We share the enthusiasm of Rafael San-Juan and colleagues, Markus Zeitlinger and Marco Idzko, and Jae Chol Choi and Won-Young Kim in the search for an effective treatment in early COVID-19, and in the findings of the STOIC study.1Ramakrishnan S Nicolau Jr, DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial.Zeitlinger and Idzko and Choi and Kim commented on the weakness of an open-label design and that the absence of an effect of the intervention on oxygen saturations negate the value of the trial findings. However, in a recently published open-label phase 3 trial investigating the use of azithromycin in treating early COVID-19,2Butler CC Dorward J Yu L-M et al.Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. open-label azithromycin compared with usual care did not lead to quicker symptom resolution or reduction in medical assessments, nor was a placebo effect found when compared with the other study groups despite widespread media support for azithromycin in COVID-19. Furthermore, the preprint report of the interim analysis of budesonide in early COVID-19 in the PRINCIPLE trial has replicated our phase 2 findings regarding quicker symptom resolution and potentially reduced urgent care visits and deaths.3Yu L-M Bafadhel M Dorward J et al.Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. Choi and Kim discussed the interesting issue of interferons in atopy and their effect on susceptibility to SARS-CoV-2 infection. Although interesting, at present further mechanistic insight is awaited.However, we find that our esteemed colleagues restricted their concern to the patients with most severe COVID-19, primarily the participant who had respiratory failure associated with SARS-CoV-2 infection. Although we agree that respiratory failure is important and indeed would be considered in the STOIC primary and secondary endpoints, we respectfully disagree on what constitutes an important clinical deterioration event in the COVID-19 syndrome. At the time of the STOIC trial, as we reported in our Article,1Ramakrishnan S Nicolau Jr, DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. all people in the UK with COVID-19 symptoms seeking additional medical care were advised to contact a government telephone line for all urgent COVID-19 queries. This government-led change was instituted after the trial was registered. This telephone line was operated and managed by medical practitioners, and triaged individuals who needed additional assessment either directing them to a COVID-19 urgent care hub or an emergency department. The STOIC participants who attended the urgent COVID-19 hubs clearly had sufficient symptoms to pass the telephone triage, be seen in an urgent clinical setting, and necessitate further investigations in a hospital. Furthermore, as noted in our Article, approximately 20% of participants had oxygen saturations at or below 94% at any one point during the study, which did not all result in a primary endpoint but would have been of concern to many respiratory physicians.Contrary to our respected colleagues, we believe the urgent events in STOIC, whether seen by a senior clinician in primary care or in the emergency department, are important for the patient and the health-care system, and the time and cost associated with presumed so-called mild COVID-19 should not be discounted.4Economic burden of COVID-19, China, January-March, 2020: a cost-of-illness study. Although events like diabetic ketoacidosis, acute renal failure, and cough-related rib fractures are not primary ventilatory failure, we disagree that they do not constitute COVID-19 events. As our knowledge increases, COVID-19 is widely accepted to cause systemic illness, ranging from anosmia to fever to gastrointestinal symptoms. Renal failure of varying severities has been reported in COVID-19.5Ronco C Reis T Husain-Syed F Management of acute kidney injury in patients with COVID-19. Dismissing a life-threatening event such as diabetic ketoacidosis or acute kidney injury occurring after anorexia and gastrointestinal syndrome, which are typical after early or mild COVID-19, would be imprudent.Finally, we hope that our colleagues agree, that early interventions that lead to improvement of symptoms are important to patients. Patients with COVID-19 who deteriorate are seeking medical care encompassing a much wider syndrome3Yu L-M Bafadhel M Dorward J et al.Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. and as clinicians we cannot assume that an illness that occurs in the community is thus all mild.

SR reports grants and non-financial support from the National Institute for Health Research Biomedical Research Centre, during the conduct of the study; and non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside of the submitted work. MB reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, and scientific adviser to Albus Health and ProAxsis outside of the submitted work.

References1.Ramakrishnan S Nicolau Jr, DV Langford B et al.

Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial.

Lancet Respir Med. ()2.Butler CC Dorward J Yu L-M et al.

Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

Lancet. 397: 1063-10743.Yu L-M Bafadhel M Dorward J 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. () 4.

Economic burden of COVID-19, China, January-March, 2020: a cost-of-illness study.

Bull World Health Organ. 99: 112-1245.Ronco C Reis T Husain-Syed F

Management of acute kidney injury in patients with COVID-19.

Lancet Respir Med. 8: 738-742Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S2213-2600(21)00212-5

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ScienceDirectAccess this article on ScienceDirect Linked ArticlesInhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial

Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19.

Full-Text PDF Inhaled budesonide for early treatment of COVID-19

We have thoroughly read the results of the phase 2 randomised clinical trial reported by Sanjay Ramakrishnan and colleagues1 in The Lancet Respiratory Medicine investigating the role of inhaled budesonide compared with usual care in adults within the first 7 days from the onset of mild COVID-19 symptoms.

Full-Text PDF Inhaled budesonide for early treatment of COVID-19

We read the Article by Sanjay Ramakrishnan and colleagues in The Lancet Respiratory Medicine with great interest.1 The results of their phase 2 randomised clinical trial indicated that early treatment with inhaled budesonide in patients with COVID-19 might prevent clinical deterioration, as determined by a reduced number of urgent care visits.1 The rational for the use of inhaled corticosteroids in patients with COVID-19 was already discussed by Alvar Agusti and colleagues.2 However, we here highlight that the open-label study design and the subjective primary endpoint both introduce an unknown level of bias, making interpretation of data difficult.

Full-Text PDF Inhaled budesonide for early treatment of COVID-19

We read with interest the Article by Sanjay Ramakrishnan and colleagues1 in The Lancet Respiratory Medicine on the efficacy of inhaled budesonide in the treatment of early COVID-19 illness in people in the community. The use of inhaled corticosteroids might be associated with poor outcomes among people being treated for COVID-19 in hospital.2 However, generally, users of inhaled corticosteroid have more comorbidities than non-users, which might have influenced the study's findings. The study by Ramakrishnan and colleagues is important because the selection bias introduced by a non-hospital setting is less than that introduced by a hospital setting, and a non-hospital setting allows researchers to assess independent drug action.

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