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Date: January 22nd, 2022

Reference: Yu et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet 2021

Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the creator of the #FOAMed project called First10EM.com.

Case: A 65-year-old woman with a history of diabetes, hypertension, and gastroesophageal reflux disease (GERD) presents with three days of fever, cough, and myalgias. She is fully vaccinated against COVID-19. Her husband tested positive for COVID-19 yesterday, and she used a home rapid test this morning that is also positive. Her vitals signs are all normal and she feels well enough to isolate at home. As you are preparing to discharge her, she asks if there is anything you can prescribe her to help. She thinks her friend might have been prescribed a puffer of some sort.

Background: I’ve tried not to focus too much on COVID-19. There are many great FOAMed resources that have done a good job of covering the topic. The SGEM has only done a few shows over the two years including:

The First10EM has done more than 30 blog posts about COVID-19 at this point, with a lot more to come. I know we all wish COVID-19 would just go away. But unfortunately, wishful thinking won’t help us, but hopefully science will. There is strong evidence that systemic steroids improve outcomes in patients with severe COVID-19 (First10EM: Steroids for COVID). This has raised the question of whether inhaled steroids might be helpful. After all, the infection is primarily in the lungs.

Early in the pandemic, there was some observational data that concluded that inhaled steroids were associated with an increased mortality from COVID-19 in patients with asthma and COPD (Schultze Lancet Resp Med 2020). However, the most likely explanation was not causal. Sicker patients are prescribed steroids more often, and so the association is not surprising.

The STOIC trial was an initial phase 2 open-label randomized control trial of inhaled budesonide for patients with mild symptoms of COVID-19 (Ramakrishnan et al Lancet Resp Med 2021). It did report positive results. Their primary outcome was a ‘COVID-19 related’ urgent care visit, emergency department assessment, or hospitalization, and was significantly reduced in the budesonide arm (15% vs 3%, p=0.009).

However, the unblinded trial design, less relevant composite outcome, and fact that the trial was stopped early limit confidence in the results. That bring us to the PRINCIPLE trial.

Clinical Question: Does inhaled budesonide improve clinical outcomes in high-risk outpatients with COVID-19?

Reference: Yu et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet 2021

  • Population: Outpatients with symptomatic COVID-19 within 14 days of symptom onset who were considered high risk for adverse events. This included adults over 65 years of age, or over 50 years of age with co-morbidities.
    • Exclusions: Known allergy or contraindication to inhaled budesonide, were unable to use an inhaler, or already using inhaled or systemic glucocorticoids.
  • Intervention: Inhaled budesonide 800 ug BID for 14 days
  • Comparison: Usual care (there was no placebo)
  • Outcome:
    • Primary Outcome: Composite outcome of COVID-19-related hospital admission or death within 28 days. However, partway through the trial they realized hospitalization was lower than normal, and so they added a second primary outcome: illness duration.
    • Secondary Outcomes: Recovery by 14 days, daily symptoms rating, time to sustained alleviation of symptoms, time to initial reduction of symptoms, contact with health services, oxygen administration, ICU admission, mechanical ventilation and adherence to study medication
  • Trial Design: Multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial

Authors’ Conclusions: “Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.” 

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Unsure
  5. The study patients were recruited consecutively (i.e. no selection bias). No
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. No
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. No
  11. The treatment effect was large enough and precise enough to be clinically significant. Unsure
  12. Funding and Conflicts of Interest: This is primarily government funded. However, multiple authors declared COIs associated with AstraZeneca.

Results: They recruited 1,959 into the trial for the primary analysis (833 budesonide and 1,126 usual care). Mean age was 64 years, 81% had comorbidities, 52% female, 11% had been vaccinated (1 or 2 shots), 5% were current smokers and median duration of illness was 6 days.

Key Result: No statistical difference in hospitalization or death but quicker recovery reported in budesonide group.

  • Primary Outcome:
    • There was no statistical difference for the original primary outcome of hospital admission or death due to COVID-19: 6.8% with budesonide versus 8.8% with usual care (ARR 2.0%, 95% CI -0.2 to 4.5%)
    • For the added primary outcome of time to first reported recovery, budesonide was better at 11.8 vs 14.7 days, absolute benefit 2.9 days (95% CI: 1.2-5.1 days)
  • Secondary Outcomes: 
    • No statistical difference in mortality (1% v 1%), mechanical ventilation (2% v 2%), need for supplemental oxygen (7% v 9%) or need for ICU (1% v 3%)
    • There are a large number of symptom-based outcomes. In general, they demonstrate statistically less symptoms with budesonide, although the actual clinical difference seems small, and this is an unblinded study. We will discuss this further in the Talk Nerdy section.

1) Unblinded Trial: The biggest limitation in this study is its lack of blinding, especially considering they added a second primary outcome that was entirely symptom based. In any unblinded trial, we should expect that the treatment group will have fewer symptoms, so those results are unreliable here. However, even seemingly objective outcomes like hospitalizations can end up biased in unblinded trials. Imagine a patient who feels like ‘nothing is being done for them’, struggling with the cough and fatigue of COVID-19. They may not meet any formal admission criteria for COVID-19, but if it is there third ED visit, they might end up admitted anyway. (I have seen this happen many times.) Therefore, symptoms translate into hospitalizations, and so the unblinded nature of the trial even biases their original primary outcome.

2) Disease Specific Outcomes: For their original primary outcome, they looked at “COVID-19-related hospital admission or death” rather than just hospital admission or all death. This is an issue and can bias a trial from the outset. These outcomes fundamentally ignore harms of medications. If a patient is admitted to hospital because of a medication-related adverse event, then don’t get counted in this primary outcome. Luckily, adverse events are rare from inhaled budesonide, so this bias probably did not have a huge impact on these results.

3) Adding a Second Primary Outcome: The original primary outcome was a composite of COVID-19-related hospital admission or death within 28 days. This was changed to add a co-primary outcome of illness duration. The rationale was that the hospital admission rates in the UK were lower than the authors initially expected. Ethics approval was provided for this amendment and implemented before performing any interim analyses. The more objective primary outcome of hospitalization and death were not statistically different, but the subjective outcome of illness duration was better with budesonide. As mentioned in nerdy point #1 the lack of blinding likely impacted the additional primary outcome and may have impacted hospitalizations.

4) Extrapolation: Most of these patients were unvaccinated. Vaccinated patients have better outcomes after COVID-19 infection, and therefore are much less likely to benefit from treatment. Therefore, we shouldn’t expect to see the same degree of benefit in vaccinated populations. The same concern may apply to the shifting severity we see from new COVID-19 variants.

5) Threshold for Evidence During a Pandemic: This is a longer and more philosophical discussion. For any study, we will see a range of possible interpretations. During COVID-19, in particular, I have found myself disagreeing with some very smart evidence-based doctors who I usually agree with, and I think the difference comes down to a question of philosophy of science. Personally, I think we should be using the same standards for science now as we always have.

I agree that we should not lower our standards during a global pandemic. We discussed this with our good friend Dr. Simon Carley from St. Emlyns on an SGEM Xtra.  He said, “the principles of EBM are more important now than at any other time in our careers”. 

There is an alternative argument that, I will admit, sounds very convincing on the surface. The arguments states that we have an urgent need for action right now. Our health care systems are crumbling around us. We need to do anything we can to improve COVID-19 outcomes. There is just not time to wait for more certainty.

This argument seems very reasonable, but I think it is flawed. It contains the inherent assumption that unproven medications will cause more good than harm, which may not be a very good assumption.

This is an example of intervention bias. It is a form of bias to intervene (tests, medication, or procedures) when non-intervening would be a reasonable alternative (Foy and Filippone 2013). One of my favourite papers of all times is titled “Don’t just do something, stand there! The value and art of deliberate clinical inertia” by Keijzers et al 2018. This is something our mentor Dr. Jerome Hoffman has been saying for years.

All treatments may cause harm. Any unproven treatment could actually end up increasing demands on hospital resources through adverse events, especially as use expands beyond the tightly controlled trial setting. For a variety of reasons, medical studies generally overestimate benefits and underestimate harms. Harms are also known to be under-reported in randomized control trials and systematic reviews and meta-analyses (Saini et al BMJ 2014, Hodgkinson et al BMJ 2013 and Zorzela et al BMJ 2014). Therefore, we should advocate for solid evidence of benefit before implementing new therapies. The same should apply to COVID-19.

Empirically, throughout the history of medicine, most new potential therapies fail. The overall chance that a drug entering clinical development will be approved for marketing is just over 10% (DiMasi et al J Health Econ 2016). Even if treatments are approved, close to one-third are withdrawn due to safety concerns, receive FDA black box warnings, or FDA safety communications (Downing et al JAMA 2017). It is hard to have a positive impact on the complex homeostasis that is human biology.

We also know that a huge number of apparently positive trials are never replicated (Begley and Ellis Nature 2012, Prinz et al Nature Reviews Drug Discoveries 2011, and Ioannidis JPA JAMA 2005). If we have a problem in medicine, it is with overestimating the benefit of our purported therapies.

The argument that novel therapies could reduce healthcare demands during a pandemic contains the hidden assumption that the therapy will work, which historically and empirically speaking, may be a bad assumption.

The problem of overestimating benefit is almost certainly magnified during the COVID-19 pandemic. Around the world, scientists and clinicians have thrown essentially any chemical they can think of at COVID-19. If we throw hundreds of potential drugs randomly towards a target, we shouldn’t be surprised that some hit the bullseye. The problem is that at least some of the options will hit the bullseye by statistical chance alone.

If 20 different drugs were tested in a single trial, and one happened to have a statistically significant result, we would know to be cautious. But that is exactly what is happening worldwide; the drugs just happen to be tested in separate trials. Since early 2020 it was obvious, given the sheer number of randomized control trials being run, that some COVID-19 trials would be positive by for reasons unrelated to treatment efficacy.

When you combine the ongoing chance of harm from novel therapeutics with the increased risk of false positives during the COVID-19 research frenzy, we need to maintain the same stringent scientific standards we always use to keep patients safe.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: The unblinded nature of this study leave us very skeptical about the claim that budesonide improves symptoms. We agree with the authors that is still a chance that budesonide could improve objective outcomes like hospitalization, but that their data were not statistically significant for that claim, and so more research would be needed.

SGEM Bottom Line: Currently, there does not appear to be a role for the routine use of inhaled budesonide in the management of COVID-19.

Case Resolution: You discuss the risks, benefits, and costs of inhaled budesonide, as well as the significant remaining uncertainty with your patient. She decides against treatment.

Dr. Justin Morgenstern

Clinical Application:  After two randomized control trials, it remains unclear if inhaled budesonide has any role in the management of COVID-19. It may relieve symptoms, but it also may just be an expensive placebo. This is a well-known medication with a relatively low risk of side effects, so shared decision making is reasonable in the face of this uncertainty.

What Do I Tell the Patient? There is a puffer that has been tested against COVID-19. At this point, we don’t know if it provides any real help, but it might help relieve your cough a day or two earlier.

However, all medications have possible side effects. This is a steroid puffer that has been used for a long time, and its pretty safe if used for the short term, but side effects like thrush, sort throats, and pneumonia do occur. It is also relatively expensive. I do not routinely recommend it, but if you want to know more, I am happy to discuss further.

Keener Kontest: Last weeks’ winner was David Bowden. He knew ketamine was first tested on human prisoners in 1964 and compared to PCP.

Listen to the SGEM podcast for this weeks’ question.  If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.