Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE)

Author(s): Alexandre Duvignaud ¹ ^, ² ^, ³ ^, ^† , Edouard Lhomme ¹ ^, ⁴ ^, ⁵ ^, ⁶ ^, ^† , Racha Onaisi ⁷ , Rémi Sitta ⁴ ^, ⁶ , Ambre Gelley ⁴ , Julie Chastang ⁸ ^, ⁹ , Lionel Piroth ¹⁰ ^, ¹¹ , Christine Binquet ¹¹ , Julie Dupouy ¹² ^, ¹³ , Alain Makinson ¹⁴ ^, ¹⁵ , Benjamin Lefèvre ¹⁶ ^, ¹⁷ , Jean-Marc Naccache ¹⁸ , Caroline Roussillon ¹⁹ , Roland Landman ²⁰ ^, ²¹ , Cédrick Wallet ⁴ , Sophie Karcher ¹ , Valérie Journot ¹ , Duc Nguyen ¹ ^, ² ^, ³ , Thierry Pistone ¹ ^, ² ^, ³ , Stéphane Bouchet ²² , Marie-Edith Lafon ²³ , Mathieu Molimard ¹⁹ , Rodolphe Thiébaut ³ ^, ⁴ , Xavier de Lamballerie ²⁴ , Jean-Philippe Joseph ⁷ , Laura Richert ⁴ ^, ⁵ ^, ⁶ , Olivier Saint-Lary ²⁵ ^, ²⁶ , Sarah Djabarouti ²⁷ ^, ²⁸ , Linda Wittkop ³ ^, ⁴ ^, ⁵ ^, ^‡ , Xavier Anglaret ¹ ^, ^∗ ^, ^‡ , Denis Malvy ¹ ^, ² ^, ^‡ , the Coverage Study Group ^∗ , SA1-1: Members of the COVERAGE France Study Group. Sponsor (CHU Bordeaux), National Trial Coordination Unit: CIC-EC 1401/EUCLID, MEREVA, National Coordinating Pharmacy, National Coordinating Laboratories, Bordeaux, Créteil, Bordeaux Study center, Investigating physicians, Coordination, Dijon Study center, Investigating physicians, Coordination, Nancy Study center: Investigating physicians, Coordination, Toulouse Study sites, Investigating physicians, Coordination, Bastia Study center, Investigating physicians, Coordination, Montpellier Study center: Investigating physicians, Coordination, Paris Study center 1: Collège National des Généralistes Enseignants (CNGE), Investigating physicians, Coordination, Paris Study center 2, Groupe Hospitalier Paris Saint Joseph (GHPSJ), Investigating physicians, Coordination, Paris Study center 3: Institut de Médecine et d’Epidémiologie Appliquée (IMEA), Coordination, Nantes/Angers Study center, Investigating physicians, Coordination, Others contributors, Scientific Advisory Board: Voting members, Non-voting members, Data Safety Monitoring Board

Publication date (Electronic): 15 March 2022

Journal: Clinical Microbiology and Infection

Publisher: The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

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Abstract

Objectives

To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness.

Methods

COVERAGE is an open-label, randomised controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms <7 days and absence of criteria for hospitalisation are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalisation, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO OSCI, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial’s Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here.

Results

The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years [Interquartile range (IQR) 59-68]. 157/217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days [IQR 3-5]. During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]) and 24 were hospitalised (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day14, including 12/106 (11. 3%, 95% CI 6.0 to 18.9%) in the control arm and 14/106 (13.2%; 95% CI 7.4 to 21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms.

Conclusions

Our findings are consistent with the European Medicines Agency’s COVID-19 taskforce statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for people with COVID-19.

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Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

Sangeun Jeon, Meehyun Ko, Jihye Lee … (2020)

Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC50s), and in particular, two FDA-approved drugs—niclosamide and ciclesonide—were notable in some respects.

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

Sanjay Ramakrishnan, Dan V. Nicolau, Beverly Langford … (2021)

Background Multiple early reports of patients admitted to hospital with COVID-19 showed that patients with chronic respiratory disease were significantly under-represented in these cohorts. We hypothesised that the widespread use of inhaled glucocorticoids among these patients was responsible for this finding, and tested if inhaled glucocorticoids would be an effective treatment for early COVID-19. Methods We performed an open-label, parallel-group, phase 2, randomised controlled trial (Steroids in COVID-19; STOIC) of inhaled budesonide, compared with usual care, in adults within 7 days of the onset of mild COVID-19 symptoms. The trial was done in the community in Oxfordshire, UK. Participants were randomly assigned to inhaled budsonide or usual care stratified for age (≤40 years or >40 years), sex (male or female), and number of comorbidities (≤1 and ≥2). Randomisation was done using random sequence generation in block randomisation in a 1:1 ratio. Budesonide dry powder was delivered using a turbohaler at a dose of 800 μg per actuation. Participants were asked to take two inhalations twice a day until symptom resolution. The primary endpoint was COVID-19-related urgent care visit, including emergency department assessment or hospitalisation, analysed for both the per-protocol and intention-to-treat (ITT) populations. The secondary outcomes were self-reported clinical recovery (symptom resolution), viral symptoms measured using the Common Cold Questionnare (CCQ) and the InFLUenza Patient Reported Outcome Questionnaire (FLUPro), body temperature, blood oxygen saturations, and SARS-CoV-2 viral load. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. This trial is registered with ClinicalTrials.gov, NCT04416399. Findings From July 16 to Dec 9, 2020, 167 participants were recruited and assessed for eligibility. 21 did not meet eligibility criteria and were excluded. 146 participants were randomly assigned—73 to usual care and 73 to budesonide. For the per-protocol population (n=139), the primary outcome occurred in ten (14%) of 70 participants in the budesonide group and one (1%) of 69 participant in the usual care group (difference in proportions 0·131, 95% CI 0·043 to 0·218; p=0·004). For the ITT population, the primary outcome occurred in 11 (15%) participants in the usual care group and two (3%) participants in the budesonide group (difference in proportions 0·123, 95% CI 0·033 to 0·213; p=0·009). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. Clinical recovery was 1 day shorter in the budesonide group compared with the usual care group (median 7 days [95% CI 6 to 9] in the budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test p=0·007). The mean proportion of days with a fever in the first 14 days was lower in the budesonide group (2%, SD 6) than the usual care group (8%, SD 18; Wilcoxon test p=0·051) and the proportion of participants with at least 1 day of fever was lower in the budesonide group when compared with the usual care group. As-needed antipyretic medication was required for fewer proportion of days in the budesonide group compared with the usual care group (27% [IQR 0–50] vs 50% [15–71]; p=0·025) Fewer participants randomly assigned to budesonide had persistent symptoms at days 14 and 28 compared with participants receiving usual care (difference in proportions 0·204, 95% CI 0·075 to 0·334; p=0·003). The mean total score change in the CCQ and FLUPro over 14 days was significantly better in the budesonide group compared with the usual care group (CCQ mean difference −0·12, 95% CI −0·21 to −0·02 [p=0·016]; FLUPro mean difference −0·10, 95% CI −0·21 to −0·00 [p=0·044]). Blood oxygen saturations and SARS-CoV-2 load, measured by cycle threshold, were not different between the groups. Budesonide was safe, with only five (7%) participants reporting self-limiting adverse events. Interpretation Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19. Funding National Institute for Health Research Biomedical Research Centre and AstraZeneca.

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Characteristics and predictors of hospitalization and death in the first 11 122 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: a nationwide cohort

Mette Reilev, Kasper Kristensen, Anton Pottegård … (2020)

Abstract Background Population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) is urgently needed to inform targeted protection strategies in the general population. Methods We examined characteristics and predictors of hospitalization and death in a nationwide cohort of all Danish individuals tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 27 February 2020 until 19 May 2020. Results We identified 11 122 SARS-CoV-2 polymerase chain reaction-positive cases of whom 80% were community-managed and 20% were hospitalized. Thirty-day all-cause mortality was 5.2%. Age was strongly associated with fatal disease {odds ratio [OR] 15 [95% confidence interval (CI): 9–26] for 70–79 years, increasing to OR 90 (95% CI: 50–162) for ≥90 years, when compared with cases aged 50–59 years and adjusted for sex and number of co-morbidities}. Similarly, the number of co-morbidities was associated with fatal disease [OR 5.2 (95% CI: 3.4–8.0), for cases with at least four co-morbidities vs no co-morbidities] and 79% of fatal cases had at least two co-morbidities. Most major chronic diseases were associated with hospitalization, with ORs ranging from 1.3–1.4 (e.g. stroke, ischaemic heart disease) to 2.6–3.4 (e.g. heart failure, hospital-diagnosed kidney disease, organ transplantation) and with mortality with ORs ranging from 1.1–1.3 (e.g. ischaemic heart disease, hypertension) to 2.5–3.2 (e.g. major psychiatric disorder, organ transplantation). In the absence of co-morbidities, mortality was <5% in persons aged ≤80 years. Conclusions In this nationwide population-based COVID-19 study, increasing age and multimorbidity were strongly associated with hospitalization and death. In the absence of co-morbidities, the mortality was, however, <5% until the age of 80 years.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Microbiol Infect

Journal ID (iso-abbrev): Clin Microbiol Infect

Title: Clinical Microbiology and Infection

Publisher: The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

ISSN (Print): 1198-743X

ISSN (Electronic): 1469-0691

Publication date PMC-release: 15 March 2022

Publication date (Electronic): 15 March 2022

Affiliations

[1 ]Inserm 1219 Bordeaux Population Health, Université de Bordeaux, F-33000 Bordeaux, France

[2 ]CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, F-33000 Bordeaux, France

[3 ]IRD, F-33000 Bordeaux, France

[4 ]CIC 1401, EUCLID/F-CRIN Clinical Trials Platform, F-33000 Bordeaux, France

[5 ]Inria SISTM, F-33000 Bordeaux, France

[6 ]CHU Bordeaux, Department of Public Health, F-33000 Bordeaux, France

[7 ]Bordeaux University, Department of General Practice, F-33000 Bordeaux, France

[8 ]Sorbonne Université, Département de Médecine Générale, F-75012 Paris, France

[9 ]Inserm 1136 IPLESP, Sorbonne Université, F-75012 Paris, France

[10 ]CHU de Dijon, Département d’Infectiologie, F-21231 Dijon, France

[11 ]Université de Bourgogne, CIC Inserm 1432, Module Épidémiologie Clinique, F-21231 Dijon, France

[12 ]Inserm 1295 CERPOP, Université Toulouse III Paul Sabatier, F-31860 Toulouse

[13 ]Université Toulouse III Paul Sabatier, Département universitaire de médecine générale, F-31860 Toulouse

[14 ]Université. de Montpellier, Inserm 1175, CIC 1411, F-3400 Montpellier, France

[15 ]CHU de Montpellier, Département des Maladies Infectieuses, F-3400 Montpellier, France

[16 ]CHRU Nancy, Service des Maladies Infectieuses et Tropicales, F-54000 Nancy, France

[17 ]Université de Lorraine, APEMAC, F-54000 Nancy, France

[18 ]Groupe Hospitalier Paris Saint Joseph, Service de Pneumologie-Allergologie-Oncologie Thoracique, F-75014 Paris, France

[19 ]CHU Bordeaux, Clinical Research and Innovation Department, Safety and Vigilance Unit, F-33000 Bordeaux, France

[20 ]Inserm 1137 IAME, Université Paris Diderot, IMEA, F-75018 Paris, France

[21 ]CHU Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, AP-HP, F- 75018 Paris, France

[22 ]CHU Bordeaux, Service de Pharmacologie, F-33000 Bordeaux, France

[23 ]CNRS UMR 5234, Bordeaux University, F-33000, Bordeaux France

[24 ]Université Aix-Marseille, Unité des Virus Émergents, IRD 190, Inserm 1207, F-13385 Marseille Cedex 05, France

[25 ]Université Paris-Saclay Villejuif, Centre for Research in Epidemiology and Population Health, INSERM 1018, F-94807 Villejuif Cedex, France

[26 ]Univ. Versailles Saint-Quentin en Yvelines, Faculty of Health Sciences Simone Veil, Department of Family Medicine, F- 78180 Montigny Le Bretonneux, France

[27 ]CHU Bordeaux, Pharmacy, F-33000 Bordeaux, France

[28 ]INSERM U1034, Université de Bordeaux, Bordeaux, France

Author notes

[∗ ]Corresponding author. Inserm U1219 146 Rue Léo Saignat 33076 Bordeaux Cedex France

[∗]

The list of the members of the COVERAGE Study Group is detailed in the Supplemental Appendix 1 (section SA1-1).

[†]

Contributed equally to this work.

[‡]

Contributed equally to this work.

Article

Publisher Item ID: S1198-743X(22)00108-2

DOI: 10.1016/j.cmi.2022.02.031

PMC ID: 8920965

PubMed ID: 35304280

SO-VID: 51992568-0c68-4561-9d24-6e561317eb50

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 1 November 2021

Date revision received : 8 February 2022

Date accepted : 20 February 2022

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Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE)

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Abstract

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Novel Coronavirus Disease COVID-19

Most cited references 21

Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

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

Characteristics and predictors of hospitalization and death in the first 11 122 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: a nationwide cohort

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Cited by 14

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