Table 5b. Inhaled Corticosteroids: Selected Clinical Trial Data

Last Updated: July 21, 2023

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for inhaled corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

Table 5b. Inhaled Corticosteroids: Selected Clinical Trial Data
Methods	Results	Limitations and Interpretation
PRINCIPLE: Open-Label RCT of Inhaled Budesonide in Nonhospitalized Patients With COVID-19 in the United Kingdom¹
Key Inclusion Criteria Aged ≥65 years or aged ≥50 years with comorbidities PCR-confirmed or suspected COVID-19 ≤14 days of symptoms Key Exclusion Criteria Already taking inhaled or systemic corticosteroids Unable to use an inhaler Contraindication to inhaled budesonide Interventions Usual care plus budesonide 800 mcg inhaled twice daily for 14 days (n = 1,069) Usual care (n = 787) Primary Endpoints COVID-19–related hospitalization or death up to 28 days from randomization Time to reported recovery up to 28 days from randomization	Participant Characteristics Mean age 64.2 years; 52% women; 92% White 81% with comorbidities Median of 6 days from symptom onset to randomization Primary Outcomes Hospitalization or death due to COVID-19 within 28 days: 6.8% in budesonide arm vs. 8.8% in usual care arm (OR 0.75; 95% CrI, 0.55–1.03) Median time to reported recovery: 11.8 days in budesonide arm vs. 14.7 days in usual care arm (HR 1.21; 95% CrI, 1.08–1.36)	Key Limitations Open-label trial Primary endpoint of time to recovery based on participant self-report Interpretation Inhaled budesonide reduced time to reported recovery but not COVID-19–related hospitalization or death. The clinical significance of self-reported time to recovery in an open-label study is unclear.
STOIC: Open-Label, Phase 2 RCT of Inhaled Budesonide in Nonhospitalized Adults With Early COVID-19 in the United Kingdom²
Key Inclusion Criteria Aged ≥18 years ≤7 days of symptoms Key Exclusion Criteria Use of inhaled or systemic glucocorticoids in past 7 days Known allergy or contraindication to budesonide Interventions Usual care plus budesonide 800 mcg inhaled twice daily until symptom resolution (n = 70) Usual care (n = 69) Primary Endpoint COVID-19–related urgent care visit, including ED visit or hospitalization Key Secondary Endpoint Time to clinical recovery	Participant Characteristics Mean age 45 years; 58% women 9% with CVD, 5% with DM 95% with positive SARS-CoV-2 RT-PCR result Median of 3 days from symptom onset to randomization Primary Outcome COVID-19–related urgent care visit or hospitalization: 1% in budesonide arm vs. 14% in usual care arm (difference in proportion 0.131; 95% CI, 0.043–0.218; P = 0.004) Secondary Outcome Median time to clinical recovery: 7 days in budesonide arm vs. 8 days in usual care arm	Key Limitations Small, open-label trial Terminated early after statistical analysis determined that additional participants would not alter study outcome Primary endpoint of time to recovery based on participant self-report Interpretation In adult outpatients with mild COVID-19, inhaled budesonide may reduce the need for urgent care, ED assessment, or hospitalization. The clinical significance of self-reported time to recovery in an open-label study is unclear.
Phase 3, Double-Blind RCT of Inhaled Ciclesonide in Nonhospitalized Patients With COVID-19 in the United States³
Key Inclusion Criteria Aged ≥12 years Positive SARS-CoV-2 molecular or antigen diagnostic test result in previous 72 hours ≥1 symptom of fever, cough, or dyspnea Key Exclusion Criteria Use of inhaled or intranasal corticosteroid within 14 days of enrollment or systemic corticosteroid within 90 days of enrollment Unable to use an inhaler Interventions Ciclesonide MDI 160 µg/actuation, 2 actuations twice a day for 30 days (n = 197) Placebo MDI twice a day for 30 days (n = 203) Primary Endpoint Time to alleviation of all COVID-19–related symptoms by Day 30 Key Secondary Endpoints Alleviation of COVID-19–related symptoms by Day 30 ED visit or hospital admission for COVID-19 by Day 30 Hospital admission or death by Day 30	Participant Characteristics Mean age 43.3 years; 55.3% women; 86.3% White Mean BMI 29.4 22.3% with HTN, 7.5% with type 2 DM Higher rates of DM and asthma in ciclesonide arm Primary Outcome Median of 19 days in both arms for alleviation of all COVID-19–related symptoms (HR 1.08; 95% CI, 0.84–1.38) Secondary Outcomes Alleviation of COVID-19–related symptoms by Day 30: 70.6% in ciclesonide arm vs. 63.5% in placebo arm ED visit or hospital admission for COVID-19 by Day 30: 1.0% in ciclesonide arm vs. 5.4% in placebo arm (OR 0.18; 95% CI, 0.04–0.85) Hospital admission or death by Day 30: 1.5% in ciclesonide arm vs. 3.4% in placebo arm (OR 0.45; 95% CI, 0.11–1.84) No deaths by Day 30 in either arm	Key Limitations ED or hospitalization outcome based on small number of events Primary endpoint of time to alleviation of all symptoms based on participant self-report Interpretation Inhaled ciclesonide did not reduce time to reported recovery. The robustness of the conclusion that inhaled ciclesonide reduced COVID-19-related ED visits or hospitalization is uncertain. The small number of events is most likely due to the relatively low rate of comorbidities in the study population.
CONTAIN: Double-Blind RCT of Inhaled and Intranasal Ciclesonide in Nonhospitalized Patients With COVID-19 in Canada⁴
Key Inclusion Criteria Aged ≥18 years Positive SARS-CoV-2 molecular diagnostic test result ≥1 symptom of fever, cough, or shortness of breath ≤5 days of symptoms Key Exclusion Criteria Receiving an inhaled corticosteroid or received a corticosteroid PO or IM within 7 days of enrollment Unable to use an inhaler Has only nonrespiratory symptoms Use of oxygen at home Vaccinated against COVID-19 Interventions Ciclesonide MDI 600 µg/actuation and intranasal ciclesonide 100 µg, both twice a day for 14 days (n = 105) Saline placebo MDI and intranasal saline, both twice a day for 14 days (n = 98) Primary Endpoint Resolution of fever and all respiratory symptoms at Day 7 Key Secondary Endpoints Resolution of fever and all respiratory symptoms at Day 14 Hospital admission by Day 14	Participant Characteristics Median age 35 years; 54% women; 61% White 20% with comorbid condition Primary Outcome Resolution of fever and all respiratory symptoms at Day 7: 40% in ciclesonide arm vs. 35% in placebo arm (adjusted risk difference 5.5%; 95% CI, -7.8% to 18.8%) Secondary Outcomes Resolution of fever and all respiratory symptoms at Day 14: 66% in ciclesonide arm vs. 58% in placebo arm (adjusted risk difference 7.5%; 95% CI, -5.9% to 20.8%) Hospital admission by Day 14: 6% in ciclesonide arm vs. 3% in placebo arm (adjusted risk difference 2.3%; 95% CI, -3.0% to 7.6%)	Key Limitation Small study with a relatively young, healthy population Interpretation The use of inhaled ciclesonide plus intranasal ciclesonide did not improve resolution of fever and respiratory symptoms in nonhospitalized patients with COVID-19.
COVERAGE: Open-Label RCT of Inhaled Ciclesonide in Nonhospitalized Adults With COVID-19 in France⁵
Key Inclusion Criteria Aged ≥60 years or aged ≥50 years with comorbidities Positive SARS-CoV-2 nasopharyngeal RT-PCR or antigen test result ≤7 days of symptoms Key Exclusion Criteria Chronic use of inhaled corticosteroid therapy Unable to use an inhalation chamber Ongoing therapy with a potent CYP3A4 inhibitor Interventions Ciclesonide 160 µg via inhalation chamber, 2 puffs twice daily for 10 days (n = 110) Vitamin and trace element supplement, 2 capsules PO once or twice daily for 10 days (n = 107) Primary Endpoint Hospitalization from any cause, need for COVID-19–related oxygen therapy at home, or death by Day 14 Key Secondary Endpoint Sustained alleviation of symptoms by Day 14	Participant Characteristics Median age 63 years; 51% women 72% with ≥1 comorbid conditions 14% with ≥1 COVID-19 vaccine dose Primary Outcome Hospitalization from any cause, need for COVID-19–related oxygen therapy at home, or death by Day 14: 16% in ciclesonide arm vs. 12% in control arm Secondary Outcome Sustained alleviation of symptoms by Day 14: 54% in ciclesonide arm vs. 57% in control arm	Key Limitation Small, open-label study Interpretation In adult outpatients with mild COVID-19, inhaled ciclesonide did not reduce deaths, hospitalizations, or the need for COVID-19–related oxygen therapy at home.
ACTIV-6: Decentralized, Placebo-Controlled, Platform RCT of Inhaled Fluticasone in Outpatients With COVID-19 in the United States⁶
Key Inclusion Criteria Aged ≥30 years Positive SARS-CoV-2 nasopharyngeal RT-PCR or antigen test result ≤7 days with ≥2 COVID-19 symptoms Key Exclusion Criterion Use of inhaled or systemic corticosteroids in preceding 30 days Interventions Fluticasone 200 µg inhaled once daily for 14 days (n = 656) Matching inhaled placebo (n = 350) or placebo from a different study (n = 271) Primary Endpoint Days to sustained recovery (i.e., the last of 3 consecutive days without symptoms) Key Secondary Endpoints Hospitalization or death by Day 28 Urgent care visit, ED visit, or hospitalization through Day 28 Number of days unwell with ongoing symptoms	Participant Characteristics Median age 45 years; 63% women 39% with BMI >30 kg/m2 26% with HTN 65% received ≥2 COVID-19 vaccine doses Primary Outcome Days to sustained recovery: no difference between arms (HR 1.01; 95% CrI, 0.91–1.12) Secondary Outcomes Hospitalization or death by Day 28: 0.5% in fluticasone arm vs. 0.5% in placebo arm Urgent care visit, ED visit, or hospitalization through Day 28: 3.7% in fluticasone arm vs. in 2.1% placebo arm (HR 1.9; 95% CrI, 0.8–3.5) Mean days unwell: 11.2 days in fluticasone arm vs. 11.3 days in placebo arm	Key Limitation Low number for some clinical events (e.g., hospitalization) Interpretation In adult outpatients with mild COVID-19, inhaled fluticasone did not reduce the time to sustained symptom recovery or clinical events such as hospitalizations, urgent care visits, and ED visits.
TOGETHER: Placebo-Controlled, Platform RCT of Oral Fluvoxamine and Inhaled Budesonide in Adults With Early-Onset COVID-19 in Brazil⁷
Key Inclusion Criteria Aged ≥50 years or aged ≥18 years with comorbidities Laboratory-confirmed SARS-CoV-2 infection ≤7 days of symptoms Key Exclusion Criteria Use of an SSRI Severe mental illness Cirrhosis, recent seizures, or severe ventricular cardiac arrythmia Interventions Fluvoxamine 100 mg PO twice daily and budesonide 800 mcg inhaled twice daily for 10 days (n = 738) Placebo (n = 738; route, dosing frequency, and duration may have differed from fluvoxamine arm) Primary Endpoint Composite endpoint of emergency setting observation for >6 hours or hospitalization due to progression of COVID-19 within 28 days after randomization Key Secondary Endpoints Hospitalization Health care attendance Any emergency setting visit Treatment-emergent AEs	Participant Characteristics Median age 51 years; 61% women 42% with BMI >30 kg/m² 44% with high blood pressure, 68% with multiple comorbidities 94% received ≥2 COVID-19 vaccine doses Primary Outcome Composite endpoint: 1.8% in fluvoxamine and budesonide arm vs. 3.7% in placebo arm (relative risk 0.50; 95% CrI, 0.25–0.92) Secondary Outcomes Hospitalization: 0.9% in fluvoxamine and budesonide arm vs. 1.1% in placebo arm Health care attendance: 2.6% in fluvoxamine and budesonide arm vs. 4.1% in placebo arm (relative risk 0.64; 95% CrI, 0.36–1.11) Any emergency setting visit: 12.2% in fluvoxamine and budesonide arm vs. 13.0% in placebo arm Treatment-emergent AEs: 17.6% in fluvoxamine and budesonide arm vs. 12.9% in placebo arm (relative risk 1.37; 95% CrI, 1.07–1.75); mostly Grade 2 events	Key Limitation Multiple investigational treatments or placebos were evaluated simultaneously. Not all patients in the placebo arm received a matched placebo. Interpretation Adult outpatients with mild COVID-19 who received a combination of fluvoxamine and inhaled budesonide had fewer emergency setting observations >6 hours or hospitalizations due to COVID-19 by Day 28 than those who received placebo. The use of fluvoxamine and inhaled budesonide did not reduce hospitalizations, health care attendance, or emergency setting visits. Defining the clinical relevance of the >6-hour emergency setting observation endpoint is difficult, as is applying that endpoint to practice settings in different countries. More AEs occurred with the use of fluvoxamine and inhaled budesonide than with placebo.
Key: AE = adverse event; BMI = body mass index; CVD = cardiovascular disease; CYP = cytochrome P450; DM = diabetes mellitus; ED = emergency department; HTN = hypertension; IM = intramuscular; MDI = metered dose inhaler; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PO = oral; RCT = randomized controlled trial; RT-PCR = reverse transcription polymerase chain reaction; SSRI = selective serotonin reuptake inhibitor

References

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