Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Abstract

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated.

Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615.

Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60.

Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments.

Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

Keywords: Coronavirus disease 2019; Interleukin-6; Randomised controlled trial; Severe acute respiratory syndrome coronavirus-2; Tocilizumab; Viral load.

Figure 1

COVACTA trial profile. *Three patients were rescreened and subsequently randomly assigned. ^†Patient was randomly assigned again and later received study treatment. Abbreviations: IRB, Institutional Review Board; SOC, standard of care.

Figure 2

Summary forest plots showing the hazard ratio of time to death by day 60 associated with (a) demographics, (b) baseline disease characteristics and concomitant medications, (c) comorbidities, and (d) biomarkers (mITT population). Hazard ratios were estimated using Cox proportional hazards model (unstratified). A hazard ratio of <1 favoured tocilizumab over placebo. Patients who did not die were censored at study completion or early withdrawal. (b) Baseline ordinal scale refers to clinical status assessed on a 7-category ordinal scale (1, discharged/ready for discharge; 2, non–ICU hospital ward/ready for hospital ward, not requiring supplemental oxygen; 3, non–ICU hospital ward/ready for hospital ward, requiring supplemental oxygen; 4, ICU or non–ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death). *Ordinal scale 6 included one patient who was initially in ordinal scale 6 on day 1 but died (ordinal scale 7) on day 1. Baseline steroid or antiviral use was defined as between day –7 and day 1. Steroid treatments included corticosteroids except those reported as topical, inhalant or dermatological. Antiviral treatments included lopinavir/ritonavir, remdesivir, lopinavir, ritonavir, chloroquine, hydroxychloroquine, or hydroxychloroquine sulphate. (c) Any comorbidities include patients with ≥1 comorbidity of obesity, diabetes, cardiovascular impairment, hepatic impairment, hypertension, or chronic lung disease. (d) Baseline nasopharyngeal/oropharyngeal swab or serum viral load was defined as a patient's most recent assessment before the first dose of study medication. If no assessment was available with a time before the first dose of study medication, the assessment labelled as ‘day 1 predose’ assessment was treated as baseline. Baseline IL-6, ferritin, and CRP levels were determined by a patient's most recent pretreatment assessment. Patients whose baseline CRP or ferritin values were above the upper limit of the assay were assigned to the highest category. Patients whose baseline IL-6 or viral load values were below the limit of quantification or were negative (viral load only) were assigned to the lowest category. Abbreviations: CRP, C-reactive protein; ICU, intensive care unit; IL-6, interleukin-6; mITT, modified intention-to-treat; NE, not evaluable.

Figure 3

Viral load from (a) swab and (c) serum samples over time and time to first negative RT-qPCR result in (b) swab and (d) serum samples in patients with positive test results at baseline (safety population). (a, b) Nasopharyngeal or oropharyngeal swab samples. (a, c) Data shown are median (95% CI). Horizontal dashed line represents the LOQ of 0.12 copies/μL. Any values reported as below the LOQ were set to the LOQ value minus 0.001 (0.119 copies/μL), and any values reported as negative were set to half the LOQ value (0.06 copies/μL). Baseline is the last pretreatment assessment. If no assessment was available with a time before the first dose of study medication, the assessment labelled as ‘day 1 predose’ assessment was treated as baseline. The AUC was calculated post hoc using the trapezoidal method adjusted by the date and time of the last available assessment of each patient. (b, d) Data are shown as 1 minus the Kaplan-Meier estimator. Time to negative RT-qPCR result was defined as days from the first dose of study drug to time of negative RT-qPCR result in swab or serum samples. Only patients with ≥1 virology assessment were included. Patients who discontinued the study or were lost to follow-up before a virus negativity result were censored at their last virology assessment. Patients who died were censored at day 28 (swab samples) or day 17 (serum samples). Cox proportional hazards model stratified by region and mechanical ventilation at randomisation. Abbreviations: AUC, area under the curve; CI, confidence interval; LOQ, limit of quantification; RT, qPCR-reverse transcriptase–quantitative polymerase chain reaction; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.