Clarification on the use of Tociluzimab for critically ill patients with COVID-19
A joint statement from the Faculty of Intensive Care Medicine and the Intensive Care Society.
Tociluzimab is a monoclonal antibody which until recently has been used predominantly in the treatment of rheumatoid arthritis.
It is one of a number of immunomodulatory drugs being evaluated in clinical trials for the treatment of COVID-19; of most relevance in the UK are RECOVERY and REMAP-CAP. See the trial websites www.recoverytrial.net and www.remapcap.org for specific inclusion/exclusion criteria for the trials.
REMAP-CAP and RECOVERY are ‘adaptive platform trials’ (thereby comparing several different interventions in multiple trial ‘limbs’). Adaptive platform trials are relatively new in critical care, and mean that regular interim analyses are conducted to evaluate if there are clear signals for benefit or harm, and pre-specified changes to the protocol are applied based on these analyses.
An announcement was made by the investigators of REMAP-CAP following a planned interim analysis by their independent Data and Safety Monitoring Committee (DSMC) of data from 303 subjects enrolled into the immunomodulatory domain of the trial. This analysis found that there was a high probability that tociluzimab was better than no immune modulation at improving a combined primary endpoint of mortality and days free of organ support on ICU at 21 days after randomisation. For this reason, the DMSC told the trial team to stop recruiting to the no immune modulation arm of the trial, but to continue to recruit to the arms which are evaluating tociluzimab, anakinra, interferon-beta 1a and sarilumab.
To date, RECOVERY has recruited more than 2000 patients to tocilizumab or usual care. They have also undertaken interim analyses of their data (last after 1838 patients had been enrolled into this arm). However, their DSMB have not suggested that they halt recruitment into this arm of RECOVERY.
Of note, REMAP-CAP and RECOVERY are enrolling different patient populations (ICU patients within 24h of admission vs. all hospitalised patients, respectively) and have different study end-points (composite of death and organ-support-free days on ICU at day 21 vs. all-cause mortality at day 29, respectively).
The CMOs issued a position statement and a CAS-ALERT in the light of the interim results from REMAP-CAP. We hope that these points will help clinicians interpret the trial findings so far, and the context of the CMOs’ statement and CAS-ALERT.
- There is a pressing and on-going need to recruit to trials evaluating the place of Tociluzimab in the treatment of patients with COVID19. In the UK, these trials would be RECOVERY and REMAP-CAP.
- The investigators for both trials are in full support of continuing recruitment, in preference to changing practice based on these preliminary interim findings. We support this, as does NHS England/NHS Improvement.
- The REMAP-CAP interim data so far do not indicate whether the benefit arises from an improvement in mortality, organ-support free days, or both. In addition, the final result from REMAP-CAP (when the full cohort of patients has been recruited and followed-up) may differ from the one released at the interim analysis.
- The interim data released from REMAP-CAP do not inform us whether tocilizumab provides additional benefit over the current standard of care (dexamethasone).
- While no safety concerns have been raised, the full cohort of patients have not been recruited. Tociluzimab is not without side effects or risks.
- The CAS-ALERT and CMO statements were aimed at ensuring that for patients who cannot be recruited to trials because of hospital non-participation, there is an auditable, robust process in place at local level to support off-label prescription if the responsible clinicians wish to prescribe Tocilzimab.
- This statement and the CAS-ALERT were NOT an indication of support for the use of tocilizumab in critically ill adults with COVID-19; it was aimed at ensuring that the governance around off-label prescribing is more robust than it was before the interim results were released. This involves getting approval from the local Drug and Therapeutics Committee (or similar) both for Hospital use and individual patient prescription.