Covid-19 living Data

Inhaled corticosteroids vs Standard care/Placebo (RCT)

Mild outpatients

Studies included but not extracted/included in the analysis: Terada J, Drug Discov Ther, 2022

FOREST PLOTS -2022-10-07

Studies description

Trial NCT04377711
Publication Clemency B, JAMA Intern Med (2021) (published paper)
Dates: 2020-06-11 to 2020-11-03
Funding: Private (Covis Pharma GmbH; National Center for Advancing Translational Sciences of the National Institutes of Health (NIH); National Heart, Lung, and Blood Institute of the NIH)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 60
Inclusion criteria	At least age 12 years Had a positive SARS-CoV-2 molecular or antigen diagnostic sample obtained during the previous 72 hours Were not hospitalized or under consideration for hospitalization had an oxygen saturation level of at least 93% on room air Were able to demonstrate successful use of an MDI Had at least 1 of the following symptoms of COVID-19: fever, cough, or dyspnea
Exclusion criteria	History of hypersensitivity to ciclesonide Had taken an inhaled or intranasal corticosteroid within 14 days had taken oral corticosteroids within 90 days Had participated in any other clinical trial or used any investigational agent within 30 days Had a history of cystic fibrosis Had a history of idiopathic pulmonary fibrosis Receiving treatment with hydroxychloroquine/chloroquine Pregnant
Interventions
	Treatment Ciclesonide Two inhalations of 160 mcg twice a day for 30 days
	Control Standard care
Participants
	Randomized participants : Ciclesonide=197 Standard care=203
	Characteristics of participants N= 400 Mean age : NR 179 males Severity : Mild: n= 400/ Asymptomatic: n=0
Primary outcome
	In the register Time to alleviation of COVID-19-related symptoms by Day 30 [ Time Frame: Day 30 ]
	In the report 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
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the pre-print, the trial registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. The primary outcome in the article reflects that in the registry/protocol. The primary outcome was changed prior to start of recruitment from emergency department visits or hospital admission to symptom resolution. The study achieved its target sample size. This study was updated on the 15th of December, 2021 with data from the published article. This study was updated on September 28th, 2022 with new data extracted from the trial registry.

Trial NCT04356495, EudraCT 2020-001435-27
Publication COVERAGE - Duvignaud A, Clin Microbiol Infect (2022) (published paper)
Dates: 2020-12-29 to 2021-07-23
Funding: Public/non profit (French Ministry of Health, French National Research Agency, University of Bordeaux, Inserm/REACTing)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France Follow-up duration (days): 28
Inclusion criteria	Age ≥60 years regardless of the presence of other risk factors, or ≥50 years with at least one of the following risk factors: high blood pressure, body mass index ≥30 kg/m2, diabetes, ischemic heart disease, heart failure, history of stroke, chronic obstructive pulmonary disease, stage ≥3 chronic kidney disease, solid or haematological malignancy diagnosed <5 years ago, immunosuppressive therapy, or HIV infection with CD4 <200/mm3) COVID-19 with first symptoms ≤7 days before positive SARS-CoV-2 nasopharyngeal RT-PCR or antigen test no criteria for hospitalisation or acute oxygen therapy written informed consent.
Exclusion criteria	inability to understand or decide on participation lack of health insurance chronic inhaled corticosteroid therapy hypersensitivity to ciclesonide history of incompletely treated pulmonary tuberculosis pulmonary fungal infection inability to use the inhalation chamber and ongoing treatment with a potent CYP3A4 inhibitor.
Interventions
	Treatment Ciclesonide 2 puffs (160 mcg each) by inhalation twice a day for 10 days
	Control Standard care vitamin supplementation (AZINC vitality®, 2 pills per day) for 10 days
Participants
	Randomized participants : Ciclesonide=110 Standard care=107
	Characteristics of participants N= 217 Mean age : NR 106 males Severity : Mild: n= 217/ Asymptomatic: n=0
Primary outcome
	In the register 1) Proportion of participants who had a Grade 3 or 4 adverse event [ Time Frame: From inclusion (day0) to day 14 ]; 2) Efficacy phase: Death [ Time Frame: From inclusion (day0) to day 14 ], Efficacy phase: oxygen therapy [ Time Frame: From inclusion (day0) to day 14 ], Efficacy phase: hospitalization [ Time Frame: From inclusion (day0) to day 14 ]
	In the report 1) occurrence of grade 3-4-5 adverse events; 2) combination of hospitalisation, need for COVID19-related oxygen therapy at home or death
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the protocol, statistical analysis plan, supplementary appendices and study registry were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. The study (n = 217) did not achieve its target sample size (n = 702) because recruitment was terminated after futility was determined in a pre-planned interim analysis. This study was updated on September 1st, 2022 with data extracted after contact with authors.

Trial NCT04435795
Publication CONTAIN - Ezer N, BMJ (2021) (published paper)
Dates: 2020-09-15 to 2021-06-08
Funding: Mixed (McGill University Health Centre Foundation and the McGill Interdisciplinary Initiative in Infection and Immunity. The placebo metered dose inhaler was donated by GlaxoSmithKline. Nasal saline, and spacers for the inhalers were purchased by NE. The study drug was donated by COVIS Pharma. )
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Canada Follow-up duration (days): 29
Inclusion criteria	Adults Aged 18 years and older Had polymerase chain reaction confirmed covid-19 at enrolment At least one of the symptoms of fever, cough (wet or dry), or shortness of breath (including dyspnoea, chest congestion, or chest tightness as synonyms)
Exclusion criteria	Already on inhaled corticosteroid medication Currently using systemic steroids (oral or intravenous or intramuscular such as Prednisone) or use of steroids 7 days prior to enrolment Severely ill patients at enrollment (i.e., admitted to ICU at admission) Unable to self-administer the inhaler Known or suspected pregnancy and breastfeeding Known allergy to study medication or its components (non-medicinal ingredients including lactose allergy (type I)) Patients with untreated fungal, bacterial, or tubercular infections of the respiratory tract Current hospitalization Current use of oxygen at home or in the hospital Receipt of a COVID vaccine.
Interventions
	Treatment Ciclesonide 600 mcg inhaled twice a day + 200 mcg intranasally once a day for 14 days
	Control Placebo
Participants
	Randomized participants : Ciclesonide=108 Placebo=107
	Characteristics of participants N= 215 Mean age : NR 94 males Severity : Mild: n= 203/ Asymptomatic: n=0
Primary outcome
	In the register Proportion of participants with no symptoms of cough, fever or dyspnea [ Time Frame: day 7 ]
	In the report Resolution of self-reported fever and all respiratory symptoms at day 7 of treatment. Respiratory symptoms included cough (wet or dry) or dyspnoea (which included the description of shortness of breath, chest congestion, or chest tightness as synonyms).
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the protocol, the statistical analysis plan, the supplementary and the study registry were used in data extraction and risk of bias assessment. The study (n=215) did not achieve the target sample size (n=318) and was terminated early for expected futility to meet total enrolment. There is no change from the trial registration in the intervention and control treatments. The primary outcome indicated in registry reflects the primary outcome reported in the paper. Adverse events were reported in the paper but were not specified in the registry. This study was updated on March 16th, 2022 with data extracted after contact with authors.

Trial NCT04885530
Publication ACTIV 6 - Naggie S, medRxiv (2022) (preprint)
Dates: 2021-08-10 to 2022-02-12
Funding: Mixed (National Center for Advancing Translational Sciences (NCATS); Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority; GSK provided the product used in the study.)
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / USA Follow-up duration (days): 28
Inclusion criteria	Outpatients with mild-to-moderate Covid-19 confirmed SARS-CoV-2 infection ≤10 days - confirmed positive polymerase chain reaction (PCR) or antigen test for SARS-CoV-2 infection, including home-based testing aged ≥30 years experiencing ≥2 Covid-19 symptoms for ≤7 days from enrollment. Symptoms included the following: fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and new loss of sense of taste or smell.
Exclusion criteria	Hospitalization known allergy or contraindication including prohibited concomitant medications study drug use within 14 days of enrollment pregnancy, breastfeeding milk protein hypersensitivity use within <30 days of inhaled or systemic corticosteroids.
Interventions
	Treatment Fluticasone 200 mcg by inhalation once a day for 14 days
	Control Placebo
Participants
	Randomized participants : Fluticasone=715 Placebo=692
	Characteristics of participants N= 1407 Mean age : NR 470 males Severity : Mild: n= 1277/ Asymptomatic: n=0
Primary outcome
	In the register Number of hospitalizations as measured by patient reports. [ Time Frame: Up to 28 days ]; Number of deaths as measured by patient reports [ Time Frame: Up to 28 days ]; Number of symptoms as measured by patient reports [ Time Frame: Up to 28 days ]
	In the report Time to recovery, defined as the third of 3 consecutive days without symptoms.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article, the trial registry and supplementary appendices were used in data extraction and assessment of risk of bias. Neither protocol no statistical analysis plan was available. There is no change from the trial registration in the intervention and control treatments. The primary outcome in the article (time to recovery) differed from the three primary outcomes available in the platform study in the in the registry (number of hospitalizations, deaths and symptoms). A substantial proportion (9.2%) of those randomized were not included in follow up and analysis because they did not receive the study interventions due to the study’s decentralized design and reliance on home delivery. Nevertheless, the trial (n = 1277) achieved its target sample size (n = 1200).

Trial NCT04416399
Publication STOIC - Ramakrishnan S, Lancet Respir Med (2021) (published paper)
Dates: 2020-07-16 to 2020-12-09
Funding: Mixed (Oxford NIHR Biomedical Research Centre; AstraZeneca )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Single center / UK Follow-up duration (days): 28
Inclusion criteria	Participant is willing and able to give informed consent for participation in the trial Male or Female, aged 18 years or above New onset of symptoms suggestive of COVID-19 e.g. new onset cough and/or fever, and/or loss of smell or taste within 7 or fewer days of participant being seen at visit 1 In the Investigator's opinion, is able and willing to comply with all trial requirements
Exclusion criteria	A known allergy to investigational medicine product (IMP) (budesonide) Any known contraindication to any of the IMPs (budesonide) Patient currently prescribed inhaled or systemic corticosteroids Recent use, within the previous 7 days of inhaled or systemic corticosteroids Patient needs hospitalisation at time of study consent Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
Interventions
	Treatment Budesonide Two 400 mcg inhalations twice a day for up to 28 days
	Control Standard care
Participants
	Randomized participants : Budesonide=73 Standard care =73
	Characteristics of participants N= 146 Mean age : NR 62 males Severity : Mild: n= 146/ Asymptomatic: n=0
Primary outcome
	In the register Emergency department attendance of hospitalisation related to COVID-19 [ Time Frame: Day 1 to day 28 ]
	In the report COVID-19-related Urgent Care visit, Emergency Department assessment or hospitalisation
Documents avalaible	Protocol NR Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	*
General comment	No review-specific outcome data extracted. Pending contact with authors. In addition to the published/pre-print article, the trial registry, statistical analysis plan and supplementary appendix were used in data extraction and assessment of risk of bias. The study protocol was not available. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. As a result, the target sample size specified in the registry was not achieved. There were no differences between the trial registration and the article in the intervention and control treatments or the participant inclusion and exclusion criteria. Outcomes listed in the registry were reported, but none were relevant for the COVID-19 NMA. Consequently, no outcome data have been extracted for this study. On 13th of April ,2021, this study was updated based on the published report.

Trial ISRCTN86534580; EudraCT 2020-001209-22
Publication PRINCIPLE - Yu LM, Lancet (2021) (published paper)
Dates: 2020-11-27 to 2021-03-31
Funding: Public/non profit (UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	People in the community aged ≥65 years, or ≥50 years with comorbidities ongoing symptoms from polymerase chain reaction (PCR) confirmed or suspected COVID-19 (in accordance with the United Kingdom National Health Service definition of high temperature and/or new, continuous cough and/or change in sense of smell/taste) which started within the past 14 days Comorbidities required for eligibility in those aged 50–65 years were heart disease, hypertension, asthma or lung disease, diabetes, hepatic impairment, stroke or neurological problems, weakened immune system (eg, receiving chemotherapy), and self-reported obesity or body-mass index of at least 35 kg/m²
Exclusion criteria	Already already taking inhaled or systemic corticosteroids unable to use an inhaler inhaled budesonide contraindicated.
Interventions
	Treatment Budesonide 800 mcg (2 x 400 mcg inhalations) twice a day for 14 days.
	Control Standard care
Participants
	Randomized participants : Budesonide =1073 Standard care=NR
	Characteristics of participants N= 1073 Mean age : NR 835 males Severity : Mild: n= 1719/ Asymptomatic: n=0
Primary outcome
	In the register 1. Time taken to self-reported recovery, defined as the first instance that a participant reports feeling recovered from possible COVID-19; 2. Hospitalisation and/or death. Both collected within 28 days of randomization (ISRCTN).
	In the report 1) Time to first reported recovery defined as the first instance that a participant reports feeling recovered; and 2) Hospitalization or death related to COVID-19.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the trial registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. PRINCIPLE is an adaptive platform trial. The primary outcome was changed from hospitalization or death within 28 days to first instance that a participant reports feeling recovered on the recommendation of the Trial Management Group and Trial Steering and with ethical approval due to low incidence of the original outcome. The Data Monitoring and Safety Committee determined that the pre-specified superiority criterion was met on time to recovery, in both the SARS-CoV-2 positive population and the overall study population. Recruitment was stopped because the Trial Steering Committee decided that accumulating further data to reach pre-specified futility or superiority criteria on hospitalization/death was unlikely due to the successful vaccine rollout and lower than originally anticipated event rate. Therefore the study did not achieve the target sample size specified in the trial registry. On 16th of August, 2021, this study was updated based on the published report.