COVID-19 treatments and the importance of randomised trials

Currently, just two COVID-19 treatments have shown benefit in randomised trials: remdesivir and dexamethasone. No benefit was found for hydroxychloroquine, lopinavir-ritonavir, and tocilizumab. Prof. Martin Landray (University of Oxford, United Kingdom) gave an overview of randomised trials of COVID-19 treatments with a focus on hospitalised patients [1].

For most people, an infection with SARS-CoV-2 is self-limiting, but for hospitalised patients, mortality is high (10-20%) and for ventilated patients even higher (40-50%). The pathophysiology of COVID-19 is characterised by 2 components: a viral response in the first week to 10 days, and an increasing inflammatory response, where the immune system is initially combating the virus but can also drive lung damage and need for ventilation.

Current treatment falls into 3 categories: repurposed anti-virals, immunomodulatory drugs, and some drugs targeted specifically at SARS-CoV-2. In addition, there are some treatments targeted at complications, such as antithrombotics. Currently, hundreds of candidate drugs exist but very little reliable data is available (only uncontrolled case series and inconclusive randomised trials). According to Prof. Landray, it is worth remembering that it is unlikely to have a single “big win,” but that moderate benefits will be important.

RECOVERY trial

The controlled, open-label RECOVERY trial evaluated hospitalised patients with SARS-CoV-2 in 176 hospitals in the United Kingdom and Northern Ireland [2]. The most important outcome was 28-day mortality, but it also evaluated use of ventilation and duration of hospitalisation. Patients were randomised between a range of suitable and available treatments:

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    • repurposed antivirals, i.e. hydroxychloroquine and lopinavir-ritonavir;
    • immunomodulatory drugs, i.e. dexamethasone, azithromycin, and tocilizumab; and
    • targeted anti-SARS-CoV-2, i.e. convalescent plasma.

Both hydroxychloroquine and lopinavir-ritonavir had no effect on all-cause mortality among these hospitalised patients. In contrast, dexamethasone reduced mortality with about a third in patients requiring oxygen or ventilation.

Remdesivir and tocilizumab

In a similar patient population, a double-blind, randomised, placebo-controlled trial found that remdesivir reduced time to recovery with approximately 4 days (11 vs 15 days; RR 1.32; P<0.001) [3]. However, no impact on mortality was found (RR 0.70).

There is one reported trial evaluating the anti-IL-6 monoclonal antibody tocilizumab. This relatively small study showed no impact on either clinical status (OR 1.19; P=0.36) or mortality (19.7 vs 19.4%; P=0.94) at day 28, but did observe a shorter hospitalisation duration (20 vs 28 days; P=0.04). Additional studies are ongoing, including the evaluation of >800 patients in the RECOVERY study.

Figure: Incidence of in-hospital events in COVID-19 patients [1]

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   1. Landray M. Randomized trials of COVID-19 treatments. COVID and Cardiovascular Disease session, ESC Congress 2020, 30 Aug.
   2. The RECOVERY Collaborative Group. N Engl J Med 2020; 17 July. DOI: 10.1056/NEJMoa2021436.
   3. Beigel JH, et al. N Engl J Med 2020; 22 May. DOI: 10.1056/NEJMoa2007764.

 

Posted on 5 November, 20205 November, 2020