Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial

Abstract

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients.Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization.Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39–1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00–17.5] vs. 18.5 days [3.00–53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC.Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to 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.Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

COVID-19 Disease and Dermatomyositis: A Mini-Review

“…Tacrolimus has a positive effect on survival in liver transplant patients with symptoms of COVID-19 compared to other immunosuppressants, including cyclosporine and mycophenolate mofetil (65). Nevertheless, there was no improvement in severe COVID-19 patients who received a combination of methylprednisolone pulses and tacrolimus (66).…”

“…Tacrolimus has a positive effect on survival in liver transplant patients with symptoms of COVID-19 compared to other immunosuppressants, including cyclosporine and mycophenolate mofetil ( 65 ). Nevertheless, there was no improvement in severe COVID-19 patients who received a combination of methylprednisolone pulses and tacrolimus ( 66 ). A prospective study demonstrated that a combination of high-dose glucocorticoids, tacrolimus and intravenous cyclophosphamide improved survival in anti-MDA5 + DM patients complicated with ILD.…”

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper

“…Whilst antimetabolic drugs seem to have a negative effect [ 104 ], calcineurin inhibitors (e.g. tacrolimus, ciclosporin) and mTOR inhibitors may have a favourable impact on disease course [ [109] , [110] , [111] , [112] ]. Therefore, adjustments to the dose and type of immunosuppression during SARS-CoV-2 infection should be individually tailored based on COVID-19 severity, the specific regimen used, time post-transplant, and the risk of allograft rejection.…”

“…A single small randomized controlled trial of 55 patients with severe COVID-19 indicated that combination therapy with methylprednisolone and tacrolimus resulted in numerically lower all-cause mortality compared with standard treatment. However this difference was not significant and dual therapy was associated with an increased risk of secondary infections [ 111 ].

EASL position Calcineurin inhibitors should not be routinely modified following SARS-CoV-2 infection (exception: see statement on nirmatrelvir/r).

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Effect of corticosteroid therapy on mortality in COVID‐19 patients—A systematic review and meta‐analysis

“…A total 24 studies demonstrated the beneficial effects of the corticosteroid therapy on the prevention of mortality in the COVID-19 patients 3,7,8,10,12,34,42,43,45,46,48,[50][51][52][53][54][55]57,59,61,63,64,66,67 while 17 studies were reported the increased mortality in the corticosteroid therapy received COVID-19 patients 32,33,[35][36][37][38][39][40][41]44,48,[56][57][58]60,65 while 2 studies reported the neutral effects of the corticosteroid therapy on the prevention of mortality in the COVID-19 patients. 49,62 Four types of corticosteroid were used as single or multiple steroids individually including Methylprednisolone (n = 24), Dexamethasone (n = 6), Hydrocortisone (n = 1), Prednisone (n = 1), corticosteroid used individually including Methylprednisolone and Dexamethasone in the study (n = 6) unknown corticosteroid (n = 5) (Table 1).…”