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.
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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.
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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.
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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.
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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 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.
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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.
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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.
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