Background
The dysregulated host response observed in severe COVID-19 infection with the release of cytokines has been implicated as a perpetrator of poor outcomes in COVID-19. The “cytokine storm” typically leads to the release of several mediators, including interleukins, interferons, and tumor necrosis factor. Although this innate response is directed to combat and eliminate the infective pathogen, an overexuberant response can result in irreversible damage to the host. Several clinical trials have explored the effect of cytokine inhibition and its potential for improving clinical outcomes in COVID-19. The results of small randomized controlled trials that evaluated the efficacy of tocilizumab in severe COVID-19 have largely been negative (1–3), except for a trend towards a reduced requirement for mechanical ventilatory support in one study (4). Against this background, the results of two recent trials have added a new dimension to the potential benefit of anti-cytokine therapy in COVID-19 (5,6).
The REMAP-CAP trial
Methodology
The REMAP-CAP trial adopted a response-adaptive randomization design. This design employs frequent interim analyses to evaluate the response to assigned treatments; more patients are assigned to the treatment modality that appears to be beneficial based on a “learn as you go” approach. This is known as the Bayesian approach and aims to maximize power with less likelihood of persisting with ineffective treatment modalities. Multiple modalities of treatment may be tested at the same time under several domains. In the immune modulation domain of the REMAP-CAP trial, the efficacy of two interleukin-6 receptor antagonists tocilizumab and sarilumab were evaluated against a control arm.
Patients
Adult patients admitted to the ICU and requiring respiratory or cardiovascular support were enrolled in the REMAP-CAP trial. Respiratory support was defined as the requirement for invasive or non-invasive mechanical ventilation, high-flow nasal cannula with an FiO2 more than 0.4 and a flow of more than 30 l/min. Cardiovascular support was defined as the requirement for any dose of vasopressor or inotropic support.
Intervention and control
Tocilizumab was administered in a dose of 8 mg/kg actual body weight intravenously, with a maximum dose of 800 mg. A repeat dose was administered in 12 to 24 hours if no clinical improvement occurred. Sarilumab was administered 400 mg/day as a single dose infusion. Both drugs were administered as open label. The standard of care at each center was followed in the control arm. Patients could be randomly assigned to interventions involving other domains. This included the use of corticosteroids based on recommendations following the RECOVERY trial that showed clinical outcome benefit with the use of dexamethasone. The trial included 353 patients in the tocilizumab and 48 in the sarilumab arms; 402 patients were included in the control arm. Patients were severely ill at baseline, with 71% of patients requiring invasive or non-invasive ventilator support.
Outcomes
The primary outcome of the study was organ support-free days. Organ support-free days were significantly higher with tocilizumab and sarilumab therapy compared to the control group (median adjusted OR: 1.65, credible interval 1.25–2.14 for tocilizumab; an OR >1 denotes significantly higher organ support-free days). The in-hospital survival was also significantly better with both therapies compared to the control group. Median adjusted OR for survival: 1.64, credible interval 1.14–2.35 for tocilizumab; an OR >1 denotes a significantly higher hospital survival). Furthermore, the 90-day survival, respiratory support-free days, cardiovascular support-free days, time to ICU discharge, time to hospital discharge, and improvement on an ordinal scale at day 14 were significantly more favorable with both drugs compared to the control group.
The RECOVERY trial
Methodology
The RECOVERY trial was also conducted on an adaptive platform that evaluated multiple modalities of treatment for COVID-19, including dexamethasone, lopinavir-ritonavir, hydroxychloroquine, and azithromycin, compared to a control arm. Patients from the main RECOVERY trial were considered for inclusion in the tocilizumab vs. control study within 21 days of the initial randomization to the respective treatment allocations. Patients with clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75mg/L) were considered for randomization to tocilizumab vs. usual care alone.
Patients and interventions
Among the 21550 patients screened from the main RECOVERY trial, 2022 were randomized to receive tocilizumab and 2094 were assigned to usual care. Overall,14% of patients were receiving invasive mechanical ventilation, 41% were on non-invasive ventilation, and 45% were on supplemental oxygen alone at the time of randomization. Tocilizumab was administered based on body weight, up to a maximum dose of 800 mg intravenously with repeat dosing after 12–24 h if no improvement. Patients were followed up at 28 days after randomization or until death or discharge from hospital, whichever occurred earliest.
Outcomes
The primary outcome, the 28-day mortality, was significantly lower with tocilizumab compared to the control group [29% vs. 33%, relative risk: 0.86 (0.77–0.96); p = 0.0066]. Among the secondary outcomes, a significantly larger number of patients were discharged alive from the hospital at 28 days with tocilizumab use. Among patients who were not ventilated at randomization, the requirement for invasive mechanical ventilation was significantly lower with tocilizumab. Successful weaning and liberation from invasive mechanical ventilation were similar in both groups. However, the use of hemodialysis or hemofiltration was significantly lower in the tocilizumab arm. On subgroup analysis, reduced 28-day mortality was observed regardless of age, gender, ethnicity, level of respiratory support, and duration of symptoms.
The favorable effect on 28-day mortality was most evident when corticosteroids were combined with tocilizumab. The RECOVERY trial is currently in the pre-print format and not been peer-reviewed. The study was limited by only 92% of patients being evaluated for 28-d mortality; 17% of patients randomized to tocilizumab did not receive it. A longer duration of follow-up may be required as the 28-day interval may be too short to evaluate outcomes in patients with severe COVID-19 who may require more prolonged supportive care.
Are we heading towards calming the cytokine storm?
The REMAP-CAP and RECOVERY trials have switched the focus back to immunomodulatory therapy with tocilizumab in patients with COVID-19 infection. We seem to have gone through a full circle with anti-cytokine therapy, with initial unfulfilled promise and renewed hope for the future in light of the new evidence. However, there are several important points that need to be considered.
Tocilizumab inhibits interleukin-6 alone, while corticosteroids exert influence along several inflammatory pathways. When caught in the middle of a cytokine storm, a single-pronged strategy may not suffice. The REMAP-CAP and the RECOVERY trials perhaps exemplify this effect, with 88% of patients in the former and 82% in the latter trial receiving combination therapy with corticosteroids. Indeed, in the RECOVERY trial, improved 28-day mortality was confined to the subgroup of patients who received corticosteroids.
The REMAP-CAP and RECOVERY trials offer fresh insight into cytokine inhibition-directed therapy in COVID-19. Both trials used an adaptive platform. Although innovative and pragmatic, the adaptive design is more complex, and results are often difficult to interpret compared to a head-to-head randomized controlled trial. The favorable results of these two trials need to be tempered with the findings of the more conventional, double-blind, randomized controlled, COVACTA trial. No difference was observed in clinical status or 28-day mortality between the tocilizumab and control groups in this trial (7).
Indeed, it is unlikely that we have heard the last word on calming the cytokine storm in severe COVID-19. A point to ponder is the rapidly evolving therapeutic strategies, as physicians gain more experience with the disease, that has led to perceptibly improved outcomes compared to the early phase of the pandemic. Clinical trials carried out at different points of time in the pandemic may thus come up with divergent results.
Summary
- Severe COVID-19 is characterized by cytokine release, potentially leading to adverse clinical outcomes
- Several studies have evaluated the effect of anti-cytokine therapy, with conflicting results
- The REMAP-CAP trial revealed improvement in several clinical outcomes, including a reduced number of organ support-free days and improved in-hospital survival with tocilizumab and sarilumab compared to a control group
- The RECOVERY trial also resulted in reduced 28-day mortality and a lower requirement for invasive mechanical ventilation with tocilizumab
- Both these trials, conducted on a responsive-adaptive randomization platform, have added a possible new dimension to our practice regarding the management of COVID-19
- Although pragmatic and convenient, the findings of a response-adaptive design need to be further evaluated in head-to-head randomized controlled trials
References
1. Veiga VC, Prats JAGG, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021 Jan 20;372:n84.
2. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Dec 10;383(24):2333–44.
3. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24–31.
4. Hermine O, Mariette X, Tharaux P-L, Resche-Rigon M, Porcher R, Ravaud P, et al. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):32–40.
5. REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Feb 25;
6. Horby PW, Pessoa-Amorim G, Peto L, Brightling CE, Sarkar R, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021 Feb 11;2021.02.11.21249258.
7. Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Feb 25;0(0):null.
