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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. 

References

  1. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-855. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34388395.
  2. Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
  3. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med. 2021;182(1):42-49. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34807241.
  4. Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN Phase II randomised controlled trial. BMJ. 2021;375:e068060. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34728476.
  5. Duvignaud A, Lhomme E, Onaisi R, et al. Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE). Clin Microbiol Infect. 2022;28(7):1010-1016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35304280.
  6. Boulware DR, Lindsell CJ, Stewart TG, et al. Inhaled fluticasone furoate for outpatient treatment of COVID-19. N Engl J Med. 2023;389(12):1085-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37733308.
  7. Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, et al. Oral fluvoxamine with inhaled budesonide for treatment of early-onset COVID-19: a randomized platform trial. Ann Intern Med. 2023;176(5):667-675. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37068273.