A randomized controlled trial of inhaled ciclesonide for outpatient treatment of symptomatic COVID-19 infections
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Abstract
Importance
Systemic corticosteroids are commonly used in the treatment of severe COVID-19. However, their role in the treatment of patients with mild to moderate disease is less clear. The inhaled corticosteroid ciclesonide has shown early promise as a potential treatment for COVID-19.
Objective
To determine whether the inhaled steroid ciclesonide is efficacious in patients with high risk for disease progression and can reduce the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2.
Design
This was a phase III, multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of ciclesonide metered-dose inhaler (MDI) for the treatment of non-hospitalized participants with symptomatic COVID-19 infection. Patients were screened from June 11, 2020 to November 3, 2020.
Setting
The study was conducted at 10 centers throughout the U.S. public and private, academic and non-academic sites were represented among the centers.
Participants
Participants were randomly assigned to ciclesonide MDI 160 µg per actuation, two actuations twice a day (total daily dose 640 µg) or placebo for 30 days.
Main Outcomes and Measures
The primary endpoint was time to alleviation of all COVID-19 related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by Day 30. Secondary endpoints included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19.
Results
413 participants were screened and 400 (96.9%) were enrolled and randomized (197 in the ciclesonide arm and 203 in the placebo arm). The median time to alleviation of all COVID-19-related symptoms was 19.0 days (95% CI: 14.0, 21.0) in the ciclesonide arm and 19.0 days (95% CI: 16.0, 23.0) in the placebo arm. There was no difference in resolution of all symptoms by Day 30 (odds ratio [OR] 1.28, 95% CI: 0.84, 1.97). Participants treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19 (OR 0.18, 95% CI: 0.04 - 0.85). No subjects died during the study.
Conclusions and Relevance
Ciclesonide did not achieve the primary efficacy endpoint of time to alleviation of all COVID-19-related symptoms. Future studies of inhaled steroids are needed to explore their efficacy in patients with high risk for disease progression and in reducing the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2.
Trial Registration
ClinicalTrials.gov
NCT04377711
https://clinicaltrials.gov/ct2/show/NCT04377711
Key Points
Question
Can the inhaled steroid ciclesonide be efficacious in patients with high risk for disease progression and reduce the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2?
Findings
In this randomized clinical trial of 413 patients, ciclesonide did not reduce the time to alleviation of all COVID-19-related symptoms. However, patients treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19.
Meaning
Future studies of inhaled steroids are needed to explore their efficacy in patients with high risk for disease progression and in reducing the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2.
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SciScore for 10.1101/2021.09.07.21261811: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was approved by the Western Institutional Review Board (IRB).
Consent: All participants, parents/legal guardians, or legally authorized representatives provided written informed consent.Sex as a biological variable Participants were excluded if they (1) had a history of hypersensitivity to ciclesonide, (2) had taken an inhaled or intranasal corticosteroid within 14 days, (3) had taken oral corticosteroids within 90 days, (4) had participated in any other clinical trial or use of any investigational agent within 30 days, (5) had a history of cystic fibrosis, (6) has a history of idiopathic pulmonary fibrosis, (7) were receiving treatment with hydroxychloroquine/chloroquine, or … SciScore for 10.1101/2021.09.07.21261811: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was approved by the Western Institutional Review Board (IRB).
Consent: All participants, parents/legal guardians, or legally authorized representatives provided written informed consent.Sex as a biological variable Participants were excluded if they (1) had a history of hypersensitivity to ciclesonide, (2) had taken an inhaled or intranasal corticosteroid within 14 days, (3) had taken oral corticosteroids within 90 days, (4) had participated in any other clinical trial or use of any investigational agent within 30 days, (5) had a history of cystic fibrosis, (6) has a history of idiopathic pulmonary fibrosis, (7) were receiving treatment with hydroxychloroquine/chloroquine, or (8) were pregnant. Randomization Study design and participants: This was a phase III, multicenter, double-blinded, randomized placebo-controlled trial to assess the safety and efficacy of ciclesonide metered-dose inhaler (MDI) for the treatment of non-hospitalized patients with symptomatic COVID-19 infection. Blinding Individual site personnel dispensed individual kits in order, blinded to the assignment. Power Analysis For the final primary outcome, a sample size of approximately 232 patients (116 per arm) was required to achieve 90% power at α = 0.05. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04377711 Completed A Study of the Safety and Efficacy of Ciclesonide in the Tre… NCT04193878 Enrolling by invitation ARrest RESpiraTory Failure From PNEUMONIA NCT04330586 Completed A Trial of Ciclesonide in Adults With Mild-to-moderate COVID… NCT04331054 Terminated Protective Role of Inhaled Steroids for Covid-19 Infection NCT04331470 Recruiting Evaluation of Efficacy of Levamisole and Formoterol+Budesoni… NCT04355637 Recruiting Inhaled Corticosteroid Treatment of COVID19 Patients With Pn… NCT04356495 Recruiting Trial of COVID-19 Outpatient Treatment in Individuals With R… NCT04381364 Recruiting Inhalation of Ciclesonide for Patients With COVID-19: A Rand… NCT04416399 Terminated STerOids in COVID-19 Study ISRCTN86534580 NA NA Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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