Trial NCT04341038; EudraCT 2020-001445-39
Publication Solanich X, Front Med, 2021 (published paper)
Dates: 2020-04-01 to 2020-05-02
Funding: Public/non profit (Departament de Salut de la Generalitat de Catalunya)
Conflict of interest: No

Methods
RCT
Blinding: Unblinded
Location : Single center / Spain
Follow-up duration (days): 56
Inclusion criteriaCOVID-19 infection confirmed by nasopharyngeal RT-PCR; New pulmonary infiltrates (either by chest X-ray or computerized axial tomography); Respiratory failure defined by PaO2/FiO2 < 300 or SpO2/FiO2 < 220; High analytical inflammatory parameters: CRP > 100 mg/L, and/or D-Dimer > 1,000 μg/L, and/or Ferritin > 1,000 μg/L.
Exclusion criteriaCritically ill patients with life expectancy ≤ 24 h; Glomerular filtration ≤ 30 ml/min/1.73m2; Leukopenia ≤ 4,000 cells/μl or other conditions that cause immunosuppression; Concomitant potentially serious infections; Contraindication for the use of corticosteroids or tacrolimus according to the Summary of Product Characteristics; Known hypersensitivity to any of the study drugs, their metabolites, or formulation excipient; Previous participation in a RCT in the last 3 months.
Interventions
Treatment
Methylprednisolone pulse+Tacrolimus
IVMP 120 mg/day on 3 consecutive days (higher doses or longer duration was allowed per physicians discretion) + TAC starting dose of 0.2 mg/kg every 2 days (or 0.1 mg/kg/day) - Thereafter, TAC dosing was individualized to achieve blood trough levels of 8–10 ng/ml.
Control
Standard care ( / )
Definition of Standard care: supplemental oxygen and respiratory support, fluid therapy, antipyretic treatment, postural measures, low molecular weight heparins, and could also include treatments with unproved antiviral (lopinavir-ritonavir, hydroxichloroquine, etc.) or immunosuppressive (any regimen of corticosteroids, tocilizumab, anakinra, etc.) drugs, or those necessary at the discretion of the treating physician, except for cyclosporine and/or tacrolimus.
Participants
Randomized
55 participants (n1=27 / n2= 28)
Characteristics of participants
N=55
Mean age : 63.2
44 males
Severity : Mild: n=0 / Moderate: n=0/ Severe: n=55 Critical: n=0
Primary outcome
In the register
Time to reach clinical stability [Time Frame: 28 days]: Assess the days until clinical stability is achieved after initiating randomization in hospitalized patients with elevated inflammatory parameters and severe COVID-19 lung injury. Clinical stability is defined if all the following criteria are met for 48 consecutive hours: Body temperature ≤ 37.0ºC; PaO2 / FiO2> 400 and / or SatO2 / FiO2> 300; Respiratory rate ≤ 24 rpm.
In the report
time (days) to clinical stability within 56 days after randomization. Clinical stability was defined as fulfilling all of the following criteria for 48 consecutive hours: body temperature ≤37.5◦C; PaO2/FiO2 >400 and/or SpO2/FiO2 > 300; and respiratory rate ≤ 24 rpm.
Documents
available

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing stated
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment The trial was ended prematurely. It didn't reach the target sample size of 84 and the authors state it was thus underpowered. In addition to the preprint, the protocol, statistical analysis plan and study registry were used in data extraction and risk of bias assessment. The primary outcome in the report (time to clinical stability within 56 days) differed slightly from one registry (28 days). The 8-point ordinal scale upon which the outcome clinical improvement and WHO score 7 and above are based was added to the trial protocol during follow up after enrollment of the last patient, but before termination of the study. There were no other substantive changes from the registry/protocol in the study population, procedures, intervention and control treatments. Unblinded study. The methylprednisolone cumulative dose was higher in the control group compared to the intervention group.