NHS supports selected use of inhaled budesonide for COVID-19 in people at risk of severe events

Simon Collins, HIV i-Base

Interim results from a randomised open-label UK study using the inhaled steroid budesonide reported faster recovery and reduced hospitalisation in people with mild COVID-19 at higher risk of progression.

The Principle Study is a multicenter, open-label, multi-arm, adaptive platform trial that randomised 4663 participants to inhaled budesonide (800 ug twice daily for 14 days), or standard of care. Entry criteria included being with 65 years or older, or 50 years and older with comorbidities. Participants were enrolled from November 2020 to March 2021 and needed to be unwell for less than 14 days with suspected COVID-19.

Co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, both over 28 days.

Overall, 2617/4663 participants (56%) tested SARS-CoV-2 positive and contributed data: 751 budesonide, 1028 usual care and 643 to other interventions.

Time to first self-reported recovery was shorter in the budesonide group compared to usual care (HR 1.208, 95% BCI: 1.076 to 1.356). Estimated benefit of 3.0 days (95% BCI: 1.1 to 5.4).

Among those with 28 days follow up, there was no significant benefit in reduced COVID-19 related hospitalisations or mortality: 59/692 (8.5%) vs 100/968 (10.3%). The estimated percentage benefit was 2.1% (95% BCI: −0.7% to 4.8%).

More than 80% of participants reported taking budesonide for more than a week.

A second UK study also reported benefits from inhaled steroid budesonide with results published in Lancet Respiratory Medicine. [2]

The STOIC study was an open-label, parallel-group phase 2 that randomised 146 adults within seven days of symptoms to inhaled budesonide (800 ug twice daily until symptoms resolved), or standard of care.

Median age was 45 years (range: 19 to 79) with no significant differences in baseline characteristics between groups. Just over half were women, 93% were white and most people had only one comorbidity. The median duration of symptoms before randomisation was 3 days (IQR: 2 to 4) with median recovery after 7 days (IQR: 5 to 11). Budesonide was taken for a median of 7 days (IQR: 4 to 10).

Budesonide was associated with significantly reduced primary outcome of the need for an urgent care (often hospitalised): reported in 1/69 (1%) vs 10/70 (14%) participants, respectively; (difference 0.131, 95%CI: 0.043 to 0.218; p=0·004). Results were similar in the ITT analysis.

Clinical recovery was 1 day shorter: median 7 v 8 days log-rank test p=0·007.

Fewer participants reported fever or use of anti-fever medication (p=0.025) or reported persistent symptoms at days 14 and 28 (p=0·003).

However, oxygen saturations (p=0.943) and SARS-CoV-2 viral load (p=0.554), measured by cycle threshold, were not different between the groups.

There were no serious side effects with only five (7%) participants reporting self-limiting adverse events.

This produced a number needed to treat (NNT) of 8 to prevent one serious hospitalisation.

The study was also stopped early after a DSMB recommendation that further enrolment would not change the outcome.

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The results from the PRINCIPLE study were also reported in a press release from NHS England with recommendation to consider use based on meeting all the following eligibility criteria.

• Symptomatic, with onset within 14 days.
• PCR-confirmed COVID-19 within the past 14 days.
• Age 65 years and over or 50 years with a long-term significant comorbidity.

For more details, including dosing and important exclusion criteria and contraindications please see full statement. [3]

This document also noted the positive results from the published phase 2 STOIC trial.

It is unfortunate that a placebo steroid was not available or used especially given the reliance on self-reported recovery, but without significant differences in viral load.

References

1. Yu L-M et al. Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. MedRxiv pre-print. 10.1101/2021.04.10.21254672. (12 April 2021).
   https://www.medrxiv.org/content/10.1101/2021.04.10.21254672v1
2. Ramakrishnan S et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Resp Med 9(7):763-772. DOI: 10.1016/S2213-2600(21)00160-0. (1 July 2021).
   https://www.thelancet.com/article/S2213-2600(21)00160-0/fulltext
3. NHS UK. Interim Position Statement: Inhaled budesonide for adults (50 years and over) with COVID-19. (12 April 2021).
   https://www.england.nhs.uk/coronavirus/publication/interim-position-statement-inhaled-budesonide-for-adults-50-years-and-over-with-covid-19 (html)
   https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2021/04/C1253-interim-position-statement-inhaled-budesonide-for-adults.pdf (PDF)

This report was first published on 16 July 2021.