The first clinical trial update for this week is the recent publication on Tocilizumab in COVID-19 (Stone JH, et al. 2020). Tocilizumab is an anti-IL-6 receptor monoclonal antibody (mAb) that was being tested as a potential treatment for COVID-19 associated IL-6 cytokine storm. The study demonstrated no efficacy of Tocilizumab in reducing intubation or death in the 243 moderate hospitalized patients that were recruited. Although a small study size, this report confirms previous findings from other anti-IL-6 and anti-IL-6 receptor antibody trials and suggests targeting IL-6 may not be the silver bullet for treatment of COVID-19 associated cytokine storm.
In response to the pressing need for cytokine storm therapies, the National Institutes of Health (NIH) has announced the ACTIV-1 Immune Modulators (IM) trial which will focus on specifically treating the COVID-19 associated cytokine storm. This trial has been designed to be flexible and focus on multiple investigational therapies and rotate between them as they become available and more evidence emerges for each of them. Currently three immune modulators (out of a list of 130) have been selected: infliximab, abatacept, and cenicriviroc (CVC). All therapies will be combined with the standard of care remdesivir, with physician and site director discrecion on using dexamethasone and convalescent plasma for study participants. The study will be using disease severity, recovery speed, mortality, and hospital resource utilization/strain as its primary endpoints with the NIH expecting the trial to last approximately six months.
The National Institute of Allergy and Infectious Diseases (NIAID), under the NIH, announced another new trial to specifically test early development investigational drugs for COVID-19. This trial, named ACTIV-5 Big Effect Trial (BET), will focus on repurposed or late-stage therapies that have shown initial promise in COVID-19, and help execute and design their Phase 2 double-blind studies. BET aims to use approximately 100 hospitalized volunteers for each study arm and will not test more than three therapies at any given point. Initially, the trial will test risankizumab (anti-IL23A mAb) + remdesivir, lenzilumab (anti-GM-CSF mAb) + remdesivir, both of which will be compared to the standard of care remdesivir. More therapies will be announced as the trial progresses.
The World Health Organization has also recently published a preliminary pre-print of their findings on Remdesivir (n=2750), Hydroxychloroquine (n=954), Lopinavir-Ritonavir (n=1411), and interferon-β1a (n=2063, mostly subcutaneous with dosing of Lopinavir in some patients) which were compared to 4088 COVID-19 control patient on no study drug (WHO Solidarity trial consortium, et al. 2020). They found that none of the study drugs reduced mortality, initiation of ventilation, or time to discharge. Overall, this paper does an excellent job incorporating findings from other clinical trials of the same therapies and is perhaps one of the most critical papers of late on COVID-19 therapies. However, one weakness of the trial is its less controlled recruitment which allowed for any hospitalized patient to be recruited, thus creating a myriad of patient populations who were started on therapies at potentially very different time points relative to disease onset. An emerging trend in clinical trials for COVID-19 is that timing of therapy is critical, and that earlier antiviral treatment may have higher efficacy. Late stage severe patients usually have a dwindling viral load, and many of their complications come from secondary pathologies including pneumonia, autoimmunity, and widespread inflammation all a result of the prolonged viral load. Thus, it will be important to more clearly address the timing of treatment in these patients as they prepare the paper for publication. Of course, as a pre-print the paper has yet to withstand peer review.
References
Stone JH, et al. (2020) Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. doi:10.1056/NEJMoa2028836.
WHO Solidarity trial consortium, Pan H, et al. (2020) Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. medRxiv:2020.10.15.20209817.
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