Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial

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Abstract

Objective

To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19.

Design

Randomised, double blind, placebo controlled trial.

Setting

Three Canadian provinces (Quebec, Ontario, and British Columbia).

Participants

203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea.

Intervention

Participants were randomised to receive either inhaled ciclesonide (600 μg twice daily) and intranasal ciclesonide (200 μg daily) or metered dose inhaler and nasal saline placebos for 14 days.

Main outcome measures

The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex.

Results

The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval −7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered.

Conclusion

Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed.

Trial registration

ClinicalTrials.gov NCT04435795.

Related collections

Most cited references 15

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Abstract: found
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Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Mark Peters (2021)

Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)

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REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

David Weinreich, Sumathi Sivapalasingam, Thomas S. Norton … (2020)

Abstract Background Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. Methods In this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients. Results Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. Conclusions In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

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Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

(2021)

Abstract Background The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. Methods We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support–free days, on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both. Results Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 (interquartile range, −1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. Conclusions In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

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Author and article information

Contributors

Nicole Ezer:

ORCID: https://orcid.org/0000-0003-1803-6418

Role: assistant professor

Sara Belga: Role: assistant professor

Nick Daneman: Role: associate professor

Adrienne Chan: Role: associate professor

Benjamin M Smith: Role: associate professor

Shay-Anne Daniels: Role: postgraduate medical trainee

Kristen Moran: Role: research assistant

Charlotte Besson: Role: research assistant

Louisa Y Smyth: Role: student

Susan J Bartlett: Role: professor

Andrea Benedetti: Role: associate professor

James G Martin: Role: professor

Todd C Lee: Role: associate professor

Emily G McDonald: Role: associate professor

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): BMJ-UK

Journal ID (hwp): bmj

Title: The BMJ

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2021

Publication date (Electronic): 02 November 2021

Publication date PMC-release: 02 November 2021

Volume: 375

Electronic Location Identifier: e068060

Affiliations

[1 ]Department of Medicine, Division of Respirology, McGill University Health Centre, Montreal, Quebec, Canada

[2 ]Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

[3 ]Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia, Canada

[4 ]Department of Medicine, Division of Infectious Diseases, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

[5 ]Clinical Practice Assessment Unit, Department of Medicine, Montreal, Quebec, Canada

[6 ]Department of Medicine, Division of Clinical Epidemiology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada

[7 ]Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada

[8 ]Department of Medicine, Division of General Internal Medicine, McGill University Health Centre, Montreal, Quebec, Canada

Author notes

Correspondence to: N Ezer Centre for Outcomes Research and Evaluation, Montreal, QC H4A 3S9, Canada nicole.ezer@ 123456mcgill.ca (or @ezer_nicole on Twitter)

Author information

Nicole Ezer https://orcid.org/0000-0003-1803-6418

Article

Publisher ID: BMJ-2021-068060.R1 Publisher ID: ezen068060

DOI: 10.1136/bmj-2021-068060

PMC ID: 8561042

PubMed ID: 34728476

SO-VID: 56e8b88c-97d4-470a-bb0f-e9ed2fcb11fc

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date accepted : 14 October 2021

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Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial

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Abstract

Objective

Design

Setting

Participants

Intervention

Main outcome measures

Results

Conclusion

Trial registration

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 15

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

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Cited by 38