Patients were randomly (1:1) assigned to one of the following arms with no baseline stratification:1. The administration of higher doses or longer duration of corticosteroids was allowed if their treating physicians considered it appropriate. Tacrolimus starting dose was 0.

Patients using lopinavir-ritonavir received 0. In addition, patients in the experimental arm could receive standard of care (SoC) for their management in incidencias with treating physicians. Control arm (SoC): SoC included measures of supplemental oxygen and endometriosis org support, fluid therapy, antipyretic treatment, evolutionary measures, low molecular weight heparins, and could also include treatments with unproved antiviral (lopinavir-ritonavir, hydroxichloroquine, etc.

The experimental endometriosis org were started immediately after the participants were randomly assigned to that group. The experimental treatment was discontinued after patients achieved clinical stability, which was endometriosis org in the outcomes section.

All patients were followed from day 0 through day 56 or death. The planned visits and procedures are detailed endometriosis org the TACROVID trial protocol endometriosis org Table 1) (21). Follow endometriosis org visits were face-to-face to evaluate disease outcomes, and data was collected using an eCRF. The Bellvitge Biomedical Research Institute (IDIBELL) Clinical Research and Clinical Trials Unit (UICEC-IDIBELL) carried Imbruvica (Ibrutinib Capsules)- FDA the monitoring of the trial.

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