Tocilizumab and remdesivir in hospitalised patients with severe COVID‑19 pneumonia

The Coronavirus 2019 infection (COVID-19) has affected the global health since its initial outbreak in 2019. Most patients exhibit a mild presentation and need only symptomatic treatment and supportive care. Nonetheless, 20% of patients progress to a grave condition with acute respiratory distress syndrome (ARDS), multiorgan failure, and death.

The REMDACTA trial, a randomised, double-blind, placebo-controlled, multicenter, phase 3 study, evaluated the efficacy and safety of tocilizumab plus remdesivir (T+R) versus placebo plus remdesivir (P+R) in hospitalised patients with severe COVID-19 pneumonia, between June 2020 and March 2021. The primary hypothesis was that the combination of remdesivir and tocilizumab (intervention group) would be more beneficial than remdesivir alone to SOC (control group).

Inclusion criteria were: a positive SARS-CoV-2 PCR result within 7 days of randomisation, pneumonia confirmed by radiology, and hypoxemia requiring > 6 L/min supplemental oxygen.

Exclusion criteria comprised of an age limit at 12 years old, a glomerular filtration rate <30 mL/min (including patients under renal replacement therapy), an elevation of > 5× for alanine and/or aspartate aminotransferase levels, and suspicions of active bacterial, fungal, viral, or other infection except for COVID- 19. Systemic corticosteroids for COVID-19 pneumonia were permitted, as well as ≤ 2 doses of remdesivir before randomisation. Contrarily, convalescent plasma, chloroquine or hydroxychloroquine, antivirals, biologics, and Janus kinase inhibitors were prohibited during the trial.

The trial was sponsored by F. Hoffmann-La Roche Ltd and conducted with the help of a contract research organisation that monitored the trial under the direction and supervision of the sponsor.

Recruited patients received tocilizumab plus remdesivir or placebo plus remdesivir after their randomisation, in a blinded manner, in a 2:1 ratio. This process was stratified by location and clinical presentation at screening, based on a 7-category scale. All drugs were administered intravenously with tocilizumab 8 mg/kg (maximum, 800 mg) or placebo on day 1, following the initial injection of Remdesivir. According to the protocol, a blinded second injection of tocilizumab or placebo within 8 to 24 h of the first administration could be used in cases of persistent fever or clinical worsening.

The primary outcome was time to actual hospital discharge or “ready for discharge,” or a clinical category 1 (equivalent clinical status), assessed by the investigator on the 7-category ordinal scale till day 28. The secondary outcomes (also assessed on day 28) were the elapsed time from randomisation to initiation of mechanical ventilatory support or death and clinical status on the ordinal scale at day 14. Mortality was assessed at days 28 and 60.

Overall, 4 countries with 53 sites screened 709 and enrolled 649 patients from June 2020 to January 2021. Of those, 434 were randomised to the tocilizumab plus remdesivir group and 215 to the placebo plus remdesivir group. Three-quarters of patients completed the trial till day 28: 336 (77.4%) in the T+R arm and 160 (74.4%) in the P+R arm. The most typical reason for not completing the trial was death, with similar rates in both arms (18% in the T+R and 19.5% in the P+R groups). A repeat injection of tocilizumab or placebo was administered in 85 patients (19.8%) in the study T+R arm and 48 (22.7%) in the control P+R arm (safety population) as per protocol.

The primary outcomes interpretation showed that median time from randomisation to hospital discharge, or the equivalent conditions as described above, were similar in both study groups (14 days, 95% CI 12–15 days in the T+R arm and 14 days 95% CI 11–16 in the P+R arm [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78–1.19)]. Additionally, the percentages of patients discharged or of equivalent conditions were again comparable (66% in the intervention group and 67.1% in the control group). This pattern continued, with minor differences regarding the time to hospital discharge, in the specified subgroups of patients (according to demographics, corticosteroid use at baseline, remdesivir use before randomisation, or mechanical ventilation at baseline), and according to baseline ordinal scale category. The only disparities were observed in patients of ordinal category 5 at baseline (39 in the intervention, 9 in the control group) for whom tocilizumab was associated with longer time to discharge [hazard ratio 0.36 (95% CI 0.14–0.91); however, the limited population in this specific subgroup diminishes its value].

The secondary outcomes deducted that mechanical ventilation or death, by day 28, occurred in matching percentages in both groups (123 patients, 28.6%, in the T+R and 61 patients, 29% in the P+R). Median time to initiation of ventilatory support or death was uninterpreted in both arms because it occurred in less than half of the population [log-rank P = 0.90; hazard ratio 0.98 (95% CI 0.72–1.34)]. The mean clinical status on the 7-category scale at day 14, was again comparable in both arms (2.8 (95% CI 2.6–3) in the T+R and 2.9 (95% CI 2.6–3.2) in the P+R [difference –0.07 (–0.4, 0.3); P = 0.72]. Mortality by day 28, was similar in both groups (18.1% in the T+R arm, 19.5% in the P+R arm with a weighted difference of –1.3% (95% CI –7.8%, 5.2%); P = 0.69], and the same was observed for time to death among the main study groups and the specific subgroups (based on demographics, corticosteroid use at baseline, remdesivir use before randomisation, or mechanical ventilation at baseline).

As for the safety conclusions, the population who presented ≥ 1 adverse event (AE) was 320 of 429 (74.6%) in the T+R arm and 147 of 213 (69%) in the P+R arm. Serious AE (SAE) was recorded in 128 patients (29.8%) in the T+R group and 72 (33.8%) in the P+R. Adverse events responsible for treatment discontinuation were described in 46 patients (10.7%) in the T+R and 28 (13.1%) in the P+R arm, while AEs of particular interest were similar between both groups, with severe infections [86 (20%) and 53 (24.9%)] and serious bleeding events [11 (2.6%) and 7 (3.3%)]. The most frequent severe infection (recorded in > 1% of participants in each arm) was the advancement of underlying COVID-19 infection (required to be reported as a serious adverse event if COVID-19 resulted in death), septic shock, sepsis, and pneumonia of bacterial or other aetiology.

STUDY STRENGTHS & LIMITATIONS

Strengths

• This was the first multicenter, double-blind, randomised, placebo-controlled trial to examine the inhibition of interleukin-6 in COVID-19 patients with the co-administration of remdesivir. Since it was started at the initial stages of the pandemic, it preceded other randomised controlled trials of tocilizumab administration.
• Following other investigations, the primary outcome is the time to discharge or “ready for discharge”, which is considered a more sensitive and clinically relevant outcome in severe COVID-19 infections.
• Since the trial’s initiation, remdesivir became a mainstay of SOC. Hence, the protocol was amended to include patients with up to 2 doses of remdesivir prior to randomisation.

Limitations

• This trial could not detect a clinically significant effect on mortality, as it was documented in larger studies.
• Despite the randomisation process, as described by the authors, there was a minor disproportion in baseline attributes among the treatment arms (in the tocilizumab plus remdesivir arm, more enrolled patients required invasive mechanical ventilation, were 65 years or older, and fewer received corticosteroids). These imbalances may have produced an accumulative bias, promoting the placebo plus remdesivir group.

TAKE-HOME MESSAGES

In this multicenter, randomised, double-blind, placebo-controlled trial for patients with severe COVID-19 pneumonia, the combination of tocilizumab and remdesivir did not affect the hospital discharge time compared to placebo plus remdesivir.

There were no variations in the key secondary outcomes of time to mechanical ventilation or death events up to day 28, clinical condition on assessment at day 14, and time to death, up to study conclusion dates. Serious infections remained equivalent in both study arms, and no unpredicted safety concerns were detected.

The constant refinement of SOCs during this pandemic has hinted incertitude regarding tocilizumab combined with other treatments, including corticosteroids and remdesivir.

However, the recommendation by the World Health Organization and other expert panels of interleukin-6 receptor inhibition is anticipated to reinforce the use of tocilizumab as standard of care, in patients with severe and critical COVID-19 disease.

This article review was prepared and submitted by Dimitrios Papadopoulos MD, MSc, PhD, Consultant in Intensive Care Medicine, General Hospital of Larisa, Larisa, Greece, on behalf of the ESICM Journal Review Club.