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Tocilizumab Fairytale in COVID-19

Dr Swapnil Pawar March 15, 2021 271


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    Tocilizumab Fairytale in COVID-19
    Dr Swapnil Pawar

Blog Written by – Dr Jose Chacko

REMAP-CAP

Study population

Patients 18 years of age or older, with either clinically suspected or microbiologically confirmed Covid-19, admitted to an intensive care unit (ICU) and receiving respiratory or cardiovascular organ support. Within 24 hours of commencement of organ support

Respiratory support

Intubation ventilation or NIV

High-flow nasal cannulae with flow rates more than 30 liters per minute and the fraction of inspired oxygen more than 0.4

Cardiovascular support

Vasopressor or inotrope infusion

Excluded

Imminent death, limiting of therapy

Previously participated in the REMAP-CAP trial

Design

The Immune Modulation Therapy domain included 5 arms

Bayesian design

Interim analyses at regular intervals. Randomization based on response until analysis with preferential assignment to interventions that reveal favorable responses.

Posterior probability = prior probability + new evidence (called likelihood)

Posterior odds ratios with their 95% credible intervals and the probability that:

Each intervention (including control) was the best in the domain

A particular experimental intervention was superior to control (efficacy)

Two experimental interventions were equivalent

A particular experimental intervention was futile compared with control.

Interventions

Two interleukin-6 receptor antagonists: tocilizumab and sarilumab

One interleukin-1 receptor antagonist: anakinra

Interferon beta-1a and control

At least one intervention vs. one control arm at each center

Started with balanced assignment to tocilizumab, sarilumab, or control

Open label administration

Tocilizumab: 8 mg/kg of actual body weight IV, maximum 800 mg, over 1 h. Repeat dose in 12 to 24 hours if no clinical improvement.

Sarilumab, 400 mg/d as a single dose infusion

Control

Standard of care at each site

Participants could be randomly assigned to other interventions within other domains

Corticosteroid study closed during the course of the trial (June 17, 2020); could be administered according to recommendation after this period (immune modulation therapy domain between April 19 -November 19, 2020; sarilumab was available from June 20).

October 28, Interim analysis: Tocilizumab met criteria for efficacy [posterior probability, 99.75%; (pre-defined posterior probability for efficacy = 99%) odds ratio, 1.87; 95% credible interval, 1.20 to 2.76].

113 sites across six countries

2046 patients with severe disease had been randomized to all REMAP-CAP domains

895 randomized to the Immune Modulation Therapy domain (366 to tocilizumab, 48 to sarilumab, 412 to control, and 69 to other experimental therapies in the immune modulation therapy domain) (Fig. 1).

865 were included in the final analysis; 707 after RECOVERY; 158 before RECOVERY

Of the 158 before RECOVERY

  • 107 assigned to the Corticosteroid domain of REMAP-CAP
  • 41 to a 7-day course of hydrocortisone
  • 39 to shock-dependent hydrocortisone
  • 27 to no hydrocortisone (control group of the corticosteroid domain)

707/895 enrolled after the June 17 announcement of the dexamethasone result (RECOVERY) 93% (610 of 654) were treated with glucocorticoids at enrollment or within the following 48 hours (Does this mean that 654/707 were administered corticosteroids?)

After a subsequent interim analysis, the data and safety monitoring board reported that sarilumab had also met the statistical criteria for efficacy; the outcomes with sarilumab was also published.

Primary outcome

Number of days free of respiratory and cardiovascular support at day 21

All deaths within the hospital are assigned the worst outcome (–1 day free of supports)

1.5 days considered to be the minimum meaningful clinical difference between treatment groups in previous FDA–approved trial

Organ support free days

*An odds ratio greater than 1 represents improved survival, more organ support–free days, or both.

In-hospital survival    

*An odds ratio greater than 1 represents improved survival, more organ support–free days, or both.

Analysis of the primary outcome repeated in a second model. In the second model, data were included only of patients enrolled in domains that had ceased recruitment. This constituted the Unblinded Intention To Treat (ITT) population. 

Secondary outcomes

90-day survival

Respiratory support-free days

Cardiovascular support-free days

Time to ICU discharge

Time to hospital discharge

Improvement in the ordinal scale at day 14

 

Comments

The primary outcome should have been mortality?

Open-label – caregivers knew what the patients were receiving

Although innovative and pragmatic, the adaptive design is more complex results are often difficult to interpret, compared to a head-to-head randomized controlled trial.

RECOVERY

Background

Tocilizumab used in the chimeric antigen receptor T-cell induced cytokine release syndrome

7 previous studies (8-14) in COVID-19, including REMAP-CAP

Setting

Eligible if clinically suspected of COVID-19, laboratory-confirmed disease.

Design

  1. Patients in the main RECOVERY trial were considered for up to 21 days after the main randomization. This was regardless of initial randomization and treatment allocation.
  2. Included
  3. RECOVERY trial participants with clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L) could be considered for randomisation to tocilizumab vs. usual care alone
  4. Not included
  5. Tocilizumab considered definitely indicated or contraindicated by the treating physician

Hypersensitivity to tocilizumab, evidence of active tuberculosis infection or clear evidence of active bacterial, fungal, viral, or other infection (besides COVID-19) were not eligible for randomisation to tocilizumab

Assuming a mortality of 25% recruitment of around 4000 patients to this comparison would provide 90% power at two-sided P=0.01 for a proportional reduction in mortality of one fifth

  1. 4116 (19%) of 21550 patients enrolled into the RECOVERY trial at one of the 131 sites in the UK participating in the tocilizumab comparison were eligible for randomisation.  2022 randomized to tocilizumab and 2094 were randomly to usual care
  1. Intervention

Tocilizumab, maximum of 800 mg; repeated after 12–24 h if no improvement

Common to both groups

  1. Followed up until discharge, death, or at 28 days after the initial randomization, whichever occurred earliest. Outcomes assessed at 28 days.
  2. Primary outcome
  3. All-cause mortality
  4. Secondary outcomes
  5. Time to discharge among survivors

Rate of invasive mechanical ventilation, ECMO, and death among those not on invasive mechanical at randomization

Subsidiary clinical outcomes

  1. Use of non-invasive respiratory support: (high flow nasal oxygen, continuous positive airway pressure, or non-invasive ventilation)
  2. Time to successful cessation of invasive mechanical ventilation (time to cessation of invasive mechanical ventilation among 28-day survivors)
  3. Use of renal replacement therapy
  4. Safety outcomes: Cause-specific mortality and major cardiac arrhythmia.

Prespecified subgroup analysis

Age, sex, ethnicity, level of respiratory support, days since symptom onset, and use of systemic corticosteroids (including dexamethasone)

Results

(*Analyses include only those on no ventilator support or non-invasive ventilation at second randomisation. †Analyses include only those on no ventilator support at second randomisation.)

No significant effect of tocilizumab on subsequent receipt of non-invasive respiratory support or invasive mechanical ventilation among those on no respiratory support at randomization. No difference in successful cessation of ventilation (sample size may be too small to detect a difference)

Subgroup analysis

Age, sex, ethnicity, level of respiratory support, days since symptom onset, and use of systemic corticosteroids (including dexamethasone). Effect was seen across all subgroups.

Men, white, use of corticosteroids – effect of tocilizumab was more pronounced 

Adverse events

No significant differences in the frequency of new cardiac arrhythmias. There were three reports of serious adverse reactions believed to be related to tocilizumab: one each of otitis externa, Staphylococcus aureus bacteraemia, and lung abscess, all of which resolved with standard treatment

Comments

Does tocilizumab work only in combination with steroid? Tocilizumab inhibits only one cytokine, which may not be sufficient to work amid a storm of numerous cytokines. Steroid influences more inflammatory pathways, allowing it to work as monotherapy against COVID. Nonetheless, it’s plausible that adding tocilizumab to 6 mg of dexamethasone could improve the overall potency.

Fragility index for 28-d mortality: 17

3% of those allocated to usual care received at least one dose of tocilizumab or sarilumab

Corticosteroids in 82% in RECOVERY, 88% in REMAP-CAP

Non-use of corticosteroids was associated with no difference in the 28 day mortality in RECOVERY

Would CRP rise be an indication for TOC?

When all 8 RCTs put together, there is a 13% proportional reduction in 28-day mortality (rate ratio 0·87, 95% CI 0·79-0·96, p=0·005)

mortality by about one-third for patients

The combination of corticosteroids and tocilizumab reduces mortality in patients receiving simple oxygen by one-third and by nearly one-half for those receiving invasive mechanical ventilation.

Not all patients (92%) were evaluated for 28-d mortality

17% of patients randomized to tocilizumab did not receive it

28-d follow up may be too short for the sickest of patients with COVID-19

Will other agents (e.g., sarilumab) be equally effective?

Conclusion

  1. Both trials showed that Tocilizumab reduces mortality in severe COVID-19 patients.
  2. These trials have forced us to rethink the approach in sever COVID-19 infection requiring mechanical ventilation &/or increasing oxygen requirements.
  3. Tocilizumab should be used in conjunction with dexamethasone ( or other steroids in equivalent doses) to treat severe COVID-19 infection.

 

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