We previously covered the RECOVERY trial press release on the use of HCQ for hospitalised patients with COVID19.
This is a UK based platform trial (more on this later) looking at patients admitted to hospital with Covid-19.
It’s an open label RCT that was developed out of the concepts behind the ASAP trial1. ASAP was (and still is) a hibernating trial2 that was designed to test the use of steroids in a future flu pandemic. When Covid-19 came along the systems and plans for ASAP were repurposed to test treatments for Covid-19. I was (still am) the local Principal Investigator for ASAP and now co-lead the RECOVERY trial at my hospital, one of 175 UK sites led by the chief investigator (Prof. Peter Horby) and team at Oxford University3.
The first results were released back in June from RECOVERY and can be found here4 but we can only see the full data now as published in the New England Journal of Medicine this week (12). To date
- Patients recruited to RECOVERY – Over 13000 and rising daily.
- Largest RCT in Covid-19 to date
- 1561 patients randomised to Hydroxychloroquine (HCQ)
- 3155 patients randomised to routine care
- End point is 28-day mortality
- 27% Hydroxychloroquine
- 25% usual care
- hazard ratio 1.09 [95% confidence interval 0.97-1.23]; p=0.15)
The abstract is below, but as always we strongly recommend you read the full paper.
The trialists have concluded that it is highly unlikely that there is any meaningful benefit to HCQ in patients with Covid-19 and its use should be discontinued. Interestingly the confidence intervals are close to suggesting that HCQ may be harmful.
The authors also looked at subgroup analyses to see if there were any signals for benefits in sub-groups, but as the table below shows, there were no groups that experienced a benefit with HCQ.
So no benefit overall, no benefits in the sicker ventilated patients and no benefits in any sub-groups. It is therefore very unlikely that HCQ at this dose, in hospitalised patients has any benefit and may be harmful.
The trial has been criticised in some quarters. There does appear to be strong support for HCQ amongst Trump supporters and others. Their arguments have largely revolved around timing, dosage and concomitant medications.
In terms of timing the argument is that HCQ was given too late in this trial. This is plausible as HCQ is an anti-viral and most patients admitted to hospital are in the inflammatory phase of disease. This trial tells us about the hospitalised patients only. However, there is little evidence that early or prophylactic use of HCQ improves outcomes in other randomised controlled trials.
The dosage has attracted a lot of criticism, with many suggesting a toxic dosage, but it is in keeping with treatment with other conditions. If you want to depress yourself then have a wander around twitter and read the ad-hominem and threatening attacks on the lead authors. It’s really quite scary. The dose was high in order to rapidly reach antiviral levels. Again this is a reasonable question to ask, it’s just that on twitter it’s not being reasonably asked. RECOVERY had hardly any exclusion criteria and it is possible that subgroups of people who might be more prone to complications of HCQ were included (e.g. underlying risk of dysrhythmias). At the point of recruitment clinicians could decide whether or not to include a specific patient based on their past medical history but it is unclear how this happened in practice.
Lastly, there is a view that HCQ should be co-administered with Zinc. This is not an area of expertise for me, but again may be worthy of consideration if there is a biological plausibility to the idea.
We must also remember that this is an open label trial and therefore potentially open to bias.
What other trials are out there on Hydroxychloroquine?
This is a fascinating question. Early and small open label trials failed to show a benefit5,6 , or showed only a proxy patient benefit7. A recent study in the Lancet suggested that HCQ may be harmful base on an observational database led by Mehra et al8. However, this trial has now been retracted9 in one of the most controversial scientific events of the pandemic10. Despite these earlier and retracted trial results it’s clear that there was no clear high quality evidence to advocate or refute the use of hydroxychloroquine before this, unless of course you live in the White House. Having said that, Trump has been taking HCQ prophylactically and that is not tested in this trial. However, from recent reports during his current illness there has been no mention of him taking HCQ so I can only surmise that his doctors read the earlier reports from RECOVERY.
What’s a platform trial?
The astute amongst you will have noticed that the numbers in the HCQ + Control groups do not add up to >13000 and that’s because RECOVERY is a platform trial that is testing a range of treatments.
Platform trials, also referred to as multi-arm, multi-stage (MAMS) design trials, are trials that evaluate several interventions against a common control group and can be perpetual. This design has pre-specified adaptation rules to allow dropping of ineffective intervention(s) and flexibility of adding new intervention(s) during the trial. 11 During a pandemic these trials offer a pragmatic and extremely agile way to test old and new therapies against an emergency threat.
The RECOVERY Trial is a large, randomised controlled trial of possible treatments for patients that has a consistent design (in this case an open label RCT) but which permits treatments to enter and exit the trial as the become available. Thus far we have been randomising patients to the following treatments as part of RECOVERY.
- Lopinavir-Ritonavir NOW STOPPED
- Low-dose Dexamethasone NOW STOPPED
- Hydroxychloroquine NOW STOPPED
- Convalescent plasma
- Monoclonal antibodies
The use of Tociluzamab and convalescent plasma are in subgroups of patients using the following flowchart, which is a little complex, but will allow us to look at individual and combined therapies. This was the flow chart as it existed at the time of recruitment. It has now changed as new therapies come into the trial and others leave.
Interim analyses are pre-planned and overseen by a data monitoring committee. The investigators remain blinded to the outcomes unless the DMC permits the release of data. All trials like this need a very robust DMC.
The NIHR approach, developed during the last flu pandemic and now actioned in Covid-19 is a model for all nations to plan for the pandemic that will follow Covid-19. We will see more results from RECOVERY and other trials soon.
The NIHR Urgent Public Health strategy seeks to support a series of platform trials designed to evaluate multiple interventions with the same protocol to be ultra efficient. We have RECOVERY for inpatients, REMAP-CAP (an international platform trial) for critical care [pneumonia], PRINCIPLE for outpatients and ACCORD (plus a couple of new additions) for phase 2 evaluations. Even pharma is being pushed down this route – and it means standardised outcomes, inclusion criteria and methodology. It’s a lesson in how to do research in a pandemic and a plea to get these set up in advance of the next (likely flu) pandemic.
To give some perspective my trust has recruited over 3000 patients to 12 different Covid-19 trials thus far. The pace and scale of this is extraordinary effort with more to come as we continue with anti-viral trials, but now also start to include new studies on immuno-modulation for the most seriously affected.
- Lim WS, Brittain C, Duley L, et al. Blinded randomised controlled trial of low-dose Adjuvant Steroids in Adults admitted to hospital with Pandemic influenza (ASAP): a trial ‘in hibernation’, ready for rapid activation. Health Technology Assessment. Published online February 2015:1-78. doi:10.3310/hta19160
- Simpson CR, Beever D, Challen K, et al. The UK’s pandemic influenza research portfolio: a model for future research on emerging infections. The Lancet Infectious Diseases. Published online August 2019:e295-e300. doi:10.1016/s1473-3099(18)30786-2
- Horby P, Nunn M. A randomised trial of treatments to prevent death in patients hospitalised with COVID-19 (coronavirus). http://isrctn.com/. Published online April 2, 2020. doi:10.1186/isrctn50189673
- Recovery trial investigators. Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine, 5 June 2020. RECOVERY trial. Published June 5, 2020. Accessed June 5, 2020. https://www.recoverytrial.net/files/hcq-recovery-statement-050620-final-002.pdf
- 5.Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial. Published online April 14, 2020. doi:10.1101/2020.04.10.20060558
- 6.Chen J, Liu D, Liu L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49(2):215-219. https://www.ncbi.nlm.nih.gov/pubmed/32391667
- 7.Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. Published online March 2020:105949. doi:10.1016/j.ijantimicag.2020.105949
- Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. Published online May 2020. doi:10.1016/s0140-6736(20)31180-6
- Mehra MR, Ruschitzka F, Patel AN. Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. Published online June 2020. doi:10.1016/s0140-6736(20)31324-6
- Rezzaie S. COVID-19 Update: Just Say No to Hydroxychloroquine or Chloroquine With or Without Macrolides. REBEL EM. Published June 2020. Accessed June 2020. https://rebelem.com/covid-19-update-just-say-no-to-hydroxychloroquine-or-chloroquine-with-or-without-macrolides/
- Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. Published online September 18, 2019. doi:10.1186/s13063-019-3664-1
- Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report https://www.nejm.org/doi/full/10.1056/NEJMoa2022926