A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors for the treatment of influenza in otherwise healthy patients

Figures & data

Table 1. Inclusion and exclusion criteria for the NMA.

Inclusion/exclusion elements	Inclusion criteria	Exclusion criteria
Population	Otherwise healthy patients with flu symptoms (influenza-like illness orconfirmed influenza)	High-risk patients
Interventions/comparators	Baloxavir marboxil 40 mg for patients <80 kg, and 80 mg for patients ≥80 kg single administration; oseltamivir 75 mg twice a day for five days; zanamivir 10 mg twice a day for five days; laninamivir 40 mg single administration; peramivir 300 mg single administration; placebo
Outcomes	Efficacy: Time to alleviation of all symptoms, time to resolution of fever, time to cessation of viral shedding, change in virus titer from baseline to 24 h, change in virus titer from baseline to 48 h, time to return to pre-influenza health status, incidence of pneumonia Safety: Total adverse events (AEs), drug-related AEs, drug-related vomiting, drug-related diarrhea
Study designs	Randomized controlled trials	Case reports, letters and historical articles
Publication timeframe	Only for conferences/congresses: 2015–2016 and 2014 for ESWI as no conference took place in 2015

Figure 1. PRISMA flow chart of study selection process for clinical efficacy and safety.

Table 2. List of studies included in the NMA.

Author	Trial number	Status of influenza	Age range	Intervention	Comparators
Shionogi phase II trial	JapicCTI-153090	CI	20–64	Baloxavir 10, 20, 40 mgsingle dose	Placebo
Shionogi phase III trial	NCT02954354	CI	12–64	Baloxavir 40, 80 mgsingle dose	Oseltamivir 75 mgBID + placebo
Kohno et al., 2010^17	NR	CI	20–64	Peramivir 300 mg	Placebo
Treanor et al., 2000^18	NR	ILI	18–65	Oseltamivir 75 mg BID	Placebo
Nicholson et al., 2000^19	NR	ILI	18–65	Oseltamivir 75 mg BID	Placebo
Matsumoto et al., 1999^20	NR	ILI	16–65	Zanamivir 10 mg BID	Placebo
Li et al., 2003^21	NR	ILI	18–65	Oseltamivir 75 mg BID	Placebo
Puhakka et al., 2003^22	NR	ILI	17–29	Zanamivir 10 mg BID	Placebo
Kohno et al., 2011^23	JapicCTI-R100123	CI	20–80	Peramivir 300 mg once daily	Oseltamivir 75 mg BID
Duval et al., 2010^24	NCT00799760	CI	18–85	Zanamivir 10 mgBID + placebo	Oseltamivir 75 mgBID + placebo
Watanabe et al., 2010^25	NCT00803595	CI	20–77	Laninamivir 40 mg	Oseltamivir 75 mg BID
Boivin et al., 2000^26	NR	ILI	>12	Zanamivir 10 mg BID	Placebo
Makela et al., 2000^27	NR	ILI	12–81	Zanamivir 10 mg BID	Placebo
Monto et al., 1999^28	NR	ILI	>13	Zanamivir 10 mg BID	Placebo
Hayden et al., 1997^29	NR	ILI	>13	Zanamivir 10 mg BID	Placebo
Campion et al., 1998^30	NR	ILI	>12	Zanamivir 10 mg BID	Placebo
NCT00419263, 2007^31	NCT00419263	CI	>18	Peramivir 300 mg	Placebo
Ikematsu, 2011^32	NR	CI	children + adults	Laninamivir 40 mg	Zanamivir 10 mg BID
Kashiwagi et al., 2000^33	NR	ILI	16–80	Oseltamivir 75 mg BID	Placebo
PMDA zanamivir package insert^34	NR	CI	Adults	Zanamivir 20 mg	Placebo
PMDA laninamivir report^35	NR	NR	Adults	Laninamivir 40 mg	Oseltamivir 150 mgPlacebo
FDA oseltamivir^36	NR	CI	>13	Oseltamivir 150 mg	Placebo

Abbreviations. NMS, network meta-analysis; CI, Confirmed influenza; NR, not reported; ILI, influenza-like illness; BID, twice a day.

Figure 2. Evidence network.

Figure 3. Efficacy outcome results versus baloxavir.

Figure 4. Safety outcome results versus baloxavir.

Table 3. Summary of evidence for efficacy and safety outcome measures.

Outcome	Number of studies included	Number of patients included	References
Efficacy
Time to alleviation of all symptoms	14	5403	Treanor et al., 2000^Citation18,a; Kohno et al., 2011^23; Duval et al., 2010^24; Watanabe et al., 2010^25; Kohno et al., 2010^17; Li et al., 2003^Citation21,a; Nicholson et al., 2000^Citation19,a; Matsumoto et al., 1999^Citation20,a; Hayden et al., 1997^Citation29,a; NCT00419263, 2007^31; Kashiwagi et al., 2000^Citation33,a; Shionogi phase III trial; Shionogi phase II trial; PMDA zanamivir package insert
Time to resolution of fever	9	3772	Kohno et al., 2011^23; Watanabe et al., 2010^25; Li et al., 2003^Citation21,a; Nicholson et al., 2000^Citation19,a; NCT00419263, 2007^31; Ikematsu, 2011^32; Kashiwagi et al., 2000^Citation33,a; Shionogi phase II trial; Shionogi phase III trial
Time to cessation of viral shedding	3	1078	Boivin et al., 2000^Citation26,a; Hayden et al., 1997^Citation29,a; Shionogi phase III trial
Change in virus titer from baseline to 24 h	9	3195	Treanor et al., 2000^Citation18,a; Puhakka et al., 2003^Citation22,a; Nicholson et al., 2000^Citation19,a; Boivin et al., 2000^Citation26; NCT00419263, 2007^Citation31; Shionogi phase III trial; Shionogi phase II trial; Kohno et al., 2010^Citation17; Kohno et al., 2011^Citation23
Safety
Total adverse events	10	5628	Kohno et al., 2011^Citation23; Kohno et al., 2010^Citation17; Puhakka et al., 2003^Citation22; Makela et al., 2000^Citation27; Monto et al., 1999^Citation28; Campion et al., 1998^Citation30; Kashiwagi et al., 2000^Citation33; Watanabe et al., 2010; Shionogi phase III trial; Shionogi phase II trial
Drug related adverse events	8	4,528	Kohno et al., 2011^Citation23; Li et al., 2003^Citation21; Monto et al., 1999^Citation28; Matsumoto et al., 1999^Citation20; Hayden et al., 1997^Citation29; Shionogi phase II trial; Shionogi phase III trial; Watanabe et al., 2010^Citation25
Drug related vomiting	5	3297	Treanor et al., 2000^Citation18; Kohno et al., 2011; Nicholson et al., 2000^Citation19; Shionogi phase III trial; PMDA Laninamivir Report

^aResults for the influenza-confirmed population were included in the NMA.

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