Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19

Clemency et al., JAMA Internal Medicine, doi:10.1001/jamainternmed.2021.6759, NCT04377711

Nov 2021

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RCT 400 outpatients in the USA, showing significantly lower ER visits/hospital admission with ciclesonide treatment. NCT04377711 (history).

Publication was delayed about a year after completion and the primary endpoint was changed about 4 months after the end of the trial on April 9, 2021 clinicaltrials.gov, trialsitenews.com. The original primary outcome was the more important ER visits/hospital admission, which shows a statistically significant improvement OR 0.18 [0.04-0.85].

Targeted administration to the respiratory tract provides treatment directly to the typical source of initial SARS-CoV-2 infection and replication, and allows for rapid onset of action, higher local drug concentration, and reduced systemic side effects.

1. clinicaltrials.gov, clinicaltrials.gov/ct2/history/NCT04377711?A=3&B=4&C=Side-by-Side#StudyPageTop.clinicaltrials.gov/ct2/history/NCT04377711?A=3&B=4&C=Side-by-Side#StudyPageTop.

2. trialsitenews.com, trialsitenews.com/is-regulatory-capture-behind-the-strange-observations-associated-with-the-recent-covid-19-ciclesonide-study/.trialsitenews.com/is-regulatory-capture-behind-the-strange-observations-associated-with-the-recent-covid-19-ciclesonide-study/.

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risk of hospitalization, 54.1% lower, RR 0.46, p = 0.26, treatment 3 of 197 (1.5%), control 7 of 203 (3.4%), NNT 52, odds ratio converted to relative risk.

risk of hospitalization/ER, 81.2% lower, RR 0.19, p = 0.03, treatment 2 of 197 (1.0%), control 11 of 203 (5.4%), NNT 23, odds ratio converted to relative risk, primary outcome.

risk of no recovery, 15.1% lower, RR 0.85, p = 0.25, treatment 58 of 197 (29.4%), control 74 of 203 (36.5%), NNT 14, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 30.

recovery time, 7.4% lower, relative time 0.93, p = 0.55, treatment 197, control 203, inverted to make RR<1 favor treatment, Cox regression, post-hoc primary outcome.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Clemency et al., 22 Nov 2021, Double Blind Randomized Controlled Trial, USA, peer-reviewed, 7 authors, study period 11 June, 2020 - 3 November, 2020, trial NCT04377711 (history).

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Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19

DO Brian M Clemency, MD Renoj Varughese, MD Yaneicy Gonzalez-Rojas, MD, MPH Caryn G Morse, MD Wanda Phipatanakul, MS David J Koster, MS Michael S Blaiss

JAMA Internal Medicine, doi:10.1001/jamainternmed.2021.6759

IMPORTANCE Systemic corticosteroids are commonly used in treating severe COVID-19. However, the role of inhaled corticosteroids in the treatment of patients with mild to moderate disease is less clear. OBJECTIVE To determine the efficacy of the inhaled steroid ciclesonide in reducing the time to alleviation of all COVID-19-related symptoms among nonhospitalized participants with symptomatic COVID-19 infection. DESIGN, SETTING, AND PARTICIPANTS This phase 3, multicenter, double-blind, randomized clinical trial was conducted at 10 centers throughout the US and assessed the safety and efficacy of a ciclesonide metered-dose inhaler (MDI) for treating nonhospitalized participants with symptomatic COVID-19 infection who were screened from June 11, 2020, to November 3, 2020. INTERVENTIONS Participants were randomly assigned to receive ciclesonide MDI, 160 μg per actuation, for a total of 2 actuations twice a day (total daily dose, 640 μg) or placebo for 30 days. MAIN OUTCOMES AND MEASURES The primary end point 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 end points included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19. RESULTS A total of 413 participants were screened and 400 (96.9%) were enrolled and randomized (197 [49.3%] in the ciclesonide arm and 203 [50.7%] in the placebo arm; mean [SD] age, 43.3 [16.9] years; 221 [55.3%] female; 2 [0.5%] Asian, 47 [11.8%] Black or African American, 3 [0.8%] Native Hawaiian or other Pacific Islander, 345 [86.3%] White, and 1 multiracial individuals [0.3%]; 172 Hispanic or Latino individuals [43.0%] ). 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, 1.28; 95% CI, 0.84-1.97). Participants who were treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons related to COVID-19 (odds ratio, 0.18; 95% CI, 0.04-0.85). No participants died during the study. CONCLUSIONS AND RELEVANCE The results of this randomized clinical trial demonstrated that ciclesonide did not achieve the primary efficacy end point of reduced time to alleviation of all COVID-19-related symptoms. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04377711

ARTICLE INFORMATION Accepted for Publication: October 3, 2021. Published Online: November 22, 2021. doi:10.1001/jamainternmed.2021.6759 Author Contributions: Dr Clemency and Mr Koster had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Funding/Support: The study was sponsored and funded by Covis Pharma GmbH. Research at the primary site was also supported by the National Center for Advancing Translational Sciences of the (NIH) (grant UL1TR001412; Drs Clemency and Varughese) and the National Heart, Lung, and Blood Institute of the NIH (grant K12HL138052; Dr Clemency). Role of the Funder/Sponsor: Covis Pharma GmbH had a role in the design and conduct of the study. Covis Pharma GmbH approved the plan for, but did not participate in, the collection, management and analysis of the data. Covis Pharma GmbH approved the decision to submit the manuscript for publication. Changes to the primary end point were made by the study sponsor in consultation with the study steering committee and the US Food and Drug Administration. The NIH had no role in the study design, data collection, data analysis, or decision to publish. Disclaimer: The views expressed are those of the authors and not necessarily those of Covis Pharma GmbH or the NIH. Data Sharing Statement: See Supplement 3. Additional Contributions: We thank Skyler Hime-Rupard, MS, and Yolaine Jeune-Smith, PhD, Cardinal Health Specialty..

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