Statement from the Australasian COVID-19 Trial (ASCOT) Trial Steering Committee

The ASCOT Trial Steering Committee (TSC) met on June 9 2020 to discuss recent updates on hydroxychloroquine from external studies.

1. We noted that the Mehra et al Lancet 2020 observational study has been retracted and we will no longer consider those results.
   
   
2. The RECOVERY trial in the UK has released a statement on June 5 2020 that there was ‘no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19’. The specific paragraph regarding the results states: “A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes.” 

The ASCOT TSC has decided that ASCOT should continue recruitment and randomising patients to hydroxychloroquine containing arms. The rationale for this decision includes:

1. We await a full publication of the results from RECOVERY. This will allow us to assess:
   
   Details about included patients. In particular, the RECOVERY protocol allows inclusion of any hospitalised patient with suspected COVID-19. Details of numbers of confirmed vs suspected patients and treatment effects in these subgroups are important. ASCOT only enrols patients with a confirmed diagnosis of COVID-19.
   
   At this stage, not all patients have full follow-up to 28 days (it is just over 80%) and thus the results are to be finalised.
   
   Even so, the reported mortality of ~25% is high and these may have been sick patients, late in the course of illness.
   
   
2. RECOVERY was designed as a highly pragmatic trial. ASCOT has some differences in that it has tighter eligibility criteria and clear safety protocols around the use of hydroxychloroquine (including baseline, 4 hour and 24 hour ECGs), and clear recommendations about contraindicated and relatively contraindicated medications. RECOVERY also includes paediatrics.
   
   
3. There is great benefit in obtaining data across more than 1 trial. There have been numerous instances of seemingly beneficial results or absence of treatment effect with interventions from single trials that have been over-turned with subsequent studies. ASCOT will also consider if any trials report evidence of harm.
   
   
4. The context of trial results are also critical and findings from the UK may not be applicable to other contexts such as in lower and middle income countries to which ASCOT is planning to extend.
   
   
5. ASCOT will be moving to an adaptive platform trial framework which will allow the incorporation of other domains and also allow trial sites to decide if they want to include hydroxychloroquine as one of their interventions in the antiviral domain.