Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Inhaled Budesonide for COVID-19 in People at Higher Risk of Complications in the Community: The UK National Community Randomi.

Background The effectiveness of repurposed treatments with supportive evidence for higher risk individuals with COVID-19 in the community is unknown. In the UK PRINCIPLE national platform trial we aimed to determine whether 're-purposed medicines' (hydroxychloroquine, azithromycin, doxycycline, colchicine, inhaled budesonide, and other interventions) reduced time to recovery and COVID-19 related hospitalisations/deaths among people at higher risk of COVID-19 complications in the community. We mainly report the findings for budesonide arm here. Methods Participants in this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial were aged ≥65, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community, and were randomised to usual care, usual care plus inhaled budesonide (800µg twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Trial registration: ISRCTN86534580. Funded by United Kingdom Research Innovation (MC_PC_19079). Findings The trial opened on April 2, 2020, with the first 4 intervention arms stopped on futility grounds. Randomisation to the budesonide arm occurred from November 27, 2020 until March 31, 2021, when the pre-specified time to recovery superiority criterion was met. The primary analysis model includes 2530 SARS-CoV-2 positive participants, randomised to budesonide (n=787), usual care (n=1069), and other treatments (n=674). Time to first self-reported recovery was shorter in the budesonide group versus usual care (hazard ratio 1·21 [95% credible interval 1·08 to 1·36], probability of superiority >O·999, estimated benefit 2·94 [95% credible interval 1·19 to 5·12] days). An estimated 6·8% COVID-19 related hospitalisations/deaths occurred in the budesonide group versus 8·8% in usual care (estimated absolute difference, 2·0% [95% credible interval -0.2% to 4.5%], probability of superiority 0.963). In the main secondary analysis of admissions using only concurrent controls, admissions occurred in 6.6% (3.8 to 10.1%) in the budesonide group versus 8.8% (95% CI 5.2 to 13.1%), with an absolute difference of 2.2% (0.0 to 4.9%) and a hazard ratio of 0.73 (0.53 to 1.00), meeting the pre-specified superiority probability of 0.975. Three serious adverse events occurred in the budesonide group and three in usual care.

Haemorrhagic ulcerative duodenitis in a patient with COVID-19 infection: clinical improvement following treatment with budesonide.

We present a case of a male patient in his mid-30s with COVID-19-induced lung failure requiring extracorporeal membrane oxygenation, who needed an emergency oesophagogastroduodenoscopy due to major upper gastrointestinal bleeding. Endoscopy exposed severe ulcerative duodenitis with diffuse mucosal bleeding. While CT angiography did not show any signs of ischaemia, histopathology revealed duodenitis with substantial inflammatory cell infiltrates consisting of neutrophils and CD3+ T lymphocytes with equal CD4+/CD8+ distribution. Since the composition of cell infiltrates coincides with changes in inflammatory patterns of the respiratory mucosa from patients with COVID-19 and in COVID-19-associated enterocolitis, and systemic dexamethasone treatment became standard of care in ventilated intensive care unit patients with COVID-19 infection, we initiated an individualised therapeutic attempt to treat the duodenitis with topical enteral budesonide. Follow-up oesophagogastroduodenoscopies within 4 weeks of enteral budesonide administration revealed a full clinical and histological healing of the duodenal mucosa with marked reduction of neutrophilic and lymphocytic infiltrates.To our knowledge, the current report is the first description of enteral budesonide treatment of duodenitis in a patient with COVID-19 infection and warrants further investigation, whether budesonide might constitute a novel therapeutic strategy for the management of COVID-19-related intestinal mucosal damage.