PRINCIPLE Investigators Study Inhaled Budesonide for COVID-19
Jon-Emile S. Kenny MD [@heart_lung]
“… Sartre tells us that man makes himself this lack of being in order that there might be being.”
-Simone de Beauvoir
Like many early, proposed therapies for COVID-19, inhaled corticosteroids [ICS] had suggestive, conflicting evidence. For example, in a very large observational investigation – the OpenSAFELY platform – patients with both chronic obstructive pulmonary disease and asthma who received ICS had increased risk of COVD-19-related death compared with similar patients who did not receive ICS. Further, in patients with asthma, those who were prescribed high dose, but not low or medium-dose, ICS had heightened risk of COVD-19-related death compared to those who only received short-acting beta-agonists. As well, while systemic corticosteroids benefitted patients requiring oxygen in the RECOVERY evaluation, in the sub-population of patients without supplemental oxygen requirements, corticosteroids may have been harmful.
On the other hand, ICS were noted to diminish SARS-CoV-2 replication in vitro and ICS might, in part, help ameliorate acute respiratory distress syndrome [ARDS], more generally. Finally, a relatively small [n = 146] randomized, controlled trial in outpatients with no more than 7 days of COVID-19-related symptoms measured the effect of inhaled budesonide on urgent care utilization and symptom duration. Those randomized to ICS were less likely to require urgent care evaluation/escalation [absolute risk reduction of 12%, number needed to treat of 8] and had symptom duration diminished by about 1 day.
With the aforesaid, the PRINCIPLE trial collaborative group assessed inhaled budesonide for outpatients at high-risk for COVID-19 disease progression.
What they did
Budesonide was added as a therapy to the PRINCIPLE platform investigation in late November 2020. A platform trial permits various therapies for the same disease to be explored at once. The trial’s primary protocol delineates prospective criteria for halting futile, declaring superior, or adding new, interventions.
Inclusion criteria were outpatients at least 65 years of age, or at least 50 years of age with comorbidities [i.e., heart disease, hypertension, asthma or lung disease, diabetes, hepatic impairment, stroke or neurological problems, immunocompromise, self-reported obesity or body-mass index of at least 35 kg/m² were enrolled. Patients also had to have had ongoing symptoms from PCR-confirmed or suspected COVID-19 starting within the previous fortnight.
Exclusion criteria were having already been taking inhaled or systemic corticosteroids, inability to use an inhaler, or if inhaled budesonide was contraindicated.
Participants were randomly assigned to inhaled budesonide 800 µg twice daily for 14 days, usual care, or other treatments. Participants were followed for 28 days after randomisation. There was no placebo inhaler.
The trial had two co-primary endpoints measured within 28 days of randomisation: 1.] time to first instance that a participant reported feeling ‘recovered’; 2.] hospital admission or death related to COVID-19. Importantly, COVID-19-related mortality was made by two, blinded clinicians masked to treatment allocation and study identifiers.
What they found
4700 patients were randomly assigned to budesonide [n = 1073], usual care alone [n = 1988], or other treatments [n = 1639]. 3979 eligible participants had a SARS-CoV-2 test result available, and 2655 [67%] tested positive. The primary analysis included data from 2530 of 2655 SARS-CoV-2-positive participants who provided follow-up data and were randomly assigned to inhaled budesonide [n=787], usual care alone [n=1069], and other treatments [n=674].
The observed median time to first recovery was 11 days in the inhaled budesonide group compared with 15 days in the usual care group and this was statistically-significant based on the Bayesian primary analysis model [estimated benefit of 2.94 days, probability of superiority > 0.999].
9% were admitted to hospital or died due to COVID-19 in the inhaled budesonide group compared with 11% in the usual care group. The probability of superiority of budesonide was 0.963, which was below the predefined superiority threshold of 0.975. There were two hospital admissions unrelated to COVID-19 in the budesonide group and four in the usual care group.
Large, randomized controlled trials are so terribly important and the PRINCIPLE adaptive platform investigation illustrates, yet again, why this is so. Had this study not been carried out, we might have only retrospective, observational data. We learn in our training that observational data is hypothesis-forming, not definitive, but at the bedside it is tempting to turn retrospective studies into absolute, management proclamations.
Consider the OpenSAFELY exploration, which found a signal for harm with ICS in COVID-19. The authors of OpenSAFELY quite correctly note that observational studies – even very large ones – are always confounded by unmeasured disease severity. In other words, the patients receiving high-dose ICS in their study were likely sicker to begin with and, therefore, more likely to die from COVID-19 despite statistical adjustments. At the very least, PRINCIPLE reveals a low risk of harm for inhaled budesonide even in high-risk outpatients. Though, it is important to recognize that those enrolled in PRINCIPLE did not have a lot of pre-morbid pulmonary disease, partly because pretrial use of ICS was an exclusion criterion. Thus, comparing the studied populations of PRINCIPLE and OpenSAFELY is not so straightforward.
Certainly, one obvious criticism of the trial is that there was no placebo inhaler for the usual care group. While this is unfortunate, scientifically, we can appreciate the logistical hurdles to achieve sham ICS during a pandemic. Thus, we do not know if, or how much, of the perceived wellness that the budesonide patients derived was from ‘knowing’ that they were getting an inhaled medication. Nevertheless, as noted by the authors, this was a pragmatic study and answered what the effect of adding inhaled budesonide to usual care would achieve. There was a clear trend towards reduced hospitalization and death due to COVID-19, but did not achieve statistical superiority. This trend was in-line with the observations of the STOIC randomized trial. The PRINCIPLE authors note that this may have been driven by vaccine-effects in spring 2021 and also that this, more objective, outcome points towards true pathophysiological amelioration of COVID-19 by ICS.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he is also the creator and author of a free hemodynamic curriculum at heart-lung.org. Download his free textbook here.