Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial

Kumar, Deepali; Ison, Michael G.; Mira, Jean‐Paul; Welte, Tobias; Ha, Jeonghoon; Hui, David S.; Zhong, Nanshan; Saito, Takefumi; Katugampola, Laurie; Collinson, Neil; Williams, Sarah; Wildum, Steffen; Ackrill, Andrew M.; Clinch, Barry; Lee, Nelson

doi:10.1016/s1473-3099(21)00469-2

Cited by 47 publications

(44 citation statements)

References 26 publications

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“…When resistant variants emerge, viral load and clinical symptoms can relapse transiently in immunocompetent patients; the impact on immunocompromised patients has not been well studied and high rates of resistance emergence would be expected with monotherapy in these patients [30 ▪ ,31]. Combination therapy in prospective trials is associated with a lower risk of resistance emergence during therapy, although most of the patients with resistance emergence have immunocompromising conditions [28 ▪▪ ,32]. While tempting to use baloxavir in immunocompromised patients due to its ability to reduce viral shedding quickly, current guidelines recommend against routine use in this setting [24 ▪ ].…”

Section: Influenzamentioning

confidence: 99%

Respiratory viral infections in the immunocompromised

Ison¹

2022

Current Opinion in Pulmonary Medicine

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Purpose of reviewDuring much of the COVID-19 pandemic, respiratory viruses other than SARS-CoV-2 did not infect immunocompromised patients. As mitigation strategies lighten, there has been a rapid resurgence of respiratory viruses globally. This review will summarize our current options for the management of the common respiratory viruses in transplant recipients.Recent findingsExpansion of the availability and increased utilization of multiplex molecular assays have allowed the recognition of the scope of respiratory virus infections in the transplant populations. New antivirals for influenza, respiratory syncytial virus (RSV), parainfluenza virus (PIV) and adenovirus show promise to improve outcomes of these important infections.SummarySeveral new antiviral agents, including combination therapy of oseltamivir as well as baloxavir for influenza, fusion and nucleoprotein inhibitors for RSV, DAS181 for PIV and brincidofovir for adenovirus, hold promise to speed clearance of the virus, improve clinical outcomes and reduce the risk of resistance emergence.

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Section: Influenzamentioning

confidence: 99%

Respiratory viral infections in the immunocompromised

Ison¹

2022

Current Opinion in Pulmonary Medicine

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“…For example, studies in pregnant women and hospitalised children have shown that timely antiviral treatment could greatly reduce the length of hospital stay or progression to severe disease [ 36 , 37 ]. Drug combinations are increasingly evaluated with standard of care (SOC), which is important to understand how severe outcomes with combination therapy compare to monotherapy [ 38 – 40 ].…”

Section: Introductionmentioning

confidence: 99%

“…A Phase III clinical trial (Flagstone; NCT03684044) conducted in hospitalised patients with severe influenza compared the combination of SOC NAIs with baloxavir or placebo ( Table 2 ) [ 40 ]. Combination treatment did not add clinical benefit compared to NAI alone; the median time to clinical improvement was 97.5 hours for baloxavir + NAI and 100.2 hours for SOC [ 40 ]. A secondary endpoint of the study was time to cessation of viral shedding; the median time was 23.9 hours for baloxavir + NAI and 63.7 hours for SOC, respectively [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

“…Combination treatment did not add clinical benefit compared to NAI alone; the median time to clinical improvement was 97.5 hours for baloxavir + NAI and 100.2 hours for SOC [ 40 ]. A secondary endpoint of the study was time to cessation of viral shedding; the median time was 23.9 hours for baloxavir + NAI and 63.7 hours for SOC, respectively [ 40 ]. Dual drug resistance (NA/H275Y + PA/I38T) emerged in viruses isolated from 2 immunocompromised patients treated with an NAI (oseltamivir) in combination with baloxavir [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

“…A secondary endpoint of the study was time to cessation of viral shedding; the median time was 23.9 hours for baloxavir + NAI and 63.7 hours for SOC, respectively [ 40 ]. Dual drug resistance (NA/H275Y + PA/I38T) emerged in viruses isolated from 2 immunocompromised patients treated with an NAI (oseltamivir) in combination with baloxavir [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Preclinical and clinical developments for combination treatment of influenza

2022

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Antiviral drugs are an important measure of control for influenza in the population, particularly for those that are severely ill or hospitalised. The neuraminidase inhibitor (NAI) class of drugs, including oseltamivir, have been the standard of care (SOC) for severe influenza illness for many years. The approval of drugs with novel mechanisms of action, such as baloxavir marboxil, is important and broadens potential treatment options for combination therapy. The use of antiviral treatments in combination for influenza is of interest; one potential benefit of this treatment strategy is that the combination of drugs with different mechanisms of action may lower the selection of resistance due to treatment. In addition, combination therapy may become an important treatment option to improve patient outcomes in those with severe illness due to influenza or those that are immunocompromised. Clinical trials increasingly evaluate drug combinations in a range of patient cohorts. Here, we summarise preclinical and clinical advances in combination therapy for the treatment of influenza with reference to immunocompromised animal models and clinical data in hospitalised patient cohorts where available. There is a wide array of drug categories in development that have also been tested in combination. Therefore, in this review, we have included polymerase inhibitors, monoclonal antibodies (mAbs), host-targeted therapies, and adjunctive therapies. Combination treatment regimens should be carefully evaluated to determine whether they provide an added benefit relative to effectiveness of monotherapy and in a variety of patient cohorts, particularly, if there is a greater chance of an adverse outcome. Safe and effective treatment of influenza is important not only for seasonal influenza infection, but also if a pandemic strain was to emerge.

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