Evidence based medicine (EBM) is one of the four pillars of St Emlyn’s. We are usually pretty sceptical about adopting treatments without high quality evidence publishfred in a decent journal and with critical appraisal. Covid19 has challenged all of us who seek to practice EBM. Our desire for high quality evidence must be balanced against the pace and scale of the pandemic. On the one hand we must wait for high quality trials to complete, but on the other there is the pressure to ‘do something’ right now as we see the rapid increase of patients with a life threatening disease.
As I write this there really are no proven therapies for Covid19 beyond oxygen and supportive measures. It’s difficult to think of any other critical illness for which we have so little to offer and as a clinician I (we) find this frustrating. Politicians, clinicians and the public are desperate for hope, and that appears be leading us to move away from EBM into practice guided by emotions and feelings rather than science. This worries me as many of the proposed treatments for Covid are not without risk themselves. The bottom line is that we should, wherever possible, deliver EBM.
In the last 48 hours we have seen the publication of a trial in the New England Journal of Medicine that typifies my current concerns about EBM. It’s an uncontrolled, open label trial looking at the compassionate use of Remdesivir in Covid19 patients1 . Ordinarily this would be welcome, but in contrast to the times before Covid19, this trial has been published in a very high impact journal despite a huge number of flaws. This cannot be right and is deeply counterproductive to our pursuit of science.
When we teach people how to do BestBets we talk about different sorts of practice to the EBM that we aspire to. I think this is a good time to review them and perhaps add a few more
- EBM – Evidence Based Medicine
- ABM – Authority Based Medicine (you do things because you’re told to, but you don’t know why)
- FBM – Faith Based Medicine (you do things because you ‘believe’ they work even though there is no good evidence for it)
- TBM – Trump based medicine (when politicians advocate treatments when they have a good feeling about it e.g. Hydroxychloroquine). TBM could be PBM, Political Based Medicine, but thus far only America has embraced it. TBM is similar to ABM, but is arguably more undermining to the research community
- HBM – Hope Based Medicine, a new one from today (from @kirstychallen)
Some will argue that it’s OK for us to try new treatments and ideas as science will correct itself, but that’s illogical and sadly human nature tends to make it harder for us to abandon treatments even when we are faced with the evidence that they are ineffective.
Maybe all is not lost though. The scale and pace of the pandemic is leading to a remarkable response from the research community. Here in the UK a number of trials are already recruiting into high quality RCTs and I’ll outline these below. Incredibly there are now over 2000 patients recruited to clinical Covid19 trials in the UK. This is unprecedented in my opinion, they are coordinated by NIHR (National Institute for Healthcare Research) using the well established research networks that run across all NHS organisations. This coordination is something that perhaps only the NHS can deliver. Research at pace and scale, across the UK and with central funding.
So what trials are up and running in the UK so far.
Selected EM/CC/AM trials recruiting right now in the UK.
This trial started really quickly as it has been developed from the ‘sleeping’ ASAP trial which was designed in 2016 as a trial of steroids in pandemic flu.RECOVERY2 is a 5 arm RCT of patients with confirmed or presumed Covid19. Basically the protocol, research team, trial processes were already in place. The ASAP team amended the protocol to research Covid19, added more treatment arms and RECOVERY is now live. I’m running this trial in our hospital and it’s impressive to see this trial get out of the blocks so fast. We may well get an answer to these therapies within a matter of weeks.
- Standard care
The principle outcome is all cause mortality at 28 days after treatment starts.
ISARIC is the International Severe Acute Respiratory and emerging Infection Consortium3. It’s a global federation of researchers in infectious diseases that has mobilised its networks to collect observational data on Covid19. The UK Clinical Characterisation Protocol (CCP) is primarily an observational record of patient characteristics and should help us understand the epidemiology of the disease. 1300 patients will be recruited to try and answer the following questions
- who in the population is at higher risk of severe illness
- what is the best way to diagnose the disease
- what is happening in their immune systems to help or harm them
- how drugs act in people with the infection
- how long people are infectious for and from which bodily fluids
- whether people are infected with other viruses (e.g. flu) at the same time.
Gilead are running two studies4,5 looking at the use of Remdesivir for the treatment of Covid19. Remdesivir is a novel antiviral that has shown antiviral activity, but has not really been shown to be effective in humans (yet).
One study will randomize approximately 400 patients with severe clinical manifestations of COVID-19 to receive either five or 10 days of remdesivir. The second study will randomize approximately 600 patients with moderate clinical manifestations of disease to receive five or 10 days of remdesivir or standard of care alone. Outcomes will be known at 11 (moderate group) and 14 (severe group) days.
Synairgen are a UK research company running an RCT of Interferon B in Covid19 patients.6 It is a A randomised double-blind placebo-controlled trial to determine the safety and efficacy of inhaled SNG001 (IFNβ-1a for nebulisation) for the treatment of patients with confirmed SARS-CoV-2 infection (COVID-19)
Interferon Beta is a promising drug that modulates the immune response to viral infections. It’s been shown to have antiviral activity in MERS Co-V, but again it is unproven in humans and in Covid19. The trial will recruit 400 hospitalised patients with proven Covid19. The drug is delivered by nebuliser.
REMAP-CAP6,7 is another trial that has adapted to include Covid19 patients. It looks at ICU patients with pneumonia and uses an adaptive trial design to look at several different interventions at the same time. It has similar treatment arms to RECOVERY.
- Evaluation of prolonged macrolide therapy, as a modulator of immune function
- Evaluation of alternative corticosteroid strategies (no corticosteroids, low dose hydrocortisone for 7 days, or hydrocortisone while the patient is in septic shock)
- Antiviral therapy: evaluating antiviral therapy for COVID-19 (and no placebo), and lopinavir/ritonavir (Kaletra). An amendment has been submitted to add hydroxychloroquine, and the combination of hydroxychloroquine and lopinavir/ritonavir as interventions
- Immune Modulation therapy: evaluating no immune-modulating therapy for COVID-19 (and no placebo), Interferon-beta-1a, and interleukin-1 receptor antagonist (Anakinra). An amendment is planned to add tocilizumab and sarilumab as interventions.
The adaptive design means that this trial can add or remove interventions as new research becomes available or other trials report.
This was another sleeping influenza trial (previously ‘Pandemic trial’) that has been repurposed for Covid19. It seeks to find better triage systems to identify different risk groups from the disease. It will evaluate known tools (such as CURB scores) as well as have the potential to develop new scoring systems.
This study looks at pregnant patients with Covid19. It’s largely an observational study using current surveillance data (UKOSS). It will be important to support future parents and clinicians in managing this special interest group.
There are many more trials in set up at the moment. For example there is a proposed RCT of CPAP vs. HFNO vs. standard care which is highly likely to happen (led by Gavin Perkins).
There is an RCT of Tocilizumab in severe Covid19 patients. So there is much more to come from the research community.
What does this mean to clincians and patients.
I’m impressed that so much is happening and so quickly, but the results will not be instantaneous. We won’t get results for several weeks and that means that we must wait until then, riding the first wave of this disease with supportive therapy until we know better.
We must also do as much as we can to get to the stage where every patient admitted to hospital has the opportunity to be enrolled in a clinical trial. By doing this we have the ability get evidence based answers that can really help our patients.
If you want to know more please speak to the research leads in your departments and make sure that you are trained up to recruit and randomise patients. In the UK this may require you to have GCP training. Please follow this link to get yourself trained using the online package. You will need to register to get an NIHR account to complete training.
This disease will be defeated by science and Evidence Based Medicine. You can be part of it of the army of clinicians and scientists that defeat it.
- 1.Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. April 2020. doi:10.1056/nejmoa2007016
- 2.Recovery T. Background. RECOVERY trial. https://www.recoverytrial.net/. Published 2020. Accessed April 9, 2020.
- 3.ISARIC I. International Severe Acute Respiratory and Emerging Infection Collaboration. ISARIC. https://isaric.tghn.org/. Published 2020. Accessed April 9, 2020.
- 4.Gilead S. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment. Clinical Trials. https://clinicaltrials.gov/ct2/show/NCT04292730. Published March 3, 2020. Accessed April 9, 2020.
- 5.Gilead S. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Severe Coronavirus Disease (COVID-19). Clinical Trials. https://clinicaltrials.gov/ct2/show/NCT04292899. Published March 3, 2020. Accessed April 9, 2020.
- 6.Synairgen R. A randomised double-blind placebo-controlled trial to determine the safety and efficacy of inhaled SNG001 (IFNβ-1a for nebulisation) for the treatment of patients with confirmed SARS-CoV-2 infection (COVID-19). EU clinical trials register. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001023-14/GB. Published March 17, 2020. Accessed April 9, 2020.
- 7.REMAP C. Background. REMAP-CAP. https://www.remapcap.org/. Published 2020. Accessed April 9, 2020.