SGEM#357: COVID it’s Getting Harder and Harder to Breathe but will Budesonide Help?

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: Debate regarding a universal mandate for masks early in the pandemic with Dr. Joe Vipond (SGEM Xtra: Masks4All in Canada Debate) Skeptical review of the early therapeutics with Dr. Sean Moore for the Canadian Association of Emergency Physicians (CAEP) Town Hall (SGEM Xtra: COVID19 Treatments – Be Skeptical) Diagnostic accuracy of various tests for COVID19 with Dr. Chris Carpenter (SGEM#299: Learning to Test for COVID19) Structured critical appraisal of the DANMASK trial with Dr. Joe Vipond (SGEM#309: That’s All Joe Asks of You – Wear a Mask) 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: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Unsure The study patients were recruited consecutively (i.e. no selection bias). No The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. No Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. No The treatment effect was large enough and precise enough to be clinically significant. Unsure 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,