We have been following the RECOVERY trial closely over the last few months. It’s the largest RCT of therapeutics for COVID-19 in the world and it’s already shown that hydroxychloroquine and azithromycin don’t work in COVID-19, and that Dexamethasone does. We also have reports on Lopinavir/Ritonavir (also known by its brand name Kaletra), although it seems we forgot to add this important result to the blog.
As a reminder 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 trial. ASAP was (and still is) a hibernating trial 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 (as it’s still in hibernsation), and now site-lead the RECOVERY trial at my hospital, one of 175 UK sites led by the chief investigator (Prof. Peter Horby) and team at Oxford University.
Lopiniavir/Ritonavir is a well established drug used in the treatment of HIV, but it has been shown to have anti-COVID-19 properties in vitro. That led to a lot of early interest where it was widely prescribed together with other antivirals such as hydroxychloroquine. Observational studies were inconclusive and early small RCTs were negative, but too small to see if there were truly no benefits, or whether benefits existed within sub groups.
Lopinavir/Ritonavir was one of the earliest drugs to be tested in RECOVERY which is why it was one of the earliest to report. As a reminder as to where the trial
- Patients recruited to RECOVERY – Over 21000 and rising daily.
- Largest RCT in Covid-19 to date
- 1616 patients randomised to Lopinavir/Ritonavir
- 3424 patients randomised to routine care
- End point is 28-day mortality
- 23% Hydroxychloroquine
- 22% usual care
- hazard ratio 1·03, 95% CI 0·91–1·17; p=0·60
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 Lopinavir/Ritonavir in patients with Covid-19 and its use should be discontinued.
So no benefit overall, but also no benefits in the sicker ventilated patients either. Although none of the subgroup showed statistical significance (age, sex, ethnicity, days since onset and resp support baseline risk it’s interesting that nearly all showed a lower survival with Lopinavir/Ritonavir. It is therefore very unlikely that Lopinavir/Ritonavir at this dose, in hospitalised patients has any benefit.
The trial has been criticised in some quarters. It is an open label trial and as such is potentially prone to bias.
As with other antivirals there is an argument that they are being given too late in the trial. This is plausible as most patients admitted to hospital are in the inflammatory phase of disease, and as such have passed the viraemic phase when we might expect these drugs to work. This trial tells us about the hospitalised patients only. However, there is no evidence that early or prophylactic use of Lopinavir/Ritonavir improves outcomes, although there is a trial registered looking at this.
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 >21000 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 no benefit
- Low-dose Dexamethasone NOW STOPPED shows benefit
- Hydroxychloroquine NOW STOPPED no benefit
- Azithromycin NOW STOPPPED no benefit
- Convalescent plasma
- Monoclonal antibodies (Regeneron)
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
- 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
- A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 https://www.nejm.org/doi/full/10.1056/NEJMoa2001282
- Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32013-4/fulltext
- COVID-19 Ring-based Prevention Trial With Lopinavir/Ritonavir (CORIPREV-LR) https://clinicaltrials.gov/ct2/show/NCT04321174
- Simon Carley, “Dexamethasone, COVID-19 and the RECOVERY trial. St Emlyn’s,” in St.Emlyn’s, June 28, 2020, https://www.stemlynsblog.org/dexamethasone-covid-19-and-the-recovery-trial-st-emlyns/.
- Simon Carley, “The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn’s,” in St.Emlyn’s, June 6, 2020, https://www.stemlynsblog.org/the-recovery-platform-trial-no-benefit-to-hydroxychloroquine-in-covid-19-st-emlyns/.
- Thomas Shanahan, “JC: Azithromycin in patients hospitalised with COVID-19,” in St.Emlyn’s, December 20, 2020, https://www.stemlynsblog.org/jc-azithromycin-in-patients-hospitalised-with-covid-19/.
- Dan Horner “Tocilizumaybe? Immune modulation in COVID-19 @StEmlyns,” in St.Emlyn’s, December 4, 2020, https://www.stemlynsblog.org/tocilizumaybe-immune-modulation-in-covid-19-stemlyns/.
- Simon Carley, “JC: Convalescent plasma in COVID 19 patients.,” in St.Emlyn’s, November 21, 2020, https://www.stemlynsblog.org/jc-convalescent-plasma-in-covid-19-patients/.