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expert reaction to preprint from the PRINCIPLE trial giving interim results on inhaled budesonide as a treatment in people at higher risk of adverse outcomes in the community

A preprint, an unpublished non-peer reviewed study from the PRINCIPLE trial, looks at the use of budesonide, a common corticosteroid, as a community-based treatment for COVID-19.

This Roundup accompanied an SMC Briefing.


Prof Tim Higenbottam, President, Faculty of Pharmaceutical Medicine, said:

Is this a robust study; what are the strengths and limitations?

“This is a large scale study in the community which needs to be applauded but is compromised as it is not double blind and is using the reports of subjective score of well-being as the only powered outcome measure at this time of reporting.  It does however show a positive effect with a significant in reduction of recovery time between standard of care and the investigational medicine.  Given the large confidence intervals the effect it is not that impressive.  Self-reporting of the use of the treatment was only 80% which is high for most inhaler studies but mean that 20% of patients at least did not get the therapy that had been planned.  There are also confounding issues which relate to the benefit of the introduction of vaccination and variations in the group during the study of the standard of care.  In the study reported here the relative frequency of vaccination in the two groups is not presented.

Is this peer-reviewed or early work – are the data convincing?

“This is an early report before the second co-primary variable has been analysed namely hospitalisation/death within 28 days which is as yet insufficiently powered until all the patients complete – it is not peer group reviewed report.

Is this an RCT and does that give us more confidence than if it had been observational work?

“It is a RCT bearing in mind the standard of care comparator changed during the study (but none of the treatments in that group have proved effective).  It is more important than an observational study and confirms an earlier phase II study which was smaller.

Is this good news – what is the size of the effect?

“The size of the effect, 2 or 3 days quicker to recovery perhaps is not that much value on its own but at least it was positive which earlier medicines tested in the Principle study are yet to achieve.

Are there any implications?

“It indicates the limitations of these standard of care studies, ideally a randomised double blind study would have resolved some of the uncertainty.  But let’s see what the hospitalisation/death rate results show until then perhaps we cannot get too excited.

Any other comments about this study?

“This is the first positive result from large scale community studies and is very important as yet we have no therapies that modify the progression of the disease that can used in the community.  The treatment is inexpensive and has a well described safety profile being easy to use in practice.  It deserves a full randomised control trial that is double blind, not limited by inadequate testing for SARS-CoV-2 and verification of use of the inhaler.  These researcher have shown that this is possible to do in the community setting.”


Dr Penny Ward, Faculty of Pharmaceutical Medicine, Visiting Professor in Pharmaceutical Medicine, Kings College London, said:

Is this a robust study; what are the strengths and limitations?

“The PRINCIPLE study is a platform trial investigating community based interventions for COVID-19.  This report discusses the results of the use of inhaled budesonide vs SOC therapy in older adults (>65 years of age) or middle aged adults with existing comorbidities increasing the risk of hospitalisation post COVID infection.  The trial builds on the outcomes of the STOIC trial which was a pilot study involving adults of all ages that documented faster recovery and reduced need for medical intervention (ER visits/hospitalisation) when inhaled budesonide was started within 3 days of first symptom onset.  In contrast the time to start of treatment in the current study was 6 days post symptom onset, reflecting predominantly mild disease among the patient cohort enrolled.  The trial was initially intended to investigate impact of inhaled corticosteroid use on risk of hospitalisation and death, but a lower than expected rate of hospitalisation – potentially reflecting the fact that most patients had limited/mild symptoms at enrolment – resulted in a change of endpoint to the timing of self reported recovery.  As the trial was restricted to older aged adults and mostly recruited patients with mild disease, relevance for younger persons, or those with greater symptom severity, remains somewhat uncertain.

Is this peer-reviewed or early work – are the data convincing?

“This is non peer reviewed data and although the trial was appropriately constructed with an independent review group adjudicating outcomes, the data are mixed in that the median time to intervention was 6 days (a time when many more severely affected individuals will be admitted to hospital) and recruited mostly patients with mild disease severity based on self reported symptoms, who might have been anticipated to have a lower risk of requiring hospital care.  The authors report that subjects with asthma/COPD already taking corticosteroids were excluded from the budesonide arm of the trial; however ~8% of subjects in the budesonide arm and 15% of subjects in the control group reported comorbid asthma/COPD/ling disease and it is unclear how potential confounding due to use of other corticosteroid medications/severity of existing lung disease might have affected the results.

Is this an RCT and does that give us more confidence than if it had been observational work?

“The study was randomised but was open label, so that both patients and investigators were aware of treatment assignment.  In trials with a high degree of self reporting of subjective outcomes, this design is sub optimal, and a placebo controlled study would have been preferable to ensure unbiased assessment by patient and investigator.

Is this good news – what is the size of the effect?

“The size of the effect is modest, albeit that self reported recovery was 3 days shorter in the budesonide group.  Because the study had only a 28 day follow up period, the opportunity to investigate the potential effect of treatment on the incidence and severity of ‘long COVID’ is missed.  In particular a post recovery assessment of lung function might have been helpful to assess the potential for inhaled corticosteroid to reduce lung injury.  The point estimate for need for covid related hospitalisation/death was also modest, with an age and comorbidity adjusted absolute reduction of 2.1% in hospitalisation/death in the budesonide arm relative to the usual care arm.  This suggests a number needed to treat of ~48 to prevent one hospitalisation.  It is noted that two subjects taking budesonide required hospitalisation for non COVID reasons, but insufficient information is provided to understand the reasons for these subjects needing to be hospitalised.  It might have been preferable to assess all hospitalisations and all cause mortality to remove potential bias in these assessments.

Are there any implications?

“The study was intended to investigate treatment effect in persons expected to be at higher risk of severe COVID and hospitalisation, but the subject group included and the low rate of hospitalisations observed suggest that it mainly recruited subjects with mild disease, limiting the applicability of the findings to other subjects with more severe comorbidities or at higher immediate risk of severe disease.  It could be usefully followed up by investigation within a long term care home setting, where subjects are more likely to need hospital care.

Any other comments about this study?

“The investigators are encouraged to consider blinding of intervention in future arms of the trial.  In addition, if an antiviral therapy is to be investigated in future arms of the study, more effort needs to be made to include subjects within the first 3-4 days of symptom onset.”


Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“The statistical analysis of the trial results looks appropriate to me.  The reduction in average time to recovery is quite substantial – in people with infection with SARS-CoV-2 confirmed by a swab test, if they received budesonide in addition to the usual care they would have had anyway, the median time to recovery was 11 days – that is, half the people recovered in less than 11 days, and half took longer to recover – but it was 14 days for people who got no budesonide and only the usual care.  3 days shorter certainly sounds worthwhile to me.  Inevitably there’s some statistical uncertainty about the exact improvement – plausibly, it could be anywhere between about 1 day and about 5 days, though around 3 days is the most likely.  But this all definitely sounds worthwhile, I’d say.

“There’s some evidence that budesonide reduces the risk of being hospitalised, but this hasn’t yet reached the level where the researchers can be sufficiently confident that there’s a real difference in hospitalisation risk.  But this is only an interim analysis – there are patients who were recruited to the trial and who received budesonide, but who had not yet been followed up for the full 28 days required to compare hospitalisations properly.  It’s possible, though nobody can be certain at this stage, that there will be a clearer result on hospitalisations after the full data are available and have been analysed.  The trial has already stopped randomising people to receive budesonide, on the grounds that the vaccination roll-out has led to such reductions in hospitalisation that collecting data from new patients is unlikely to lead to clearer results, but the people already under study will be followed up to the end of the planned follow-up period.

“This is a preprint and has not yet been through the peer review process.”



Preprint (not a paper): ‘Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial’ by Ly-Mee Yu et al.  This work is not peer-reviewed.



Declared interests

Prof Tim Higenbottam: “I am the president of the Faculty of Pharmaceutical Medicine.

I am a paid advisor to the Akari Therapeutics Ltd company.”

Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development.  Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections.  Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases.  Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of the Advisory Committee, but my quote above is in my capacity as a professional statistician.”

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