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Comparative Efficacy
Indication: Influenza
Guidelines
Guideline: Influenza antiviral medications: Summary for
clinicians
Reference: Centers for Disease Control and Prevention,
20189
Comments: Approved antiviral agents for the treatment of
influenza include neuraminidase inhibitors (oseltamivir,
zanamivir, and peramivir) and adamantanes (amantadine
and rimantadine). Neuraminidase inhibitors are effective
against both influenza A and B viruses, while adamantanes
are only effective against influenza A. Viral resistance can
be a problem with these antivirals. Antiviral therapy, if
needed, should be initiated as early as possible for any
patient with confirmed or suspected influenza who is hospitalized; has severe, complicated, or progressive illness;
or is at higher risk for influenza complications.
Studies
Drug: Baloxavir vs Oseltamivir vs Placebo
Reference: Hayden GF, et al, 2018 (CAPSTONE-1
study)3,10-12
Study Design: Phase 3, randomized, double-blind, multicenter, placebo- and active-controlled study
Study Funding: Shionogi
Patients: A total of 1436 patients (12-64 years of age)
with fever (axillary temperature, 38°C [100.4°F] or
higher), one or more general symptoms and one or more
respiratory symptoms (moderate to severe), and within 48
hours from symptom onset. Exclusion criteria included
pregnancy or within 2 weeks postpartum; resident of
long-term care facility (eg, welfare facility for the elderly,
nursing home); chronic respiratory diseases, including
bronchial asthma; neurological and neurodevelopmental
disorders, including disorders of the brain, spinal cord,
peripheral nerve, and muscle (eg, cerebral palsy, epilepsy
[seizure disorders], stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy,
spinal cord injury); heart disease (eg, congenital heart disease, congestive heart failure, coronary artery disease),
excluding hypertension without other heart-related symptoms; American Indian and Alaskan native ethnicity;
blood disorders (such as sickle cell disease); endocrine
disorders (including diabetes mellitus); kidney, liver, or
metabolic disorders; compromised immune system
(including patients receiving immunosuppressant therapy,
or those with cancer or HIV infection); and morbid obesity (body mass index [BMI] of 40 or higher) or weight
less than 40 kg.
Intervention: Patients were randomized to a single oral
dose of baloxavir marboxil (either 40 mg or 80 mg), oseltamivir 75 mg twice daily for 5 days, or placebo. Patients

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between 12 and 19 years of age were randomized to either
a single oral dose of baloxavir marboxil (40 mg or 80 mg)
or placebo. Patients receiving baloxavir marboxil received
oseltamivir placebo capsules on days 1 to 5, while patients
receiving oseltamivir received baloxavir marboxil placebo tablets on day 1.

Results
Primary End Point(s)
** Median time to alleviation in influenza symptoms
(cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, fatigue):
** Intention-to-treat (ITT)-infected cohort: 53.7 hours
with baloxavir marboxil and 80.2 hours with placebo
(P < .001); median treatment difference was 26.5
hours (95% confidence interval [CI], 17.8-35.8).
** ITT population: 65.4 hours with baloxavir marboxil
and 88.6 hours with placebo (P < .001); median treatment difference was 23.2 hours (95% CI, 34.2-14).
** A shorter time to alleviation of symptoms was
observed with baloxavir than with placebo in both
adolescents (median difference, 38.6 hours; P = .006)
and adults (median difference, 25.6 hours; P < .001).
** Median time to alleviation of influenza symptoms
was 53.5 hours with baloxavir marboxil and 53.8
hours with oseltamivir (P = .756).

Secondary End Point(s)
** Difference in the time to alleviation of symptoms
between the baloxavir group and the placebo group
was greater in patients who initiated the trial regimen
within 24 hours after symptom onset (median difference, 32.8 hours; P < .001) than in those who initiated it later (median difference, 13.2 hours; P = .008).
** Median duration of fever was 24.5 hours with baloxavir marboxil and 42 hours with placebo (P < .001).
** Median duration of fever was 24.4 hours with baloxavir
marboxil and 24 hours with oseltamivir (P = .9225).
** Levels of virus in the nose and throat were reduced
starting at 24 hours through 120 hours with baloxavir
marboxil compared with placebo.
** Levels of virus in the nose and throat were reduced at
24 hours and 72 hours with baloxavir marboxil compared with oseltamivir.
** Median time to viral shedding was 24 hours with baloxavir marboxil (P < .001 vs placebo), 72 hours with
oseltamivir (P < .0001 vs baloxavir marboxil), and 96
hours with placebo.
Comments: The study was conducted in the United States
and Japan. Results are similar to those observed in a phase 2
proof-of-concept study.5,7
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