Effectiveness of rosuvastatin plus colchicine, emtricitabine/tenofovir and combinations thereof in hospitalized patients with COVID-19: a pragmatic, open-label randomized trial

Abstract

Background: The use of rosuvastatin plus colchicine and emtricitabine/tenofovir in hospitalized patients with SARS-CoV-2 disease (COVID-19) has not been assessed. The objective of this study was to assess the effectiveness and safety of rosuvastatin plus colchicine, emtricitabine/tenofovir, and their combined use in these patients.

Methods: This was a randomized, controlled, open-label, multicentre, parallel, pragmatic study conducted in six referral hospitals in Bogotá, Colombia. The study enrolled hospitalized patients over 18 years of age with a confirmed diagnosis of COVID-19 complicated with pneumonia, not on chronic treatment with the study medications, and with no contraindications for their use. Patients were assigned 1:1:1:1. 1) emtricitabine with tenofovir disoproxil fumarate (FTC/TDF, 200/300 mg given orally for 10 days); 2) colchicine plus rosuvastatin (COLCH+ROSU, 0.5 mg and 40 mg given orally for 14 days); 3) emtricitabine with tenofovir disoproxil plus colchicine and rosuvastatin at the same doses and for the same period of time (FTC/TDF+COLCH+ROSU); or 4) the Colombian consensus standard of care, including a corticosteroid (SOC). The primary endpoint was 28-day all-cause mortality. A modified intention-to-treat analysis was used together with a usefulness analysis to determine which could be the best treatment. The trial was registered at ClinicalTrials.gov: NCT04359095.

Findings: Out of 994 candidates considered between August 2020 and March 2021, 649 (65.3%) patients agreed to participate and were enrolled in this study; among them, 633 (97.5%) were included in the analysis. The mean age was 55.4 years (SD ± 12.8 years), and 428 (68%) were men; 28-day mortality was significantly lower in the FTC/TDF+COLCH+ROSUV group than in the SOC group, 10.7% (17/159) vs. 17.4% (28/161) (hazard ratio [HR] 0.53; 95% CI 0.29 to 0.96). Mortality in the FTC/TDF group was 13.8% (22/160, HR 0.68, 95% CI 0.39 to 1.20) and 14.4% in the COLCH+ROSU group (22/153) (HR 0.78, 95% CI 0.44 to 1.36). A lower need for invasive mechanical ventilation was observed in the FTC/TDF+COLCH+ROSUV group than in the SOC group (risk difference [RD] - 0.08, 95% CI 0.11 to 0.04). Three patients presented severe adverse events, one severe diarrhoea in the COLCH+ROSU and one in the FTC/TDF+COLCH+ROSU group and one general exanthema in the FTC/TDF group.

Interpretation: The combined use of FTC/TDF+COLCH+ROSU reduces the risk of 28-day mortality and the need for invasive mechanical ventilation in hospitalized patients with pulmonary compromise from COVID-19. More randomized controlled trials are needed to compare the effectiveness and cost of treatment with this combination versus other drugs that have been shown to reduce mortality from SARS-CoV-2 infection and its usefulness in patients with chronic statin use.

Figure 1

Enrolment, Randomisation, and Inclusion in the intention-to-treat analysis. 1576 patients were seen in the six hospitals; 599 (38%) had some exclusion criteria, mainly chronic use of statins in 582. Overall, 994 patients were invited to participate in the study, 328 (33%) refused to sign the informed consent, 649 were randomised and assigned to one of four arms of treatment. Of them, 3 subjects did not meet protocol selection criteria, 3 subjects were lost of follow-up and 10 patients withdrew; consequently, the primary outcome was unknown in 13 patients, so they were not included in the analysis. Finally, 633 patients were considered in the modified ITT analysis.

Figure 2

Time to death analysis Kaplan-Meier plots of the cumulative estimate of the outcome of death from any cause. HR: Hazard Ratio. 95% CI: 95% confidence interval. COLCH: Colchicine. ROSU: Rosuvastatin. FTC/TDF: Emtricitabine/Tenofovir disoproxil fumarate. (A) COLCH+ROSUV compared with Standard of Care, (B) FTC/TDF + COLCH + ROSUV compared with Standard of Care, and (C) FTC/TDF compared with Standard of Care. Hazard Ratios (HR) estimated from shared-frailty (i.e., hospital random-effects) Cox models. The global test of proportional-hazards assumption on the basis of Schoenfeld residuals is chi2=5.76 (p=0.12).

Figure 3

Secondary Outcomes with Unadjusted Estimates (GEE models) Unadjusted Risk Differences were estimated using Log-binomial General Estimating Equation (GEE) models, assuming exchangeable correlation structure with each centre as a cluster. ICU: intensive care unit. FTC/TDF: Emtricitabine/Tenofovir disoproxil fumarate. 95% CI: 95% confidence interval. Patients who were in the ICU at the time of randomisation or before are excluded of the analysis of transfer to ICU outcome. Patients who required ventilation at the time of randomisation or before are excluded of the analysis of ventilation requirement outcome.