Table 5b. Inhaled Corticosteroids: Selected Clinical Data

• 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 time from symptom onset to randomization: 6 days

Primary Outcomes

• Percentage of patients who were hospitalized or died 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).

• Open-label trial
• Primary endpoint of time to reported 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.

• 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 = 73)
• Usual care (n = 73)

Primary Endpoint

• COVID-19-related urgent care visit, including ED visit or hospitalization

Participant Characteristics

• Mean age 45 years; 58% women
• 9% with CVD, 5% with DM
• 95% with positive SARS-CoV-2 RT-PCR result
• Median time from symptom onset to randomization: 3 days

Primary Outcomes

• Median duration of budesonide use: 7 days.
• Percentage of patients with COVID-19-related urgent care visit or hospitalization: 1% in budesonide arm vs.14% in usual care arm (relative risk reduction 91%).

• Small, open-label trial
• Early termination after statistical analysis determined that additional participants would not alter study outcome

Interpretation

• In adult outpatients with mild COVID-19, inhaled budesonide may reduce the need for urgent care or ED assessment and/or hospitalization.

• 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

• Taken 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 time to alleviation of all COVID-19-related symptoms: 19.0 days in ciclesonide arm vs. 19.0 days in placebo arm (HR 1.08; 95% CI, 0.84–1.38).

Secondary Outcomes

• By Day 30, percentage of patients in whom the following outcomes occurred:
  • Alleviation of COVID-19-related symptoms: 70.6% in ciclesonide arm vs. 63.5% in placebo arm.
  • Subsequent ED visit or hospital admission for COVID-19: 1.0% in ciclesonide arm vs. 5.4% in placebo arm (OR 0.18; 95% CI, 0.04–0.85).
  • Hospital admission or death: 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.

• 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; there were only a small number of events, which is most likely due to the relatively low rate of comorbidities in the study population.

• Aged ≥18 years
• Positive SARS-CoV-2 molecular diagnostic test result
• ≥1 symptom of fever, cough, or shortness of breath
• Symptom duration ≤6 days

Key Exclusion Criteria

• Already taking an inhaled corticosteroid or taken PO or IM corticosteroids within 7 days of enrollment
• Unable to use an inhaler
• No respiratory symptoms
• Use of oxygen at home
• COVID-19 vaccinated

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

• Percentage of patients with 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

• Percentage of patients with 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%).
• Percentage of patients who were admitted to the hospital by Day 14: 6% in ciclesonide arm vs. 3% in placebo arm (adjusted risk difference 2.3%; 95% CI, -3.0% to 7.6%).

• 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.